Cognitive outcome of pediatric epilepsy surgery across ages and different types of surgeries: A monocentric 1-year follow-up study in 306 patients of school age.

OBJECTIVE: The neuropsychological outcome of pediatric epilepsy surgery has been reported before, but only few studies compared different major types of surgery in differentially located epilepsies. METHODS: Neuropsychological performance of 306 children and adolescents (ages 6-17 years) were assessed before and one year after epilepsy surgery. Individual impairments, changes into and out of impairment, as well as intraindividually meaningful positive or negative changes were examined. Regression analyses addressed the effects of site, side, pathology, type of surgery, seizure outcome, and drug change on the cognitive and behavioral domains. RESULTS: Preoperatively 85% of the patients had cognitive impairments in at least one domain, 71% had behavioral problems. Postoperatively the number of impaired patients dropped considerably: 21-50% of the patients changed from impaired to unimpaired, individually significant gains were registered in 16-42%. Seizure freedom was achieved in 81% of all patients. The number of antiepileptic drugs decreased significantly. Seizure freedom, a younger age at evaluation, a later age at onset, a lower antiepileptic drug load, and less baseline damage predict better cognitive and behavioral outcomes. Gender, pathology, localization, and lateralization had little or no impact. CONCLUSION: Differentially located and lateralized epilepsies hardly differed in cognition and behavior indicating nonspecific developmental rather than domain specific impairments. Childhood epilepsy surgery is very successful and the functional improvements one year after surgery confirm the general relevance of baseline damage, mental reserve capacities, functional plasticity, the preservation of functional tissues and the functional release due to seizure freedom and drug load reduction.

Volumetry of Mesiotemporal Structures Reflects Serostatus in Patients with Limbic Encephalitis.

BACKGROUND AND PURPOSE: Limbic encephalitis is an autoimmune disease. A variety of autoantibodies have been associated with different subtypes of limbic encephalitis, whereas its MR imaging signature is uniformly characterized by mesiotemporal abnormalities across subtypes. Here, we hypothesized that patients with limbic encephalitis would show subtype-specific mesiotemporal structural correlates, which could be classified by supervised machine learning on an individual level. MATERIALS AND METHODS: T1WI MPRAGE scans from 46 patients with antibodies against glutamic acid decarboxylase and 34 patients with antibodies against the voltage-gated potassium channel complex (including 10 patients with leucine-rich glioma-inactivated 1 autoantibodies) and 48 healthy controls were retrospectively ascertained. Parcellation of the amygdala, hippocampus, and hippocampal subfields was performed using FreeSurfer. Volumes were extracted and compared between groups using unpaired, 2-tailed t tests. The volumes of hippocampal subfields were analyzed using a multivariate linear model and a binary decision tree classifier. RESULTS: Temporomesial volume alterations were most pronounced in an early stage and in the affected hemispheric side of patients. Statistical analysis revealed antibody-specific hippocampal fingerprints with a higher volume of CA1 in patients with glutamic acid decarboxylase-associated limbic encephalitis (P = .02), compared with controls, whereas CA1 did not differ from that in controls in patients with voltage-gated potassium channel complex autoantibodies. The classifier could successfully distinguish between patients with autoantibodies against leucine-rich glioma-inactivated 1 and glutamic acid decarboxylase with a specificity of 87% and a sensitivity of 80%. CONCLUSIONS: Our results suggest stage-, side- and antibody-specific structural correlates of limbic encephalitis; thus, they create a perspective toward an MR imaging-based diagnosis.

Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled.

PURPOSE: Epilepsy surgery can be a successful treatment option for temporal lobe epilepsy but there are concerns about accelerated memory decline in long-term follow-up. METHOD: 161 adult operated (77 right, 84 left temporal resections) versus a heterogeneous group of 208 non-operated patients with focal epilepsies were consecutively recruited and re-evaluated focusing on memory, executive functions, and vocational outcome after follow-up intervals of >5 years (5-22 years, mean 8 ± 3 years). RESULTS: Major losses in the operated group manifest early, at one-year follow-up. Few patients declined further. Long-term changes after surgery did not differ from those observed without surgery. The factor "surgery" caused verbal memory decline, "seizure freedom" (operated 48%, non-operated 17%) was associated with recovery of verbal memory, and "drug reduction" positively affected the course of executive functions. In terms of the critical function of verbal memory, only 3-17% of seizure-free patients showed long-term decline whereas 16-20% showed improvement (operated and non-operated). Persistent seizures were associated with decline in 12-37% and improvement in 4-12% of patients. Improvement was related to longer retest intervals and was stronger in younger patients. Independent of surgery or seizure outcome, the vocational status remained unchanged or change was negative (22%) rather than positive (3%). CONCLUSIONS: Patients' cognitive course 5-22 years after surgery is stable and may even be positive if epilepsy is controlled and drug load reduced. Depending on seizure outcome, recovery is more frequently observed than continuing decline. Recovery, however, takes time and age is a limiting factor.

