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How neuropsychology can improve the care of individual patients with epilepsy. Looking back and into the future

Open ArchivePublished:October 13, 2016DOI:https://doi.org/10.1016/j.seizure.2016.09.010

      Highlights

      • The determinants of cognitive impairment in epilepsy are known since long.
      • After 20–30 years of extensive research, neuropsychology still struggles with knowledge transfer to individual patient care.
      • Progress in regard to diagnostics, disease, and outcome monitoring is discussed.
      • National and international efforts for reaching a common diagnostics are outlined.
      • Proposals for indication of assessment and an evidence based test selection are made.
      • The impact of neuropsychology on safer surgery and drug treatment and on outcome prediction are discussed.
      • The necessity to assess and follow up patients from the beginning of epilepsy is pointed out.

      Abstract

      Some of the roots of current clinical neuropsychology go back to the early days of epilepsy surgery. Looking back a huge number of publications have dealt with cognition in epilepsy. The major factors 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 years ago. The body of neuropsychological literature in this field has accumulated much knowledge, raising the question why, apart from epilepsy surgery settings, neuropsychology has still not been fully integrated in the routine care of patients with epilepsy. This review on the occasion of Seizures 25th anniversary attempts to summarize clinically relevant diagnostic advances following a question guided, modular, and evidence-based approach. In doing so, we hope to attract the interest of readers to an 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.

      Keywords

      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) [
      • Trimble M.R.
      Cognitive hazards of seizure disorders.
      ].
      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 [
      • Bumke O.
      Die Diagnose der Geisteskrankheiten.
      ,
      • Kraepelin E.
      ,
      • Wildermuth H.A.
      Zeitschrift f. d. Behandlung Schwachsinniger und Epileptiker.
      ]. 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, 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 [
      • Feindel W.
      Development of surgical therapy of epilepsy at the Montreal Neurological Institute.
      ] 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 [
      • Loring D.W.
      History of neuropsychology through epilepsy eyes.
      ]. 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 [
      • Elger C.E.
      • Helmstaedter C.
      • Kurthen M.
      Chronic epilepsy and cognition.
      ]. 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 [
      • Wilson S.J.
      • Baxendale S.
      The new approach to classification: rethinking cognition and behavior in epilepsy.
      ]. 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 [
      • Hermann B.
      • Seidenberg M.
      • Jones J.
      The neurobehavioural comorbidities of epilepsy: can a natural history be developed?.
      ,
      • Lin J.J.
      • Mula M.
      • Hermann B.P.
      Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan.
      ]. 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 [
      • Helmstaedter C.
      • Aldenkamp A.P.
      • Baker G.A.
      • Mazarati A.
      • Ryvlin P.
      • Sankar R.
      Disentangling the relationship between epilepsy and its behavioral comorbidities—the need for prospective studies in new-onset epilepsies.
      ]. 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 diagnostics, monitoring of the disorder and its treatment, patient counseling, and therapeutic decision-making.

      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 comprehensive compendium which provides an overview of the state of the art at that time [
      ].
      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.
      Table 1Future 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.
      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 [
      • Wilson S.J.
      • 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.
      ]. The paper addresses what the role of neuropsychological assessment is, who should carry out a neuropsychological assessment, when people with epilepsy should be referred for neuropsychological assessment, and what can be expected from it. This 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 [
      • Kobulashvili T.
      • Hofler J.
      • Dobesberger J.
      • Ernst F.
      • Ryvlin P.
      • Cross J.H.
      • 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.
      ,
      • Mouthaan B.E.
      • Rados M.
      • Barsi P.
      • Boon P.
      • Carmichael D.W.
      • Carrette E.
      • et al.
      Current use of imaging and electromagnetic source localization procedures in epilepsy surgery centers across Europe.
      ], the data on neuropsychology have been evaluated and will soon be published. In concordance with older studies dating back 23 years [
      • Jones-Gotman M.
      • Smith M.L.
      • Zatorre R.J.
      Neuropsychological testing for localizing and lateralizing the epileptogenic region.
      ], 11 years [
      • Rabin L.A.
      • Barr W.B.
      • Burton L.A.
      Assessment practices of clinical neuropsychologists in the United States and Canada: a survey of INS, NAN, and APA Division 40 members.
      ] and, more recently, 5 years [
      • Jones-Gotman M.
      • Smith M.L.
      • Risse G.L.
      • Westerveld M.
      • Swanson S.J.
      • Giovagnoli A.R.
      • et al.
      The contribution of neuropsychology to diagnostic assessment in epilepsy.
      ,
      • Witt J.A.
      • Helmstaedter C.
      A survey on neuropsychological practice in German-speaking epilepsy centers.
      ] the data continue to indicate that different centers (not to mention different countries) use a tremendous diversity of neuropsychological tests and examination protocols [
      • Djordjevic J.
      • Jones-Gotman M.
      Inquiry on assessments across epilepsy centers in different countries.
      ]. 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 neuropsychological 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 experience-based preferences (voting by the feet) than suitability and validity in patients with epilepsy.
      Table 2Frequent and recommended tests for use in epilepsy.
