Seizure 44 (2017) 113–120

Contents lists available at ScienceDirect

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

Review

How neuropsychology can improve the care of individual patients with

epilepsy. Looking back and into the future$
Christoph Helmstaedter* , Juri-Alexander Witt
University of Bonn, Department of Epileptology, Germany

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

Article history:
Received 25 August 2016 Some of the roots of current clinical neuropsychology go back to the early days of epilepsy surgery.
Received in revised form 23 September 2016 Looking back a huge number of publications have dealt with cognition in epilepsy. The major factors
Accepted 23 September 2016 driving this work were questions relating to surgery, antiepileptic drugs and, more recently, also to
underlying pathology. However, most factors affecting cognition in epilepsy have been discerned many
Keywords: years ago. The body of neuropsychological literature in this field has accumulated much knowledge,
Epilepsy raising the question why, apart from epilepsy surgery settings, neuropsychology has still not been fully
Cognition integrated in the routine care of patients with epilepsy. This review on the occasion of Seizure’s 25th
Etiology
anniversary attempts to summarize clinically relevant diagnostic advances following a question guided,
Assessment
modular, and evidence-based approach. In doing so, we hope to attract the interest of readers to an
Evidence based
Treatment exciting mode of assessment which does not only have theoretical but also practical relevance. The
comorbidities of epilepsy are becoming an increasingly relevant topic. It is now widely accepted that,
while epilepsy may be defined by the occurrence of epileptic seizures, these seizures represent only one
of several possible sources of cognitive impairment. It is well-established that there are complex
interactions between epilepsy, cognition and behavior, and that both seizures and problems with
cognition or behavior may result from a common underlying pathology requiring treatment. With this
review we aim to demonstrate that neuropsychology can make a highly valuable contribution to the care
of individual patients by contributing to the diagnostic process and by serving as a tool for the monitoring
of disease and treatment, thereby improving the quality and safety of patient care. On a national,
European, and international level, first efforts are being made to homogenize diagnostics across epilepsy
centers and countries in order to achieve a common language and core standards. This should improve
communication within and outside the speciality, and help to generate the data required to allow the
field to make further progress.
ã 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction
Nearly 30 years ago, Michael Trimble, in an article published in
Epilepsia, described the cognitive hazards of seizure disorders,
identifying the major factors to be considered with cognitive
impairment in epilepsy in two groups of patients with this
disorder, i.e. underlying brain damage, age at seizure onset, seizure
type and frequency, as well as antiepileptic drugs (AEDs) [1].
$
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. Fax: +49 228 287 90 16108.
E-mail address: C.Helmstaedter@uni-bonn.de (C. Helmstaedter).
He was not the first to raise the question of what the reason for
cognitive deficits in epilepsy may be, but this early study already
revealed an understanding of the complex and multifactorial
etiology of cognitive impairment and decline in epilepsy. The
question of mental impairment and decline in epilepsy is old and
was discussed as “epileptic dementia” in medical texts as early as
at the turn of the 19th century [2–4]. At that time, with reduced
knowledge about the different structural, metabolic, and genetic
causes of epilepsy, epileptic dementia was thought to manifest in
50% of all patients. Interestingly, the mental problems were mainly
attributed to what was considered as non-lesional epilepsy in
these days. While it should be pointed out that the term
“dementia” is used differently today (when it specifically refers
to progressive mental decline) these early writings demonstrate
that, although seizures were the main focus of medical interest,