An online adaptive screening procedure for selective neuronal responses.

BACKGROUND: A common problem in neurophysiology is to identify stimuli that elicit neuronal responses in a given brain region. Particularly in situations where electrode positions are fixed, this can be a time-consuming task that requires presentation of a large number of stimuli. Such a screening for response-eliciting stimuli is employed, e.g., as a standard procedure to identify 'concept cells' in the human medial temporal lobe. NEW METHOD: Our new method evaluates neuronal responses to stimuli online during a screening session, which allows us to successively exclude stimuli that do not evoke a response. Using this method, we can screen a larger number of stimuli which in turn increases the chances of finding responsive neurons and renders time-consuming offline analysis unnecessary. RESULTS: Our method enabled us to present 30% more stimuli in the same period of time with additional presentations of the most promising candidate stimuli. Our online method ran smoothly on a standard computer and network. COMPARISON WITH AN EXISTING METHOD: To analyze how our online screening procedure performs in comparison to an established offline method, we used the Wave_Clus software package. We did not observe any major drawbacks in our method, but a much higher efficiency and analysis speed. CONCLUSIONS: By transitioning from a traditional offline screening procedure to our new online method, we substantially increased the number of visual stimuli presented in a given time period. This allows to identify more response-eliciting stimuli, which forms the basis to better address a great number of questions in cognitive neuroscience.

Gait instability in valproate-treated patients: Call to measure ammonia levels.

OBJECTIVE: Hyperammonemia induced by valproate (VPA) treatment may lead to several neurological and systemic symptoms as well as to seizure exacerbation. Gait instability and recurrent falls are rarely mentioned as symptoms, especially not as predominant ones. METHODS: We report five adult patients with frontal lobe epilepsy (FLE) who were treated with VPA and in whom a primary adverse effect was unstable gait and falls. RESULTS: There were four males and one female patients with FLE, 25-42-year-old, three following epilepsy surgery. All of them were treated with antiepileptic drug polytherapy. Gait instability with falls was one of the principal sequelae of the treatment. Patients also exhibited mild encephalopathy (all patients) and flapping tremor (three patients) that developed following the addition of VPA (three patients) and with chronic VPA treatment (two patients). VPA levels were within the reference range. Serum ammonia levels were significantly elevated (291-407 µmole/L, normal 20-85) with normal or slightly elevated liver enzymes. VPA dose reduction or discontinuation led to the return of ammonia levels to normal and resolution of the clinical symptoms, including seizures, which disappeared in two patients and either decreased in frequency or became shorter in duration in the other three. CONCLUSIONS: Gait instability due to hyperammonemia and VPA treatment is probably under-recognized in many patients. It can develop when the VPA levels are within the reference range and with normal or slightly elevated liver enzymes.

[Stereotactic laser thermocoagulation in epilepsy surgery]. / Stereotaktische Laserthermokoagulation in der Epilepsiechirurgie.

In common with other stereotactic procedures, stereotactic laser thermocoagulation (SLT) promises gentle destruction of pathological tissue, which might become especially relevant for epilepsy surgery in the future. Compared to standard resection, no large craniotomy is necessary, cortical damage during access to deep-seated lesions can be avoided and interventions close to eloquent brain areas become possible. We describe the history and rationale of laser neurosurgery as well as the two available SLT systems (Visualase® and NeuroBlate®; CE marks pending). Both systems are coupled with magnetic resonance imaging (MRI) and MR thermometry, thereby increasing patient safety. We report the published clinical experiences with SLT in epilepsy surgery (altogether approximately 200 cases) with respect to complications, brain structural alterations, seizure outcome, neuropsychological findings and treatment costs. The rate of seizure-free patients seems to be slightly lower than for resection surgery. Due to the inadequate quality of studies, the neuropsychological superiority of SLT has not yet been unambiguously demonstrated.