      DomainTests used across EU centersCommon data elements
      IntelligenceWechsler Adult Intelligence Scale (WAIS), Wechsler Intelligence Scale for Children (WISC)Wechsler Adult Intelligence Test-Fourth Edition (WAIS-IV) or short form (WASI)
      General performance levelMontreal Cognitive Assessment
      DevelopmentBayley Scales of Infant and Toddler Development (BSID), Vineland Adaptive Behavior Scales (VABS)Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), Mullen Scales of Early Learning (MSEL), Bayley Scales of Infant and Toddler Development (BSID)
      Motor functionsFinger tapping, Luria motor sequences
      Attention, executive functions, working memoryTrail Making Test (TMT) A & B, Digit span, Corsi block-tapping testTrail Making Test (TMT) A & B, Digit Span subtest from WAIS-IV/WISC-IV, Wisconsin Card Sorting Test (64 card version)
      Verbal memoryRey Auditory Verbal Learning Test (AVLT)Rey Auditory Verbal Learning Test (AVLT)
      Figural memoryRey-Osterrieth Complex Figure Test (ROCFT) delayed recallBrief Visuospatial Memory Test − Revised (BVMT-R), Rey-Osterrieth Complex Figure Test, Wechsler Memory Scale Visual Reproduction
      LanguageBoston Naming Test (BNT), phonemic & semantic fluency testsBoston Naming Test (BNT), Controlled Oral Word Association (COWA), aka FAS, Animal Fluency, aka Animal Naming
      Visual spatial functionsRey-Osterrieth Figure (ROCFT) copy, WAIS Block DesignWAIS-IV or WASI block design
      Adverse eventsAdverse Event Profile (AEP)Hague Side Effects Scale (HASES)
      Mood, quality of lifeBeck Depression Inventory (BDI), Quality of Life in Epilepsy (QOLIE), Child Behavior Checklist (CBCL)Beck Depression Inventory (BDI), Quality of life in neurological disorders (Neuro-QoL), Child behavior Checklist (CBCL), Child depression inventory (CDI)
      Language lateralizationfMRI: Word generation tasks, naming tasks
      IAT: Counting tasks, naming tasks, materialspecific memory tasks
      Transient cognitive impairmentno test which would be shared
      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://commondataelements.ninds.nih.gov/Doc/EPI/F1140_Overview_of_Recommended_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 neuropsychologically relevant diagnostic questions in a multi-centric way [
      • Loring D.W.
      History of neuropsychology through epilepsy eyes.
      ]. 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 [
      • Helmstaedter C.
      • Witt J.A.
      Clinical neuropsychology in epilepsy: theoretical and practical issues.
      ] (see Table 3, references for the measures used in epilepsy can be found in Ref. [
      • Helmstaedter C.
      • Witt J.A.
      Clinical neuropsychology in epilepsy: theoretical and practical issues.
      ]).
      Table 3Question-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 1–1½ 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 ∼3½ 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).
      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 [
      • Loring D.W.
      History of neuropsychology through epilepsy eyes.
      ]. 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 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 neuropsychological 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 [
      • Hoppe C.
      • Helmstaedter C.
      Sensitive and specific neuropsychological assessments of the behavioral effects of epilepsy and its treatment are essential.
      ]. 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 interpretation of tests of specific functions requires consideration of factors such as neurodevelopment [
      • Kaaden S.
      • Helmstaedter C.
      Age at onset of epilepsy as a determinant of intellectual impairment in temporal lobe epilepsy.
      ], processes of plasticity [
      • Helmstaedter C.
      • Kurthen M.
      • Gleissner U.
      • Linke D.B.
      • Elger C.E.
      Natural atypical language dominance and language shifts from the right to the left hemisphere in right hemisphere pathology.
      ,
      • Helmstaedter C.
      • Kurthen M.
      • Linke D.B.
      • Elger C.E.
      Patterns of language dominance in focal left and right hemisphere epilepsies: relation to MRI findings, EEG, sex, and age at onset of epilepsy.
      ], compensatory and restitutional processes [
      • Helmstaedter C.
      • Pohl C.
      • Elger C.E.
      Relations between verbal and nonverbal memory performance: evidence of confounding effects particularly in patients with right temporal lobe epilepsy.
      ,
      • Helmstaedter C.
      • Kurthen M.
      • Linke D.B.
      • Elger C.E.
      Right hemisphere restitution of language and memory functions in right hemisphere language-dominant patients with left temporal lobe epilepsy.
      ] and gender differences [
      • Helmstaedter C.
      • Kurthen M.
      • Elger C.E.
      Sex differences in material-specific cognitive functions related to language dominance: an intracarotid amobarbital study in left temporal lobe epilepsy.
      ]. 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 [
      • Helmstaedter C.
      • Wietzke J.
      • Lutz M.T.
      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.
      ].
      Meaningful neuropsychological assessment of patients with epilepsy cannot be limited to psychological performance diagnostics. 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) [
      • Phabphal K.
      • Kanjanasatien J.
      Montreal Cognitive Assessment in cryptogenic epilepsy patients with normal Mini-Mental State Examination scores.