http://dx.doi.org/10.1016/j.seizure.2016.09.010
1059-1311/ã 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
114 C. Helmstaedter, J.-A. Witt / Seizure 44 (2017) 113–120
cognitive and behavioral (personality) abnormalities were well-
recognized and thought to be directly linked to the disorder.
Stimulated by the success story of epilepsy surgery starting in
1935 [5] and by new antiepileptic drug developments from the
1960s and 70s, a large body of neuropsychological research on
cognition and epilepsy has accumulated over the past decades [6].
With an increasing understanding of the mechanisms underpinning
the epilepsies, etiological models of cognitive impairment in the
epileptic disorders became more elaborated, but the basic
determinants are still the underlying static versus dynamic brain
pathology, epileptic activity (both in terms of seizures and interictal
epileptic dysfunction), psychiatric comorbidity and treatment
effects [7]. In addition, newer models underline the relevance of
personal and sociocultural variables as well as, most importantly,
the neurodevelopmental context (i.e. differences between the
developing versus the ageing brain). Along with progress in brain
imaging, neuropathology and genetics, the number of epilepsies
with an unknown etiology has reduced significantly, prompting
changes in seizure and epilepsy classifications but also the
appreciation of the cognitive impairments in epilepsy [8]. In
contrast to a traditional epilepsy-centric view according to which
cognitive impairments and behavioral problems are the result of
having seizures, new etiological models increasingly consider
neuropsychological problems as one of several comorbidities of
epilepsy [9,10]. Cognitive impairment can be the consequence of
epilepsy but can precede the development of epilepsy as well, and
epilepsy and cognitive impairment can both be comorbidties
resulting from the same underlying pathology [11]. The major
consequence for clinical practice is that it is not sufficient to treat
seizures to resolve the cognitive problems seen in patients with
epilepsy. Neuropsychology represents an independent approach to
the patient, his disorder and its underlying pathology and may call
for therapeutic interventions other than those primarily directed at
reducing the number of seizures.
On the basis of this theoretical framework, what follows in this
review is a discussion of the highly relevant question of how, thirty
years after Michael Trimbles work, and after 80 years of epilepsy
surgery, accumulated neuropsychological knowledge does or does
not translate into the routine care of individual patients. We will
consider this question in relation to neuropsychological diagnos-
tics, monitoring of the disorder and its treatment, patient
counseling, and therapeutic decision-making.
Table 1
Future tasks for neuropsychology in epilepsy (as formulated in 2011).
1. Top priority: Definition of optimal cognitive and behavioral measures for screening epilepsy-related impairments in different types of epilepsy (i.e. epilepsies with
different etiologies), and to define . . .
- measures for assessment of developmental disorders
- measures for acute symptoms and confusional states in status epilepticus, inflammation (encephalitis), mitochondrial diseases, etc.,
- measures sensitive to antiepileptic drug treatment,
- measures sensitive to EEG pathology (electrophysiological epileptic activity, single spikes & spike waves, grouped activity, nonconvulsive (cognitive) seizures) and
sensitive to reflect successful treatment of the EEG
- common protocols for assessment of hemispheric dominance (intracarotid amobarbital test (IAT), functional MRI (fMRI), functional transcranial Doppler sonography
(fTCD), dichotic listening)
- measures sensitive to surgical treatment,
- measures and markers for assessing every day functioning
2. Secondary aims were . . .
- to come to an agreement on core screening tests or tools for a test battery,
- to identify national (language) and cultural needs,
- to find multicenter, multi-language, and transcultural solutions,
- to find new avenues for disseminating methods, techniques and normative data,
- and to have maybe another meeting to envisage the completion of this action.
2. Advances in diagnostics
UCB and John Libbey sponsored a meeting in Toronto, Canada,
on 3–6 November, 2010, involving 66 specialists from 13 countries
representing expertise in adult and pediatric neuropsychology,
psychiatry, and neurology; neuroimaging, cognitive neurosciences,
electrophysiology, pharmacology, and other fields. The overarching
idea and very practical aim of the meeting was to disseminate
evidence-based neuropsychological practice in the care of children
and adults with epilepsy around the world.
It became evident that standardized neuropsychological
assessment has become an integrated and essential tool in the
diagnostic and clinical evaluation of patients considering epilepsy
surgery. However, there was a great heterogeneity of assessments
and their application, and despite progress in other diagnostic
fields and in the treatment of epilepsy, clinical neuropsychology in
epileptology still appeared to be very focused on epilepsy surgery,
especially temporal lobe surgery. There was little indication that it
had secured a clear role in the routine care of patients with
epilepsy outside epilepsy surgery evaluation. At that time Medline
listed as many as 3000 publications under the search “epilepsy and
cognition”. Thus, major developments in cognitive neuroscience
and the vast number of clinical studies on epilepsy, cognition and
mind, had obviously not found their way into routine clinical
practice. One of the outcomes of the Toronto meeting was the
publication in the Progress of Epileptic Disorders Series by John
Libbey in 2011. This publication continues to be a very compre-
hensive compendium which provides an overview of the state of
the art at that time [12].
Following this publication and an inquiry of all members of the
ILAE Neuropsychology Task Force, Bruce Hermann, Madison
Wisconsin, who was one of the organizers of the Toronto meeting
and the leader of the Task Force at that time, summarized the
strategy for the future as listed in Table 1.
Meanwhile the ILAE task force, now under the leadership of
Sarah Wilson, University of Melbourne, Australia, has published a
consensus paper on the indications for and expectations of
neuropsychological assessment in routine epilepsy care [13].
The paper addresses what the role of neuropsychological assess-
ment is, who should carry out a neuropsychological assessment,
when people with epilepsy should be referred for neuropsycho-
logical assessment, and what can be expected from it. This
 C. Helmstaedter, J.-A. Witt / Seizure 44 (2017) 113–120
consensus document provides an excellent structural framework
for neuropsychology in epilepsy care. However it does not spell out
which tests would be most appropriate to address the priorities
listed above.
Coincidentally in 2013 a pan-European project (E-pilepsy;
www.e-pilepsy.eu) involving 13 epilepsy reference centers and 15
associated centers was initiated funded by the EU Agency for
Health and Consumers. This collaboration aims to improve
awareness and accessibility of surgery for epilepsy across the
EU. Part of this project is the homogenization and dissemination of
evidence-based best practice in imaging, EEG monitoring, and
neuropsychology. Current practice has been reviewed, a literature
search on best practice is being undertaken. The resulting
conclusions will lead to the construction of a website for patient
evaluation allowing multicenter use. Overviews on the present
state of imaging and EEG-monitoring in the EU have been
published [14,15], the data on neuropsychology have been
evaluated and will soon be published. In concordance with older
studies dating back 23 years [16], 11 years [17] and, more recently,
5 years [18,19] the data continue to indicate that different centers
(not to mention different countries) use a tremendous diversity of
neuropsychological tests and examination protocols [20]. There is,
however, general consensus on which functional domains need to
be considered but not on which tests should be chosen to
undertake the assessments. More than 160 different tests are in
use, no standardized protocols for dominance assessment and
outcome prediction are in sight, and the choice of particular tests
in epilepsy is still very much determined by general neuropsycho-
logical considerations and individual preferences rather than by
published evidence in epilepsy. Language lateralization is now
commonly done by fMRI but only two centers provided the
requested decision tree for indication and surgical decision making
according to the protocols. Nevertheless for neuropsychological
assessment a core battery could be extracted from the inquiry,
which, if confirmed by literature review, has the potential to be
agreeable across centers (see Table 2). Unfortunately most EU-
centers did not provide published evidence for use of their tests to
answer specific epilepsy-related medical questions. Frequent use
of individual tests, fMRI, or IAT paradigms thus rather reflects
Table 2
Frequent and recommended tests for use in epilepsy.
Domain Tests used across EU centers
Intelligence Wechsler Adult Intelligence Scale (WAIS), Wechsler
Intelligence Scale for Children (WISC)
General performance
level
Development Bayley Scales of Infant and Toddler Development
(BSID), Vineland Adaptive Behavior Scales (VABS)
Motor functions Finger tapping, Luria motor sequences
Attention, executive Trail Making Test (TMT) A & B, Digit span, Corsi block-
functions, working tapping test
memory
Verbal memory Rey Auditory Verbal Learning Test (AVLT)
Figural memory Rey-Osterrieth Complex Figure Test (ROCFT) delayed
recall
Language Boston Naming Test (BNT), phonemic & semantic
fluency tests
Visual spatial functions Rey-Osterrieth Figure (ROCFT) copy, WAIS Block
Design
Adverse events Adverse Event Profile (AEP)
Mood, quality of life Beck Depression Inventory (BDI), Quality of Life in
Epilepsy (QOLIE), Child Behavior Checklist (CBCL)
Language lateralization fMRI: Word generation tasks, naming tasks
IAT: Counting tasks, naming tasks, materialspecific
memory tasks
Transient cognitive no test which would be shared
impairment
115
experience-based preferences (voting by the feet) than suitability
and validity in patients with epilepsy.
Table 2 contains additional information provided by the so-
called common data elements from the National Institute of Health
(NIH, USA), a source of surveys, questionnaires, instruments,
instrument items, and other methods of data collection, which
provides the highest level of evidence in clinical studies and the
best scientific basis for research in epilepsy (https://commonda-
taelements.ninds.nih.gov/Doc/EPI/F1140_Overview_of_Recom-
mended_Neuropsychology_Instruments.docx).
Positive is the overlap of the results of the EU survey with the
NIH common data elements, indicating on where the efforts
converge.
This is the place also to mention the work of the Bozeman
Epilepsy Consortium in the US which addressed neuropsycholog-
ically relevant diagnostic questions in a multi-centric way [6]. The
knowledge gained from group studies, however was not explicitly
translated into individual diagnostics and prognostics.
In terms of what an evidence-based diagnostic toolbox for use
in epilepsy may look like, we recently proposed a strictly question-
guided and modular diagnostic approach, which does not only
provide descriptive information but should make a difference to
patients, their treatment, and treatment outcomes [21] (see
Table 3, references for the measures used in epilepsy can be
found in Ref. [21]).
Having outlined recent developments aiming to achieve more
homogeneous and evidence-based neuropsychological diagnostics
in epilepsy, we will next discuss how neuropsychology can help
improve individual patient’s care in terms of surgical and medical
treatment.
2.1. Advances in presurgical diagnostics and outcome control of
epilepsy surgery
Epilepsy surgery has been and continues to be one of the major
driving forces for progress in neuropsychology in epilepsy [6]. In its
beginnings, neuropsychology was used in the evaluation of
patients with focal epilepsies to provide the localization and
lateralization of cognitive dysfunctions and thus give hints to
Common data elements
Wechsler Adult Intelligence Test-Fourth Edition (WAIS-IV) or short form (WASI)
Montreal Cognitive Assessment
Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), Mullen Scales of
Early Learning (MSEL), Bayley Scales of Infant and Toddler Development (BSID)
Trail Making Test (TMT) A & B, Digit Span subtest from WAIS-IV/WISC-IV, Wisconsin
Card Sorting Test (64 card version)
Rey Auditory Verbal Learning Test (AVLT)
Brief Visuospatial Memory Test Revised (BVMT-R), Rey-Osterrieth Complex Figure
Test, Wechsler Memory Scale Visual Reproduction
Boston Naming Test (BNT), Controlled Oral Word Association (COWA), aka FAS, Animal
Fluency, aka Animal Naming
WAIS-IV or WASI block design
Hague Side Effects Scale (HASES)
Beck Depression Inventory (BDI), Quality of life in neurological disorders (Neuro-QoL),
Child behavior Checklist (CBCL), Child depression inventory (CDI)
116 C. Helmstaedter, J.-A. Witt / Seizure 44 (2017) 113–120