      ], or (more complex and time consuming) a Wechsler intelligence battery [
      • Baxendale S.
      • McGrath K.
      • Thompson P.J.
      Epilepsy & IQ: the clinical utility of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) indices in the neuropsychological assessment of people with epilepsy.
      ], or (even more time consuming) an additional Wechsler memory scale [
      • Baker G.A.
      • Austin N.A.
      • Downes J.J.
      Validation of the Wechsler Memory Scale-III in a population of people with intractable temporal lobe epilepsy.
      ]. 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 [
      • Baxendale S.
      • McGrath K.
      • Thompson P.J.
      Epilepsy & IQ: the clinical utility of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) indices in the neuropsychological assessment of people with epilepsy.
      ].
      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 [
      • Schramm J.
      Temporal lobe epilepsy surgery and the quest for optimal extent of resection: a review.
      ,
      • Tanriverdi T.
      • Dudley R.W.
      • Hasan A.
      • Al Jishi A.
      • Al Hinai Q.
      • Poulin N.
      • et al.
      Memory outcome after temporal lobe epilepsy surgery: corticoamygdalohippocampectomy versus selective amygdalohippocampectomy.
      ,
      • Kuang Y.
      • Yang T.
      • Gu J.
      • Kong B.
      • Cheng L.
      Comparison of therapeutic effects between selective amygdalohippocampectomy and anterior temporal lobectomy for the treatment of temporal lobe epilepsy: a meta-analysis.
      ]. 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 [
      • Heller A.C.
      • Padilla R.V.
      • Mamelak A.N.
      Complications of epilepsy surgery in the first 8 years after neurosurgical training.
      ]. 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 hippocampal sclerosis already provided evidence of the negative effects of the resection of functional tissues which were not involved in seizure generation [
      • Helmstaedter C.
      Cognitive outcomes of different surgical approaches in temporal lobe epilepsy.
      ]. Meanwhile several studies have demonstrated 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 postoperative loss in memory [
      • Helmstaedter C.
      Cognitive outcomes of different surgical approaches in temporal lobe epilepsy.
      ]. Recent developments in regard to radiotherapy and highly selective stereotactic radiofrequency therapy have the potential further to improve patients’ functional outcomes without diminishing the chance of becoming seizure free [
      • 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.
      ,
      • Drane D.L.
      • Loring D.W.
      • Voets N.L.
      • Price M.
      • Ojemann J.G.
      • Willie J.T.
      • et al.
      Better object recognition and naming outcome with MRI-guided stereotactic laser amygdalohippocampotomy for temporal lobe epilepsy.
      ,
      • Attiah M.A.
      • Paulo D.L.
      • Danish S.F.
      • Stein S.C.
      • Mani R.
      Anterior temporal lobectomy compared with laser thermal hippocampectomy for mesial temporal epilepsy: a threshold analysis study.
      ,
      • Feng E.S.
      • Sui C.B.
      • Wang T.X.
      • Sun G.L.
      Stereotactic radiosurgery for the treatment of mesial temporal lobe epilepsy.
      ]. Similar trends are seen in extratemporal lobe surgery of developmental malformations [
      • 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.
      ,
      • Wellmer J.
      • Kopitzki K.
      • Voges J.
      Lesion focused stereotactic thermo-coagulation of focal cortical dysplasia IIB: a new approach to epilepsy surgery?.
      ].
      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 [
      • Helmstaedter C.
      • Petzold I.
      • Bien C.G.
      The cognitive consequence of resecting nonlesional tissues in epilepsy surgery—results from MRI- and histopathology-negative patients with temporal lobe epilepsy.
      ]. 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 thermocoagulation 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 neuropsychological outcome measures.
      Table 4Outcome 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
      • Baxendale S.
      • Thompson P.
      • Harkness W.
      • Duncan J.
      Predicting memory decline following epilepsy surgery: a multivariate approach.
      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
      • Baxendale S.
      • Thompson P.
      • Harkness W.
      • Duncan J.
      The role of the intracarotid amobarbital procedure in predicting verbal memory decline after temporal lobe resection.
      ,
      • Helmstaedter C.
      • Brosch T.
      • Kurthen M.
      • Elger C.E.
      The impact of sex and language dominance on material-specific memory before and after left temporal lobe surgery.
      ,
      • 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.
      ,
      • Sidhu M.K.
      • Stretton J.
      • Winston G.P.
      • Symms M.
      • Thompson P.J.
      • Koepp M.J.
      • et al.
      Memory fMRI predicts verbal memory decline after anterior temporal lobe resection.
      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
        • Loring D.W.
        • Hermann B.P.
        • Meador K.J.
        • Lee G.P.
        • Gallagher B.B.
        • King D.W.
        • et al.
        Amnesia after unilateral temporal lobectomy: a case report.
        ,
        • Zubkov S.
        • Del Bene V.A.
        • MacAllister W.S.
        • Shepherd T.M.
        • Devinsky O.
        Disabling amnestic syndrome following stereotactic laser ablation of a hypothalamic hamartoma in a patient with a prior temporal lobectomy.