Table 3
Question-guided modular neuropsychological evaluation.

 Evaluation and screening of major neuropsychological impairments is performed using computerised testing of attention, reaction times, memory and executive
functions which can be applied repeatedly if required (25 min for one test battery).

 The question of developmental disorders, delay, slowing or improvement is addressed by testing of IQ and/or application of standardized neurodevelopmental
interviews (up to 1 h).

 Aura, seizure semiology, ictal and/or postictal testing provide information about positive (semiology) or negative (testing) cognitive symptoms in the context of
seizures (up to 5 min) *.

 Before performing extended testing, patients are screened for cognitive AED side effects. If the drug regimen in use has potential adverse neuropsychological effects and
if the initial screening test indicates serious impairment of executive functions, further testing is postponed until AEDs have been changed (about 10–15 min for the
initial screening).

 In patients undergoing presurgical evaluations or when information on possible focus localisation or lateralisation is required, a battery of executive and of verbal and
figural memory functions is applied (about 1–11/2 h).

 After a positive decision about a patient’s suitability for epilepsy surgery the testing above is extended by assessing IQ (short version based on 5 subtests), motor,
language, visuo-constructive, visual-spatial, and semantic memory functions (total test-battery including the tests mentioned before 31/2 h). The battery, IQ excluded,
is repeated after surgery for outcome control. The overall information is assumed to have greater external validity than single tests and the results may inform
therapeutic training or the patient’s cognitive rehabilitation if this is indicated.

 For orientation, language/memory lateralisation is noninvasively assessed via fMRI. In younger children language lateralisation is assessed by functional transcranial
Doppler sonography (fTCD).
 In very rare cases, if surgery includes suggested eloquent cortex, it is suggested that a Wada test is carried out. If the region is within or close to eloquent tissues, electro-
cortical stimulation is performed to reduce the risk of iatrogenic surgical impairments.

 Cognitive evaluation is accompanied by assessment of depression (Beck Depression Inventory), anxiety (Zung Self-Rating Anxiety Scale), personality (FPZ), and a
measure on quality of life in epilepsy (QOLIE 10 analogue) (30 min).

structural lesions and epileptic foci. This role changed very much
with the improvement of neuroimaging. Nevertheless, and this is
linked to the previous section of this review discussing diagnostics,
measures are still needed which are sensitive to detect neuropsy-
chological deficits associated with lesions or dysfunctional brain
structures in different parts of the brain and which can be reliably
used to monitor the effects of invasive treatments with the
potential to damage the brain [22]. Within certain limits such a
diagnostics can detect dysfunction associated with the left vs. right
hemisphere, frontal, central, parietal, occipital, temporal lobe or
temporo–mesial structures. However, the choice, use and inter-
pretation of tests of specific functions requires consideration of
factors such as neurodevelopment [23], processes of plasticity
[24,25], compensatory and restitutional processes [26,27] and
gender differences [28]. Mental health problems and motivational
factors need to be considered as well, the latter especially in
children. In addition practitioners have to be aware that brain
functions (and the neuropsychological test measuring them) are
complex, hierarchically structured, and not independent of each
other [29].
Meaningful neuropsychological assessment of patients with
epilepsy cannot be limited to psychological performance diag-
nostics. Simple performance measurement may be related to
everyday functioning but it is likely not to reveal detailed
information about the impact of the disease, its pathological
features or treatment on cognition. For simple performance
diagnostics it would probably be sufficient to carry out a screening
test like the Mini-Mental State Examination (MMSE) or the
Montreal Cognitive Assessment (MOCA) [30], or (more complex
and time consuming) a Wechsler intelligence battery [31], or (even
more time consuming) an additional Wechsler memory scale [32].
However, if a patient is tested whilst exposed to a high load of AEDs
with possible adverse effects on cognition, and no screening of
cognitive drug effects has been performed, IQ testing may easily
underestimate the patient’s capabilities [31].
Better imaging, more sophisticated invasive and noninvasive
EEG, advanced surgical procedures and the monitoring of surgical
outcomes with sensitive neuropsychological measures has
resulted in increasingly selective and individually tailored surgical
approaches aiming to restrict surgery to affected and non- or
dysfunctional tissues while sparing non-affected and functional
tissues. This is true for temporal as much as for extratemporal lobe
surgery, especially since imaging of focal cortical dysplasia has
improved.
Review articles are still inconclusive as to whether tailored
versus extended standard resections are more successful in terms
of patients achieving seizure freedom [33–35]. When considering
meta-analytic studies aiming to address this question, however,
one must take into consideration that they mix very different
patient groups with very different starting conditions who are
mostly not matched in terms of underlying pathology. In addition,
different centers and different surgeons may have variable and
individual surgical approaches, and they may be subject to a
personal learning curve [36]. These are all factors which have not
been systematically taken into account. Under the proposition of a
technically diligent surgery, the achievement of seizure freedom is
presumably less closely related to the surgical approach than to the
presurgical work up. If the epileptogenic lesion and zone can be
clearly localized, selective surgery should be as successful as
extended standard resections, and if the diagnostic situation is less
clear a more extended resection might be advantageous.
Early studies on the lateral extent of 2/3 anterior temporal
lobectomy (ATL) and the comparison of 2/3 ATL and selective
amygdalohippocampectomy in patients with pure mesial hippo-
campal sclerosis already provided evidence of the negative effects
of the resection of functional tissues which were not involved in
seizure generation [37]. Meanwhile several studies have demon-
strated the relevance of the damage of the temporolateral
neocortex for memory and language outcome after different
surgical approaches, and there are other studies showing that the
degree/volume of hippocampal resection correlates with postop-
erative loss in memory [37]. Recent developments in regard to
radiotherapy and highly selective stereotactic radiofrequency
therapy have the potential further to improve patients’ functional
 C. Helmstaedter, J.-A. Witt / Seizure 44 (2017) 113–120 117