        ,
        • 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.
      • -
        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)
        • Helmstaedter C.
        • Kurthen M.
        • Lux S.
        • Reuber M.
        • Elger C.E.
        Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy.
        ,
        • Helmstaedter C.A.
        Prediction of memory reserve capacity.
      • -
        Outcome is better in the presence of greater compensatory capacity of the non-affected remnant brain (in terms of IQ, executive functions, etc.)
        • Helmstaedter C.
        • Kurthen M.
        • Lux S.
        • Reuber M.
        • Elger C.E.
        Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy.
      • -
        Losses are greater with increasing age. Younger patients recover early, older patients late
        • Gleissner U.
        • Sassen R.
        • Schramm J.
        • Elger C.E.
        • Helmstaedter C.
        Greater functional recovery after temporal lobe epilepsy surgery in children.
        ,
        • Helmstaedter C.
        • Reuber M.
        • Elger C.C.
        Interaction of cognitive aging and memory deficits related to epilepsy surgery.
      • -
        Postoperative recovery can be supported by tapering drug load
        • Helmstaedter C.
        • Elger C.E.
        • Witt J.A.
        The effect of quantitative and qualitative antiepileptic drug changes on cognitive recovery after epilepsy surgery.
      • -
        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
        • Vogt V.L.
        • Witt J.A.
        • Malter M.P.
        • Schoene-Bake J.C.
        • von Lehe M.
        • Elger C.E.
        • et al.
        Neuropsychological outcome after epilepsy surgery in patients with bilateral Ammon's horn sclerosis.
      • -
        Hippocampal sclerosis and good memory does not preclude postoperative loss (may depend on approach)
        • Baxendale S.
        • Thompson P.J.
        • Sander J.W.
        Neuropsychological outcomes in epilepsy surgery patients with unilateral hippocampal sclerosis and good preoperative memory function.
      • -
        Atypical language dominance in left TLE surgical patients is protective in regard to verbal memory outcome
        • Helmstaedter C.
        • Brosch T.
        • Kurthen M.
        • Elger C.E.
        The impact of sex and language dominance on material-specific memory before and after left temporal lobe surgery.
      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
        • Helmstaedter C.
        Cognitive outcomes of different surgical approaches in temporal lobe epilepsy.
        ,
        • Sherman E.M.
        • Wiebe S.
        • Fay-McClymont T.B.
        • Tellez-Zenteno J.
        • Metcalfe A.
        • Hernandez-Ronquillo L.
        • et al.
        Neuropsychological outcomes after epilepsy surgery: systematic review and pooled estimates.
      • -
        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
        • Vogt V.L.
        • Witt J.A.
        • Malter M.P.
        • Schoene-Bake J.C.
        • von Lehe M.
        • Elger C.E.
        • et al.
        Neuropsychological outcome after epilepsy surgery in patients with bilateral Ammon's horn sclerosis.
      • -
        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
        • Baxendale S.
        • Thompson P.J.
        • Sander J.W.
        Neuropsychological outcomes in epilepsy surgery patients with unilateral hippocampal sclerosis and good preoperative memory function.
      • -
        If patients are non-lesional on MRI and turn out to have normal histopathology ∼80% will experience significant functional loss
        • Helmstaedter C.
        • Petzold I.
        • Bien C.G.
        The cognitive consequence of resecting nonlesional tissues in epilepsy surgery—results from MRI- and histopathology-negative patients with temporal lobe epilepsy.
      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 [
      • Kwan P.
      • Brodie M.J.
      Early identification of refractory epilepsy.
      ], 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 [
      • Witt J.A.
      • Elger C.E.
      • Helmstaedter C.
      Which drug-induced side effects would be tolerated in the prospect of seizure control?.
      ]. In addition, AED side effects represent a considerable economic burden [
      • de Kinderen R.J.
      • Evers S.M.
      • Rinkens R.
      • Postulart D.
      • Vader C.I.
      • Majoie M.H.
      • et al.
      Side-effects of antiepileptic drugs: the economic burden.
      ]. 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 [
      • Helmstaedter C.
      • Witt J.A.
      Comments on Ortinski P et al. Cognitive side effects of antiepileptic drugs. Epilepsy & Behavior 2004;5(Suppl. 1):S60–65.
      ,
      • Ortinski P.
      • Meador K.J.
      Cognitive side effects of antiepileptic drugs.
      ]. However, cognitive impairments in the context of AED pharmacotherapy 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 [
      • Witt J.A.
      • Elger C.E.
      • Helmstaedter C.
      Impaired verbal fluency under topiramate-evidence for synergistic negative effects of epilepsy, topiramate, and polytherapy.
      ]. 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 [
      • Helmstaedter C.
      • Witt J.A.
      The effects of levetiracetam on cognition: a non-interventional surveillance study.
      ].
      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 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 [
      • Witt J.A.
      • Elger C.E.
      • Helmstaedter C.
      Adverse cognitive effects of antiepileptic pharmacotherapy: each additional drug matters.
      ].
      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 [
      • Gilliam F.G.
      • Fessler A.J.
      • Baker G.
      • Vahle V.