outcomes without diminishing the chance of becoming seizure
free [38–41]. Similar trends are seen in extratemporal lobe surgery
of developmental malformations [42,43].
In summary, the clear and simple message which comes across
from these studies is that the resection or collateral damage of
non-affected functional brain tissues has negative cognitive
consequences. Severe postoperative memory decline in MRI
negative and histopathologically negative patients may serve as
particularly compelling proof of this principle [44]. In terms of the
surgical target region, morphological integrity as determined by
structural imaging and functional integrity as indicated by
sensitive neuropsychological testing and functional imaging
should be red flags. In addition, from a neuropsychological
perspective, minimally invasive treatment with minimal collateral
damage is preferable. It is unlikely that the historical refinement of
neurosurgical approaches would have occurred without routine
presurgical neuropsychological testing. Likewise it is unlikely that
current and future surgical techniques (for instance thermocoa-
gulation or brain stimulation) will be refined further (and that the
quality of local surgical programmes can be assured) without
neuropsychological assessment being a core feature of pre- and
postsurgical assessment.
Table 4 provides more details about procedures which can
support the individual counseling of patients with regard to the
benefit-risk-evaluation before temporal lobe surgery. It must be
noted, however, that because of variations of surgeries and surgical
approaches in combination with varying pathological conditions,
no exact functional outcome prediction can be expected, not now,
and probably also not in the near future. Furthermore, methods
validated in one center cannot simply be transferred to other
centers without matching of procedures including neuropsycho-
logical outcome measures.
Thus, individual level counseling about the likely specific
functional risks of epilepsy surgery is, at present, only possible on
the basis of a collection of clinical markers in addition to classic
neuropsychological assessment. On this basis some trend (better,
unchanged, worse) can be formulated without excluding that it
might come different. In this regard, other functional test
modalities (for instance fMRI) do not yet allow clinicians to clearly
delineate the specific risks of epilepsy surgery for individual
patients in isolation. The study which derives a good prediction
model in one cohort and which would show its value by
prospective application in another cohort is still missing.
For extratemporal surgeries comparable data are not available,
most likely because this group is too small and too heterogeneous.
The principles, however, can be assumed to be the same.
2.2. Advances in monitoring antiepileptic drug (AED) treatment
Pharmacological treatment is the main therapeutic approach in
epilepsy, controlling seizures in about 70% of the patients [61], and,
unlike many other aspects affecting cognition, treatment is in
under the direct influence of the physician. However, cognitive side
effects of antiepileptic drugs are common. They can negatively
affect tolerability, adherence, and long-term treatment retention.
Patients’ willingness to accept side effects is very low even when
seizure control is achieved, and psychiatric followed by cognitive
side effects appear least acceptable [62]. In addition, AED side
effects represent a considerable economic burden [63]. The
occurrence and severity of adverse cognitive side effects of AEDs
depends on the pharmacological agent, titration speed, dose, and,
when given in combination therapy, on the total drug load and on
potential interactions of concurrent drugs. As indicated by reviews
there are drugs which are less likely or more likely associated with
negative side effects, even when given in monotherapy [64,65].
However, cognitive impairments in the context of AED pharmaco-
therapy cannot be considered as independent of the disease, in that
they are mostly the result of a synergy of having epilepsy, being
treated at all, and being treated with a specific drug or drug
combination [66]. In addition one may not forget that seizure
control achieved by drug treatment can improve cognition through
the cessation of seizures and interictal epileptic dysfunction [67].
Apart from specific effects of individual drugs, the total drug
load appears to be a major determinant of cognitive adverse effects
of AED. Drug load can be determined simply by counting the
number of AEDs or by concurrent consideration of the given dose

Table 4
Outcome prediction, patients counseling.

1. There are so-called regression-based prediction models which take patient characteristics and performance levels into consideration. This approach is elegant but
requires a large, high-quality database and is difficult to transfer to other centers [45]
2. Intracranial EEG measures, fMRI and the Wada test have been used for individual memory prognosis but this does not apply to all temporal lobe surgery approaches and
again there is no standard to be used across centers [46–49]
3. Rules of thumb inferred from publications, as there are . . .

- It is not possible to predict with certainty which patient will experience disabling functional loss.
- Resection of functional tissue is very likely to have negative consequences
- Apart from accidental surgical complications, catastrophic outcomes such as an amnestic syndrome are very rare and appear not to be predictable [50–52]
- Those who start with better baseline performance have a greater risk to lose but still have better residual outcome than those with poor baseline performance
(= baseline as reflecting both functionality and reserve capacity) [53,54]
- Outcome is better in the presence of greater compensatory capacity of the non-affected remnant brain (in terms of IQ, executive functions, etc.) [53]
- Losses are greater with increasing age. Younger patients recover early, older patients late [55,56]
- Postoperative recovery can be supported by tapering drug load [57]
- Complete and maybe also partial seizure control promotes functional recovery.
- Due to their reduced reserve capacity, patients with bilateral hippocampal sclerosis and poor memory can still deteriorate in memory functions after unilateral
temporal lobe surgery [58]
- Hippocampal sclerosis and good memory does not preclude postoperative loss (may depend on approach) [59]
- Atypical language dominance in left TLE surgical patients is protective in regard to verbal memory outcome [47]

4. Probabilities of significant individual declines in memory (not taking into consideration the degree of loss, different dependent measures or surgical procedures):

- Range from 40 to 45% in left TLE and 20–30% in right TLE patients who will lose in verbal memory, losses in figural memory appear in 20–30% independent of the
side of surgery, and in 20–30% left TLE patients language (naming) may be affected [37,60]
- If memory is already poor with bilateral hippocampal sclerosis, 70% of patients will still experience significant losses on objective memory tests ending up with very
poor performance, most likely because of missing reserve capacities [58]
- If memory is unaffected in a patients with unilateral hippocampal sclerosis 70% will lose in at least one memory parameter if standard ATL is performed [59]
- If patients are non-lesional on MRI and turn out to have normal histopathology 80% will experience significant functional loss [44]
118 C. Helmstaedter, J.-A. Witt / Seizure 44 (2017) 113–120
related to the average recommended dose of each drug which is
called the defined daily dose (DDD). The two measures are largely
interchangeable since both measures correlate well with cognitive
measures sensitive to AED side effects [68].
Tools are at hand which can be used for the monitoring of the
cognitive impact of drug treatment in an individual patient.
Subjective assessment of antiepileptic drug side effects, i.e.
signaling the physicians’ interest, can already positively affect
therapy decisions [69]. For objective assessment repeated testing is
required, conducted before and after a new AED is added, when
treatment is first initiated, with relevant dose changes, or during
drug tempering or withdrawal. The indications and requirements
for individual cognitive monitoring of antiepileptic therapies,
available diagnostic tools and potential pitfalls are outlined in
detail in a review by Witt and Helmstaedter [70].
Although some drugs are claimed to have specific effects on
certain functional domains, like language/word fluency with
topiramate, or phenobarbital, carbamazepine or valproic acid on
memory, functions of psychomotor speed, alertness, or executive
functions seem to be sensitive to adverse effects of AEDs in general
[21]. Several computerized tests have been proven to be CNS drug
sensitive, and some of these have also been validated for use in
epilepsy [71]. In addition there are many standard paper–pencil
tests which are suitable for this purpose. Routinely used screening
of individual patients allows for comparison of the effects of
different drugs in natural in- or outpatient settings [72]. Screening
for negative cognitive antiepileptic drug effects is also useful as a
first step before comprehensive (neuro-) psychological diagnostics
is performed. Having ruled out that performance deficits were
observed under the influence of drugs, one can continue with more
extensive testing. Otherwise one would recommend to postpone a
more elaborate testing until the antiepileptic regimen has
successfully been optimized which again should be proven by a
cognitive screening. Monitoring of drug effects is particularly
recommended in new-onset epilepsies, this will be discussed in
more detail in the next section of this review.
2.3. The need for early assessment in new-onset epilepsy
A highly relevant question relating to the cognitive and
behavioral comorbidities of epilepsy was raised recently when
epidemiological studies indicated that depression and other
behavioral problems are often present before the onset of epileptic
seizures and that they may even represent a risk factor for the
development of epilepsy [73,74]. Indeed, the co-occurrence of
epilepsy and behavioral or mood problems is frequent at the onset
of the seizure disorder and common underlying pathogenic factors
should be considered. As with depression, cognitive impairment
can be understood as a marker of a pathological condition which
later, in the course of the underlying disease, may also lead to
seizures. In this case seizures would also need to be considered as a
symptom rather than the origin or cause of cognitive impairment.
As it stands, in many adult and pediatric patients with new-
onset epilepsies, cognitive impairments are already present before
the initiation of AED therapy [75–78]. With regard to clinical
practice this calls for early cognitive assessments in children,
adolescents and adults with new-onset or newly diagnosed
epilepsies before treatment is first started. The subsequent course
of the disease and treatment effects can only be observed clearly if
baseline observations were obtained. Another reason is that very
often, in the course of the disease, when the patient’s and the
physician’s focus shifts away from the primary issue of seizure
control, issues around comorbidities will become more prominent.
At that point the key question is whether the disorder, the
underlying disease dynamic or treatment have caused the
problems. The availability of a baseline assessment is obviously
very helpful in this situation. In children a brief structured clinical