      • Carter J.
      • Attarian H.
      Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial.
      ]. 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 [
      • Witt J.A.
      • Helmstaedter C.
      Monitoring the cognitive effects of antiepileptic pharmacotherapy – approaching the individual patient.
      ].
      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 [
      • Helmstaedter C.
      • Witt J.A.
      Clinical neuropsychology in epilepsy: theoretical and practical issues.
      ]. Several computerized tests have been proven to be CNS drug sensitive, and some of these have also been validated for use in epilepsy [
      • Witt J.A.
      • Alpherts W.
      • Helmstaedter C.
      Computerized neuropsychological testing in epilepsy: overview of available tools.
      ]. 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 [
      • Helmstaedter C.
      • Witt J.A.
      The longer-term cognitive effects of adjunctive antiepileptic treatment with lacosamide in comparison with lamotrigine and topiramate in a naturalistic outpatient setting.
      ]. 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 [
      • Hesdorffer D.C.
      • Hauser W.A.
      • Annegers J.F.
      • Cascino G.
      Major depression is a risk factor for seizures in older adults.
      ,
      • Hesdorffer D.C.
      • Hauser W.A.
      • Olafsson E.
      • Ludvigsson P.
      • Kjartansson O.
      Depression and suicide attempt as risk factors for incident unprovoked seizures.
      ]. 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 [
      • Hermann B.P.
      • Jones J.E.
      • Jackson D.C.
      • Seidenberg M.
      Starting at the beginning: the neuropsychological status of children with new-onset epilepsies.
      ,
      • Witt J.A.
      • Werhahn K.J.
      • Kramer G.
      • Ruckes C.
      • Trinka E.
      • Helmstaedter C.
      Cognitive-behavioral screening in elderly patients with new-onset epilepsy before treatment.
      ,
      • Soyal S.M.
      • Felder T.K.
      • 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.
      ,
      • Witt J.A.
      • Helmstaedter C.
      Cognition in the early stages of adult epilepsy.
      ]. 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 [
      • Almane D.
      • Jones J.E.
      • Jackson D.C.
      • Seidenberg M.
      • Koehn M.
      • Hsu D.A.
      • et al.
      Brief clinical screening for academic underachievement in new-onset childhood epilepsy: utility and longitudinal results.
      ]. It is interesting and perhaps surprising that behavior and competence problems in children newly diagnosed with localization-related and idiopathic generalized childhood epilepsies do not tend to get progressively worse over the next 5- to 6-years [
      • Zhao Q.
      • Rathouz P.J.
      • Jones J.E.
      • Jackson D.C.
      • Hsu D.A.
      • Stafstrom C.E.
      • et al.
      Longitudinal trajectories of behavior problems and social competence in children with new onset epilepsy.
      ]. 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 [
      • Reuner G.
      • Kadish N.E.
      • Doering J.H.
      • Balke D.
      • Schubert-Bast S.
      Attention and executive functions in the early course of pediatric epilepsy.
      ,
      • Kadish N.E.
      • 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.
      ], 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 [
      • Helmstaedter C.
      • Elger C.E.
      Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease?.
      ,
      • Helmstaedter C.
      • Aldenkamp A.P.
      • Baker G.A.
      • Mazarati A.
      • Ryvlin P.
      • Sankar R.
      Disentangling the relationship between epilepsy and its behavioral comorbidities—the need for prospective studies in new-onset epilepsies.
      ] 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. 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

        • Trimble M.R.
        Cognitive hazards of seizure disorders.
        Epilepsia. 1988; 29: S19-S24
        • Bumke O.
        Die Diagnose der Geisteskrankheiten.
        Verlag von F.J. Bergmann, Wiesbaden1919
        • Kraepelin E.
        Sechste vollständig überarbeitete Auflage Psychiatrie Ein Lehrbuch für Studierende und Aerzte. Verlag von Johann Ambrosius Barth, Leipzig1899
        • Wildermuth H.A.
        Zeitschrift f. d. Behandlung Schwachsinniger und Epileptiker.
        Warnatz & Lehmann, Königl. Hofbuchhändler, Dresden/Druck Johannes Pässler, Dresden1897
        • Feindel W.
        Development of surgical therapy of epilepsy at the Montreal Neurological Institute.
        Can J Neurol Sci. 1991; 18: 549-553
        • Loring D.W.
        History of neuropsychology through epilepsy eyes.
        Arch Clin Neuropsychol. 2010; 25: 259-273
        • Elger C.E.
        • Helmstaedter C.
        • Kurthen M.
        Chronic epilepsy and cognition.
        Lancet Neurol. 2004; 3: 663-672
        • Wilson S.J.
        • Baxendale S.
        The new approach to classification: rethinking cognition and behavior in epilepsy.
        Epilepsy Behav. 2014; 41: 307-310
        • Hermann B.
        • Seidenberg M.
        • Jones J.
        The neurobehavioural comorbidities of epilepsy: can a natural history be developed?.
        Lancet Neurol. 2008; 7: 151-160
        • Lin J.J.
        • Mula M.
        • Hermann B.P.
        Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan.