interview conducted with parents can identify children with
epilepsy who are at academic risk at the time of diagnosis. It has
been shown that this risk persists up to five years later, indicating
that early interventions after such a baseline examination may be
useful [79]. It is interesting and perhaps surprising that behavior
and competence problems in children newly diagnosed with
localization-related and idiopathic generalized childhood epilep-
sies do not tend to get progressively worse over the next 5- to 6-
years [80]. Others have demonstrated that application of a short
screening of cognition (EpiTrack Junior) is very helpful in the
objective assessment of children at epilepsy onset and over the
course of the disorder while AEDs are administered. This study also
found quite stable performance over time after AED treatment had
been initiated [81,82], providing further support to the idea that
neuropsychological deficits are typically not progressive after the
development of epilepsy, although they often precede it.
The question whether epilepsy causes cognitive deterioration in
adults has also been discussed controversially for a long time. Most
studies relying on retrospective analyses give room for the
speculation that a longer duration of epilepsy is associated with
a worsening of cognitive functioning. We have led a detailed
discussion about the complex relationship between age, duration
and age at onset of epilepsy elsewhere [83,84] and have come to
the conclusion that cognitive decline with chronic epilepsy is the
exception, that cognition is mostly very stable over time, and that
any significant decline should be considered an unexpected
development calling for additional diagnostic efforts to identify
the underlying pathology. Thus conditions in children and adults
are not that different and early neuropsychological evaluation and
monitoring is indicated for both patient groups.
3. Outlook
In the light of 25th anniversary of Seizure—European Journal of
Epilepsy, the scope of this article was to provide an overview of
developments in the neuropsychology of epilepsy and the
significance of these developments reflecting several decades of
research at group level into current clinical practice and individual
patient care. What is the value of great and high impact
publications at group level if they cannot or are not applied and
validated in individual care? Clinical neuropsychology is an
exciting subject and we hope this review has demonstrated that
it can be used to make a valuable contribution to the lives of
patients with epilepsy and their treatment.
Obviously progress is gradual, and there is great heterogeneity
of how neuropsychology in epilepsy is currently used in clinical
practice. However, there are some positive developments.
Hopefully, neuropsychologists will be able to agree to speak with
one language based on best published evidence. This should lead to
greater homogeneity of neuropsychological assessment and
practice and better communication across centers and countries.
A higher scientific esteem of clinical work and of studies which
may not necessarily produce new results but which consolidate the
role of neuropsychology in clinical practice by demonstrating the
application of neuroscientific knowledge on individual patients
should help speed up progress in the field—as would adequate
payment of neuropsychological diagnostics, and better financial
support for standardization, normalization, validation of tests and
open source instruments.
Conflict of interest statement
J.-A.Witt has no conflict of interest in regard to the submitted
work.
 C. Helmstaedter, J.-A. Witt / Seizure 44 (2017) 113–120
C. Helmstaeder receives license fees from UCB and EISAI, gets
honoraries for talks and/or consulting from GW pharmaceuticals,
UCB, EISAI, and is being funded by the Marga Boll Stiftung, and the
EU (GA 2013 1203).
References
[1] Trimble MR. Cognitive hazards of seizure disorders. Epilepsia 1988;29(Suppl.
1):S19–24.
[2] Bumke O. Die Diagnose der Geisteskrankheiten. Wiesbaden: Verlag von F.J.
Bergmann; 1919.
[3] Kraepelin E. In: Sechste vollständig überarbeitete Auflage, editor. Psychiatrie
Ein Lehrbuch für Studierende und Aerzte. Leipzig: Verlag von Johann
Ambrosius Barth; 1899.
[4] Wildermuth HA. Zeitschrift f. d. Behandlung Schwachsinniger und Epileptiker.
Dresden/Druck Johannes Pässler, Dresden: [149_TD$DIFF]Warnatz nigl.
Hofbuchhändler; 1897.
[5] Feindel W. Development of surgical therapy of epilepsy at the Montreal
Neurological Institute. Can J Neurol Sci 1991;18:549–53.
[6] Loring DW. History of neuropsychology through epilepsy eyes. Arch Clin
Neuropsychol 2010;25:259–73.
[7] Elger CE, Helmstaedter C, Kurthen M. Chronic epilepsy and cognition. Lancet
Neurol 2004;3:663–72.
[8] Wilson SJ, Baxendale S. The new approach to classification: rethinking
cognition and behavior in epilepsy. Epilepsy Behav 2014;41:307–10.
[9] Hermann B, Seidenberg M, Jones J. The neurobehavioural comorbidities of
epilepsy: can a natural history be developed? Lancet Neurol 2008;7:151–60.
[10] Lin JJ, Mula M, Hermann BP. Uncovering the neurobehavioural comorbidities of
epilepsy over the lifespan. Lancet 2012;380:1180–92.
[11] Helmstaedter C, Aldenkamp AP, Baker GA, Mazarati A, Ryvlin P, Sankar R.
Disentangling the relationship between epilepsy and its behavioral comor-
bidities—the need for prospective studies in new-onset epilepsies. Epilepsy
Behav 2014;31:43–7.
[12] Helmstadter C, Hermann B, Lassonde M, Kahane P, Arzimanoglou A, editors.
Neuropsychology in the care of people with epilepsy. Montrouge: John Libbey;
2011.
[13] Wilson SJ, Baxendale S, Barr W, Hamed S, Langfitt J, Samson S, et al. Indications
and expectations for neuropsychological assessment in routine epilepsy care:
report of the ILAE Neuropsychology Task Force, Diagnostic Methods
Commission, 2013–2017. Epilepsia 2015;56(8):1316–7.
[14] Kobulashvili T, Hofler J, Dobesberger J, Ernst F, Ryvlin P, Cross JH, et al. Current
practices in long-term video-EEG monitoring services: a survey among
partners of the E-PILEPSY pilot network of reference for refractory epilepsy and
epilepsy surgery. Seizure 2016;38:38–45.
[15] Mouthaan BE, Rados M, Barsi P, Boon P, Carmichael DW, Carrette E, et al.
Current use of imaging and electromagnetic source localization procedures in
epilepsy surgery centers across Europe. Epilepsia 2016;57:770–6.
[16] Jones-Gotman M, Smith ML, Zatorre RJ. Neuropsychological testing for
localizing and lateralizing the epileptogenic region. In: Engel J, editor. Surgical
treatment of the epilepsies. New York: Raven Press; 1993. p. 245–62.
[17] Rabin LA, Barr WB, Burton LA. Assessment practices of clinical neuro-
psychologists in the United States and Canada: a survey of INS, NAN, and APA
Division 40 members. Arch Clin Neuropsychol 2005;20:33–65.
[18] Jones-Gotman M, Smith ML, Risse GL, Westerveld M, Swanson SJ, Giovagnoli
AR, et al. The contribution of neuropsychology to diagnostic assessment in
epilepsy. Epilepsy Behav 2010;18:3–12.
[19] Witt JA, Helmstaedter C. A survey on neuropsychological practice in German-
speaking epilepsy centers. In: Helmstaedter C, Hermann B, Kahane P,
Arzimanoglou A, editors. Neuropsychology in the care of people with epilepsy.
John Libbey Eurotext; 2011.
[20] Djordjevic J, Jones-Gotman M. Inquiry on assessments across epilepsy centers
in different countries. In: Helmstaedter C, Herman B, Lassonde M, Kahane P,
Arzimanoglou A, editors. Progress in epileptic disorders: neuropsychology in
the care of people with epilepsy. .
[21] Helmstaedter C, Witt JA. Clinical neuropsychology in epilepsy: theoretical and
practical issues. Handb Clin Neurol 2012;107:437–59.
[22] Hoppe C, Helmstaedter C. Sensitive and specific neuropsychological assess-
ments of the behavioral effects of epilepsy and its treatment are essential.
Epilepsia 2010;51:2365–6.
[23] Kaaden S, Helmstaedter C. Age at onset of epilepsy as a determinant of
intellectual impairment in temporal lobe epilepsy. Epilepsy Behav
2009;15:213–7.
[24] Helmstaedter C, Kurthen M, Gleissner U, Linke DB, Elger CE. Natural atypical
language dominance and language shifts from the right to the left hemisphere
in right hemisphere pathology. Naturwissenschaften 1997;84:250–2.
[25] Helmstaedter C, Kurthen M, Linke DB, Elger CE. Patterns of language
dominance in focal left and right hemisphere epilepsies: relation to MRI
findings, EEG, sex, and age at onset of epilepsy. Brain Cogn 1997;33:135–50.
[26] Helmstaedter C, Pohl C, Elger CE. Relations between verbal and nonverbal
memory performance: evidence of confounding effects particularly in patients
with right temporal lobe epilepsy. Cortex 1995;31:345–55.
[27] Helmstaedter C, Kurthen M, Linke DB, Elger CE. Right hemisphere restitution of
language and memory functions in right hemisphere language-dominant
patients with left temporal lobe epilepsy. Brain 1994;117(Pt. 4):729–37.
119
[28] Helmstaedter C, Kurthen M, Elger CE. Sex differences in material-specific
cognitive functions related to language dominance: an intracarotid amobar-
bital study in left temporal lobe epilepsy. Laterality 1999;4:51–63.
[29] Helmstaedter C, Wietzke J, Lutz MT. Unique and shared validity of the
Wechsler logical memory test, the California verbal learning test, and the
verbal learning and memory test in patients with epilepsy. Epilepsy Res
2009;87:203–12.
[30] Phabphal K, Kanjanasatien J. Montreal Cognitive Assessment in cryptogenic
epilepsy patients with normal Mini-Mental State Examination scores.
Epileptic Disord 2011;13:375–81.
[31] Baxendale S, McGrath K, Thompson PJ. Epilepsy & IQ: the clinical utility of the
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) indices in the
neuropsychological assessment of people with epilepsy. J Clin Exp Neuro-
psychol 2014;36:137–43.
[32] Baker GA, Austin NA, Downes JJ. Validation of the Wechsler Memory Scale-III
in a population of people with intractable temporal lobe epilepsy. Epilepsy Res
2003;53:201–6.
[33] Schramm J. Temporal lobe epilepsy surgery and the quest for optimal extent of
resection: a review. Epilepsia 2008;49:1296–307.
[34] Tanriverdi T, Dudley RW, Hasan A, Al Jishi A, Al Hinai Q, Poulin N, et al. Memory
outcome after temporal lobe epilepsy surgery: corticoamygdalohippocam-
pectomy versus selective amygdalohippocampectomy. J Neurosurg
2010;113:1164–75.
[35] Kuang Y, Yang T, Gu J, Kong B, Cheng L. Comparison of therapeutic effects
between selective amygdalohippocampectomy and anterior temporal lobec-
tomy for the treatment of temporal lobe epilepsy: a meta-analysis. Br J
Neurosurg 2014;28:374–7.
[36] Heller AC, Padilla RV, Mamelak AN. Complications of epilepsy surgery in the
first 8 years after neurosurgical training. Surg Neurol 2009;71:631–7
discussion 637.
[37] Helmstaedter C. Cognitive outcomes of different surgical approaches in
temporal lobe epilepsy. Epileptic Disord 2013;15:221–39.
[38] Malikova H, Kramska L, Vojtech Z, Liscak R, Sroubek J, Lukavsky J, et al.
Different surgical approaches for mesial temporal epilepsy: resection extent,
seizure, and neuropsychological outcomes. Stereotact Funct Neurosurg
2014;92:372–80.
[39] Drane DL, Loring DW, Voets NL, Price M, Ojemann JG, Willie JT, et al. Better
object recognition and naming outcome with MRI-guided stereotactic laser
amygdalohippocampotomy for temporal lobe epilepsy. Epilepsia
2015;56:101–13.
[40] Attiah MA, Paulo DL, Danish SF, Stein SC, Mani R. Anterior temporal lobectomy
compared with laser thermal hippocampectomy for mesial temporal epilepsy:
a threshold analysis study. Epilepsy Res 2015;115:1–7.
[41] Feng ES, Sui CB, Wang TX, Sun GL. Stereotactic radiosurgery for the treatment
of mesial temporal lobe epilepsy. Acta Neurol Scand 2016, doi:http://dx.doi.
org/10.1111/ane.12562 February 4 [Epub ahead of print].
[42] Wellmer J, Parpaley Y, Rampp S, Popkirov S, Kugel H, Aydin U, et al. Lesion
guided stereotactic radiofrequency thermocoagulation for palliative, in
selected cases curative epilepsy surgery. Epilepsy Res 2016;121:39–46.
[43] Wellmer J, Kopitzki K, Voges J. Lesion focused stereotactic thermo-coagulation
of focal cortical dysplasia IIB: a new approach to epilepsy surgery? Seizure
2014;23:475–8.
[44] Helmstaedter C, Petzold I, Bien CG. The cognitive consequence of resecting
nonlesional tissues in epilepsy surgery—results from MRI- and histopatholo-
gy-negative patients with temporal lobe epilepsy. Epilepsia 2011;52:1402–8.
[45] Baxendale S, Thompson P, Harkness W, Duncan J. Predicting memory decline
following epilepsy surgery: a multivariate approach. Epilepsia 2006;47:1887–
94.
[46] Baxendale S, Thompson P, Harkness W, Duncan J. The role of the intracarotid
amobarbital procedure in predicting verbal memory decline after temporal
lobe resection. Epilepsia 2007;48:546–52.
[47] Helmstaedter C, Brosch T, Kurthen M, Elger CE. The impact of sex and language
dominance on material-specific memory before and after left temporal lobe
surgery. Brain 2004;127:1518–25.
[48] Grunwald T, Lehnertz K, Pezer N, Kurthen M, Van Roost D, Schramm J, et al.
Prediction of postoperative seizure control by hippocampal event-related