        Lancet. 2012; 380: 1180-1192
        • Helmstaedter C.
        • Aldenkamp A.P.
        • Baker G.A.
        • Mazarati A.
        • Ryvlin P.
        • Sankar R.
        Disentangling the relationship between epilepsy and its behavioral comorbidities—the need for prospective studies in new-onset epilepsies.
        Epilepsy Behav. 2014; 31: 43-47
      1. Helmstadter C. Hermann B. Lassonde M. Kahane P. Arzimanoglou A. Neuropsychology in the care of people with epilepsy. John Libbey, Montrouge2011
        • Wilson S.J.
        • 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: 1316-1317
        • Kobulashvili T.
        • Hofler J.
        • Dobesberger J.
        • Ernst F.
        • Ryvlin P.
        • Cross J.H.
        • 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
        • Mouthaan B.E.
        • Rados M.
        • Barsi P.
        • Boon P.
        • Carmichael D.W.
        • Carrette E.
        • et al.
        Current use of imaging and electromagnetic source localization procedures in epilepsy surgery centers across Europe.
        Epilepsia. 2016; 57: 770-776
        • Jones-Gotman M.
        • Smith M.L.
        • Zatorre R.J.
        Neuropsychological testing for localizing and lateralizing the epileptogenic region.
        in: Engel J. Surgical treatment of the epilepsies. Raven Press, New York1993: 245-262
        • Rabin L.A.
        • Barr W.B.
        • Burton L.A.
        Assessment practices of clinical neuropsychologists in the United States and Canada: a survey of INS, NAN, and APA Division 40 members.
        Arch Clin Neuropsychol. 2005; 20: 33-65
        • Jones-Gotman M.
        • Smith M.L.
        • Risse G.L.
        • Westerveld M.
        • Swanson S.J.
        • Giovagnoli A.R.
        • et al.
        The contribution of neuropsychology to diagnostic assessment in epilepsy.
        Epilepsy Behav. 2010; 18: 3-12
        • Witt J.A.
        • Helmstaedter C.
        A survey on neuropsychological practice in German-speaking epilepsy centers.
        in: Helmstaedter C. Hermann B. Kahane P. Arzimanoglou A. Neuropsychology in the care of people with epilepsy. John Libbey Eurotext, 2011
        • 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. Progress in epileptic disorders: neuropsychology in the care of people with epilepsy. 2011
        • Helmstaedter C.
        • Witt J.A.
        Clinical neuropsychology in epilepsy: theoretical and practical issues.
        Handb Clin Neurol. 2012; 107: 437-459
        • Hoppe C.
        • Helmstaedter C.
        Sensitive and specific neuropsychological assessments of the behavioral effects of epilepsy and its treatment are essential.
        Epilepsia. 2010; 51: 2365-2366
        • Kaaden S.
        • Helmstaedter C.
        Age at onset of epilepsy as a determinant of intellectual impairment in temporal lobe epilepsy.
        Epilepsy Behav. 2009; 15: 213-217
        • Helmstaedter C.
        • Kurthen M.
        • Gleissner U.
        • Linke D.B.
        • Elger C.E.
        Natural atypical language dominance and language shifts from the right to the left hemisphere in right hemisphere pathology.
        Naturwissenschaften. 1997; 84: 250-252
        • Helmstaedter C.
        • Kurthen M.
        • Linke D.B.
        • Elger C.E.
        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: 135-150
        • Helmstaedter C.
        • Pohl C.
        • Elger C.E.
        Relations between verbal and nonverbal memory performance: evidence of confounding effects particularly in patients with right temporal lobe epilepsy.
        Cortex. 1995; 31: 345-355
        • Helmstaedter C.
        • Kurthen M.
        • Linke D.B.
        • Elger C.E.
        Right hemisphere restitution of language and memory functions in right hemisphere language-dominant patients with left temporal lobe epilepsy.
        Brain. 1994; 117: 729-737
        • Helmstaedter C.
        • Kurthen M.
        • Elger C.E.
        Sex differences in material-specific cognitive functions related to language dominance: an intracarotid amobarbital study in left temporal lobe epilepsy.
        Laterality. 1999; 4: 51-63
        • Helmstaedter C.
        • Wietzke J.
        • Lutz M.T.
        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: 203-212
        • Phabphal K.
        • Kanjanasatien J.
        Montreal Cognitive Assessment in cryptogenic epilepsy patients with normal Mini-Mental State Examination scores.
        Epileptic Disord. 2011; 13: 375-381
        • Baxendale S.
        • McGrath K.
        • Thompson P.J.
        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 Neuropsychol. 2014; 36: 137-143
        • Baker G.A.
        • Austin N.A.
        • Downes J.J.
        Validation of the Wechsler Memory Scale-III in a population of people with intractable temporal lobe epilepsy.
        Epilepsy Res. 2003; 53: 201-206
        • Schramm J.
        Temporal lobe epilepsy surgery and the quest for optimal extent of resection: a review.
        Epilepsia. 2008; 49: 1296-1307
        • Tanriverdi T.
        • Dudley R.W.
        • Hasan A.
        • Al Jishi A.
        • Al Hinai Q.
        • Poulin N.
        • et al.
        Memory outcome after temporal lobe epilepsy surgery: corticoamygdalohippocampectomy versus selective amygdalohippocampectomy.
        J Neurosurg. 2010; 113: 1164-1175
        • Kuang Y.
        • Yang T.
        • Gu J.
        • Kong B.
        • Cheng L.
        Comparison of therapeutic effects between selective amygdalohippocampectomy and anterior temporal lobectomy for the treatment of temporal lobe epilepsy: a meta-analysis.
        Br J Neurosurg. 2014; 28: 374-377
        • Heller A.C.
        • Padilla R.V.
        • Mamelak A.N.
        Complications of epilepsy surgery in the first 8 years after neurosurgical training.
        Surg Neurol. 2009; 71 (discussion 637): 631-637
        • Helmstaedter C.
        Cognitive outcomes of different surgical approaches in temporal lobe epilepsy.
        Epileptic Disord. 2013; 15: 221-239
        • 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: 372-380
        • Drane D.L.
        • Loring D.W.
        • Voets N.L.
        • Price M.
        • Ojemann J.G.
        • Willie J.T.
        • et al.
        Better object recognition and naming outcome with MRI-guided stereotactic laser amygdalohippocampotomy for temporal lobe epilepsy.
        Epilepsia. 2015; 56: 101-113
        • Attiah M.A.
        • Paulo D.L.
        • Danish S.F.
        • Stein S.C.
        • Mani R.
        Anterior temporal lobectomy compared with laser thermal hippocampectomy for mesial temporal epilepsy: a threshold analysis study.
        Epilepsy Res. 2015; 115: 1-7
        • Feng E.S.
        • Sui C.B.
        • Wang T.X.
        • Sun G.L.
        Stereotactic radiosurgery for the treatment of mesial temporal lobe epilepsy.
        Acta Neurol Scand. 2016; (February 4 [Epub ahead of print])https://doi.org/10.1111/ane.12562
        • 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
        • 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: 475-478
        • Helmstaedter C.
        • Petzold I.
        • Bien C.G.
        The cognitive consequence of resecting nonlesional tissues in epilepsy surgery—results from MRI- and histopathology-negative patients with temporal lobe epilepsy.
        Epilepsia. 2011; 52: 1402-1408
        • Baxendale S.
        • Thompson P.
        • Harkness W.
        • Duncan J.
        Predicting memory decline following epilepsy surgery: a multivariate approach.
        Epilepsia. 2006; 47: 1887-1894
        • 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: 546-552
        • Helmstaedter C.
        • Brosch T.
        • Kurthen M.
        • Elger C.E.
        The impact of sex and language dominance on material-specific memory before and after left temporal lobe surgery.
        Brain. 2004; 127: 1518-1525
        • 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: 303-306
        • Sidhu M.K.
        • Stretton J.
        • Winston G.P.
        • Symms M.
        • Thompson P.J.
        • Koepp M.J.
        • et al.
        Memory fMRI predicts verbal memory decline after anterior temporal lobe resection.
        Neurology. 2015; 84: 1512-1519
        • Loring D.W.
        • Hermann B.P.
        • Meador K.J.
        • Lee G.P.
        • Gallagher B.B.
        • King D.W.
        • et al.
        Amnesia after unilateral temporal lobectomy: a case report.
        Epilepsia. 1994; 35: 757-763
        • Zubkov S.
        • Del Bene V.A.
        • MacAllister W.S.
        • Shepherd T.M.
        • 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: 60-62
        • 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
        • Helmstaedter C.
        • Kurthen M.
        • Lux S.
        • Reuber M.
        • Elger C.E.
        Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy.
        Ann Neurol. 2003; 54: 425-432
        • Helmstaedter C.A.
        Prediction of memory reserve capacity.
        Adv Neurol. 1999; 81: 271-279
        • Gleissner U.
        • Sassen R.
        • Schramm J.
        • Elger C.E.
        • Helmstaedter C.
        Greater functional recovery after temporal lobe epilepsy surgery in children.
        Brain. 2005; 128: 2822-2829
        • Helmstaedter C.
        • Reuber M.
        • Elger C.C.
        Interaction of cognitive aging and memory deficits related to epilepsy surgery.
        Ann Neurol. 2002; 52: 89-94
        • Helmstaedter C.
        • Elger C.E.
        • Witt J.A.
        The effect of quantitative and qualitative antiepileptic drug changes on cognitive recovery after epilepsy surgery.
        Seizure. 2016; 36: 63-69
        • Vogt V.L.
        • Witt J.A.
        • Malter M.P.
        • Schoene-Bake J.C.
        • von Lehe M.
        • Elger C.E.
        • et al.
        Neuropsychological outcome after epilepsy surgery in patients with bilateral Ammon's horn sclerosis.
        J Neurosurg. 2014; 121: 1247-1256
        • Baxendale S.
        • Thompson P.J.
        • Sander J.W.
        Neuropsychological outcomes in epilepsy surgery patients with unilateral hippocampal sclerosis and good preoperative memory function.