potentials. Epilepsia 1999;40:303–6.
[49] Sidhu MK, Stretton J, Winston GP, Symms M, Thompson PJ, Koepp MJ, et al.
Memory fMRI predicts verbal memory decline after anterior temporal lobe
resection. Neurology 2015;84:1512–9.
[50] Loring DW, Hermann BP, Meador KJ, Lee GP, Gallagher BB, King DW, et al.
Amnesia after unilateral temporal lobectomy: a case report. Epilepsia
1994;35:757–63.
[51] Zubkov S, Del Bene VA, MacAllister WS, Shepherd TM, Devinsky O. Disabling
amnestic syndrome following stereotactic laser ablation of a hypothalamic
hamartoma in a patient with a prior temporal lobectomy. Epilepsy Behav Case
Rep 2015;4:60–2.
[52] Dietl T, Urbach H, Helmstaedter C, Staedtgen M, Szentkuti A, Grunwald T, et al.
Persistent severe amnesia due to seizure recurrence after unilateral temporal
lobectomy. Epilepsy Behav 2004;5:394–400.
[53] Helmstaedter C, Kurthen M, Lux S, Reuber M, Elger CE. Chronic epilepsy and
cognition: a longitudinal study in temporal lobe epilepsy. Ann Neurol
2003;54:425–32.
[54] Helmstaedter CA. Prediction of memory reserve capacity. Adv Neurol
1999;81:271–9.
120 C. Helmstaedter, J.-A. Witt / Seizure 44 (2017) 113–120
[55] Gleissner U, Sassen R, Schramm J, Elger CE, Helmstaedter C. Greater functional
recovery after temporal lobe epilepsy surgery in children. Brain
2005;128:2822–9.
[56] Helmstaedter C, Reuber M, Elger CC. Interaction of cognitive aging and
memory deficits related to epilepsy surgery. Ann Neurol 2002;52:89–94.
[57] Helmstaedter C, Elger CE, Witt JA. The effect of quantitative and qualitative
antiepileptic drug changes on cognitive recovery after epilepsy surgery.
Seizure 2016;36:63–9.
[58] Vogt VL, Witt JA, Malter MP, Schoene-Bake JC, von Lehe M, Elger CE, et al.
Neuropsychological outcome after epilepsy surgery in patients with bilateral
Ammon's horn sclerosis. J Neurosurg 2014;121:1247–56.
[59] Baxendale S, Thompson PJ, Sander JW. Neuropsychological outcomes in
epilepsy surgery patients with unilateral hippocampal sclerosis and good
preoperative memory function. Epilepsia 2013;54:e131–134.
[60] Sherman EM, Wiebe S, Fay-McClymont TB, Tellez-Zenteno J, Metcalfe A,
Hernandez-Ronquillo L, et al. Neuropsychological outcomes after epilepsy
surgery: systematic review and pooled estimates. Epilepsia 2011;52:857–69.
[61] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med
2000;342:314–9.
[62] Witt JA, Elger CE, Helmstaedter C. Which drug-induced side effects would be
tolerated in the prospect of seizure control? Epilepsy Behav 2013;29:141–3.
[63] de Kinderen RJ, Evers SM, Rinkens R, Postulart D, Vader CI, Majoie MH, et al.
Side-effects of antiepileptic drugs: the economic burden. Seizure
2014;23:184–90.
[64] Helmstaedter C, Witt JA. Comments on Ortinski P et al. Cognitive side effects of
antiepileptic drugs. Epilepsy & Behavior 2004;5(Suppl. 1):S60–65. Epilepsy
Behav 2014;40:29–31.
[65] Ortinski P, Meador KJ. Cognitive side effects of antiepileptic drugs. Epilepsy
Behav 2004;5(Suppl. 1):S60–65.
[66] Witt JA, Elger CE, Helmstaedter C. Impaired verbal fluency under topiramate-
evidence for synergistic negative effects of epilepsy, topiramate, and
polytherapy. Eur J Neurol 2013;20:130–7.
[67] Helmstaedter C, Witt JA. The effects of levetiracetam on cognition: a non-
interventional surveillance study. Epilepsy Behav 2008;13:642–9.
[68] Witt JA, Elger CE, Helmstaedter C. Adverse cognitive effects of antiepileptic
pharmacotherapy: each additional drug matters. Eur Neuropsychopharmacol
2015;25:1954–9.
[69] Gilliam FG, Fessler AJ, Baker G, Vahle V, Carter J, Attarian H. Systematic
screening allows reduction of adverse antiepileptic drug effects: a randomized
trial. Neurology 2004;62:23–7.
[70] Witt JA, Helmstaedter C. Monitoring the cognitive effects of antiepileptic
pharmacotherapy – approaching the individual patient. Epilepsy Behav
2013;26:450–6.
[71] Witt JA, Alpherts W, Helmstaedter C. Computerized neuropsychological
testing in epilepsy: overview of available tools. Seizure 2013;22:416–23.
[72] Helmstaedter C, Witt JA. The longer-term cognitive effects of adjunctive
antiepileptic treatment with lacosamide in comparison with lamotrigine and
topiramate in a naturalistic outpatient setting. Epilepsy Behav 2013;26:182–7.
[73] Hesdorffer DC, Hauser WA, Annegers JF, Cascino G. Major depression is a risk
factor for seizures in older adults. Ann Neurol 2000;47:246–9.
[74] Hesdorffer DC, Hauser WA, Olafsson E, Ludvigsson P, Kjartansson O.
Depression and suicide attempt as risk factors for incident unprovoked
seizures. Ann Neurol 2006;59:35–41.
[75] Hermann BP, Jones JE, Jackson DC, Seidenberg M. Starting at the beginning: the
neuropsychological status of children with new-onset epilepsies. Epileptic
Disord 2012;14:12–21.
[76] Witt JA, Werhahn KJ, Kramer G, Ruckes C, Trinka E, Helmstaedter C. Cognitive-
behavioral screening in elderly patients with new-onset epilepsy before
treatment. Acta Neurol Scand 2014;130:172–7.
[77] Soyal SM, Felder TK, Auer S, Hahne P, Oberkofler H, Witting A, et al. A greatly
extended PPARGC1A genomic locus encodes several new brain-specific
isoforms and influences Huntington disease age of onset. Hum Mol Genet
2012;21:3461–73.
[78] Witt JA, Helmstaedter C. Cognition in the early stages of adult epilepsy. Seizure
2015;26:65–8.
[79] Almane D, Jones JE, Jackson DC, Seidenberg M, Koehn M, Hsu DA, et al. Brief
clinical screening for academic underachievement in new-onset childhood
epilepsy: utility and longitudinal results. Epilepsy Behav 2015;43:117–21.
[80] Zhao Q, Rathouz PJ, Jones JE, Jackson DC, Hsu DA, Stafstrom CE, et al.
Longitudinal trajectories of behavior problems and social competence in
children with new onset epilepsy. Dev Med Child Neurol 2015;57:37–44.
[81] Reuner G, Kadish NE, Doering JH, Balke D, Schubert-Bast S. Attention and
executive functions in the early course of pediatric epilepsy. Epilepsy Behav
2016;60:42–9.
[82] Kadish NE, Baumann M, Pietz J, Schubert-Bast S, Reuner G. Validation of a
screening tool for attention and executive functions (EpiTrack Junior) in
children and adolescents with absence epilepsy. Epilepsy Behav 2013;29:96–
102.
[83] Helmstaedter C, Elger CE. Chronic temporal lobe epilepsy: a neurodevelop-
mental or progressively dementing disease? Brain 2009;132:2822–30.
[84] Helmstaedter C, Aldenkamp AP, Baker GA, Mazarati A, Ryvlin P, Sankar R.
Disentangling the relationship between epilepsy and its behavioral comor-
bidities—the need for prospective studies in new-onset epilepsies. Epilepsy
Behav 2014;31:43–7.