        Epilepsia. 2013; 54: e131-134
        • Sherman E.M.
        • Wiebe S.
        • Fay-McClymont T.B.
        • Tellez-Zenteno J.
        • Metcalfe A.
        • Hernandez-Ronquillo L.
        • et al.
        Neuropsychological outcomes after epilepsy surgery: systematic review and pooled estimates.
        Epilepsia. 2011; 52: 857-869
        • Kwan P.
        • Brodie M.J.
        Early identification of refractory epilepsy.
        N Engl J Med. 2000; 342: 314-319
        • Witt J.A.
        • Elger C.E.
        • Helmstaedter C.
        Which drug-induced side effects would be tolerated in the prospect of seizure control?.
        Epilepsy Behav. 2013; 29: 141-143
        • de Kinderen R.J.
        • Evers S.M.
        • Rinkens R.
        • Postulart D.
        • Vader C.I.
        • Majoie M.H.
        • et al.
        Side-effects of antiepileptic drugs: the economic burden.
        Seizure. 2014; 23: 184-190
        • Helmstaedter C.
        • Witt J.A.
        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
        • Ortinski P.
        • Meador K.J.
        Cognitive side effects of antiepileptic drugs.
        Epilepsy Behav. 2004; 5: S60-65
        • Witt J.A.
        • Elger C.E.
        • Helmstaedter C.
        Impaired verbal fluency under topiramate-evidence for synergistic negative effects of epilepsy, topiramate, and polytherapy.
        Eur J Neurol. 2013; 20: 130-137
        • Helmstaedter C.
        • Witt J.A.
        The effects of levetiracetam on cognition: a non-interventional surveillance study.
        Epilepsy Behav. 2008; 13: 642-649
        • Witt J.A.
        • Elger C.E.
        • Helmstaedter C.
        Adverse cognitive effects of antiepileptic pharmacotherapy: each additional drug matters.
        Eur Neuropsychopharmacol. 2015; 25: 1954-1959
        • Gilliam F.G.
        • Fessler A.J.
        • Baker G.
        • Vahle V.
        • Carter J.
        • Attarian H.
        Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial.
        Neurology. 2004; 62: 23-27
        • Witt J.A.
        • Helmstaedter C.
        Monitoring the cognitive effects of antiepileptic pharmacotherapy – approaching the individual patient.
        Epilepsy Behav. 2013; 26: 450-456
        • Witt J.A.
        • Alpherts W.
        • Helmstaedter C.
        Computerized neuropsychological testing in epilepsy: overview of available tools.
        Seizure. 2013; 22: 416-423
        • Helmstaedter C.
        • Witt J.A.
        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: 182-187
        • Hesdorffer D.C.
        • Hauser W.A.
        • Annegers J.F.
        • Cascino G.
        Major depression is a risk factor for seizures in older adults.
        Ann Neurol. 2000; 47: 246-249
        • Hesdorffer D.C.
        • Hauser W.A.
        • Olafsson E.
        • Ludvigsson P.
        • Kjartansson O.
        Depression and suicide attempt as risk factors for incident unprovoked seizures.
        Ann Neurol. 2006; 59: 35-41
        • Hermann B.P.
        • Jones J.E.
        • Jackson D.C.
        • Seidenberg M.
        Starting at the beginning: the neuropsychological status of children with new-onset epilepsies.
        Epileptic Disord. 2012; 14: 12-21
        • Witt J.A.
        • Werhahn K.J.
        • 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: 172-177
        • Soyal S.M.
        • Felder T.K.
        • 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: 3461-3473
        • Witt J.A.
        • Helmstaedter C.
        Cognition in the early stages of adult epilepsy.
        Seizure. 2015; 26: 65-68
        • Almane D.
        • Jones J.E.
        • Jackson D.C.
        • Seidenberg M.
        • Koehn M.
        • Hsu D.A.
        • et al.
        Brief clinical screening for academic underachievement in new-onset childhood epilepsy: utility and longitudinal results.
        Epilepsy Behav. 2015; 43: 117-121
        • Zhao Q.
        • Rathouz P.J.
        • Jones J.E.
        • Jackson D.C.
        • Hsu D.A.
        • Stafstrom C.E.
        • et al.
        Longitudinal trajectories of behavior problems and social competence in children with new onset epilepsy.
        Dev Med Child Neurol. 2015; 57: 37-44
        • Reuner G.
        • Kadish N.E.
        • Doering J.H.
        • Balke D.
        • Schubert-Bast S.
        Attention and executive functions in the early course of pediatric epilepsy.
        Epilepsy Behav. 2016; 60: 42-49
        • Kadish N.E.
        • 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
        • Helmstaedter C.
        • Elger C.E.
        Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease?.
        Brain. 2009; 132: 2822-2830
        • Helmstaedter C.
        • Aldenkamp A.P.
        • Baker G.A.
        • Mazarati A.
        • Ryvlin P.
        • Sankar R.
        Disentangling the relationship between epilepsy and its behavioral comorbidities—the need for prospective studies in new-onset epilepsies.
        Epilepsy Behav. 2014; 31: 43-47