Suspected antibody negative autoimmune limbic encephalitis: outcome of immunotherapy.

OBJECTIVES: Whether and when to immunologically treat epilepsy patients with suggested autoantibody (AB)-negative limbic encephalitis (LE) is clinically challenging. Therefore, we evaluated the clinical outcome and eventual outcome predictors of immunotherapy in a group of AB-negative patients with recent-onset temporal lobe epilepsy (TLE), magnetic resonance imaging (MRI) indicators of LE, subjective cognitive decline, and/or psychiatric symptoms. METHODS: This retrospective, observational, uncontrolled study monitored 28 TLE patients with suggested AB-negative LE along with methylprednisolone immunotherapy. RESULTS: All patients had seizures, amygdala and/or -hippocampal enlargement, subjective cognitive decline and/or behavioral problems. Eighty-six percent (24/28) were impaired in executive or memory functions, 39% (10/25) depressed, 81% were on antiepileptic drugs when pulse therapy started. After a median follow-up of 18 months, 46% (13/28) of the patients were seizure free (>2 months), 48% (13/27) showed MRI improvements (amygdala and/or hippocampal volume reduction), cognition improved in 57% (16/28), worsened in 32% (9/28), mood improved in 14% (4/25), and deteriorated in 11% (3/25). Immunotherapy was discontinued in 75% (21/28). Clinical changes did not correlate to each other. Outcomes could not be predicted. CONCLUSION: Immunological treatment of suggested AB-negative LE showed reasonable seizure control, MRI and cognitive improvements. Treatment success was not predictable from clinical features, nor definitely attributable to immunological treatment. Lacking biomarkers for the reliable diagnosis of AB-negative LE, we suggest that in presence of mild manifestations, and after initiating antiepileptic drug therapy, negative dynamics in MRI, seizures, cognition, and behavior should be documented before immunosuppressive treatment is initiated.

Seizure control and cognitive improvement via immunotherapy in late onset epilepsy patients with paraneoplastic versus GAD65 autoantibody-associated limbic encephalitis.

OBJECTIVE: To determine the efficacy of immunotherapy in limbic encephalitis (LE) associated epilepsies with autoantibodies against intracellular antigens in the forms of paraneoplastic autoantibodies versus glutamic acid decarboxylase 65 (GAD)-autoantibodies. METHODS: Eleven paraneoplastic-antibodies+ and eleven age- and gender-matched GAD-antibodies+ patients with LE were compared regarding EEG, seizure frequency, MRI volumetry of the brain, and cognition. All patients received immunotherapy with corticosteroids add-on to antiepileptic therapy. A few patients underwent additional interventions like immunoglobulins or immunoadsorption. RESULTS: Immunotherapy led to a significantly greater proportion of seizure-free patients in the paraneoplastic antibodies+(55%) as compared to GAD-antibodies+(18%) patients (p<0.05). Impaired cognition was evident initially (total cognitive performance score based on attentional-executive function, figural/verbal memory and word fluency) in 100% of the paraneoplastic-antibodies+ and 73% of the GAD-antibodies+ group. After therapy, cognition improved significantly in the paraneoplastic-antibodies+, but not in the GAD-antibodies+ patients (p<0.05). Cognitive change did not correlate with the change in the number of antiepileptic drugs over time. MRI showed larger and unchanged volumes of the amygdala, presubiculum and subiculum in GAD-antibodies+as compared to paraneoplastic-antibodies+patients (p<0.05) over time. CONCLUSIONS: Our data provide evidence of a beneficial effect of immunotherapy added to antiepileptic drugs on seizure frequency and cognition only in the paraneoplastic-antibodies+ subgroup of LE presenting autoantibodies against intracellular antigens.

Adjunctive retigabine in refractory focal epilepsy: Postmarketing experience at four tertiary epilepsy care centers in Germany.

PURPOSE: Retigabine (RTG, ezogabine) is the first potassium channel-opening anticonvulsant drug approved for adjunctive treatment of focal epilepsies. We report on the postmarketing clinical efficacy, adverse events, and retention rates of RTG in adult patients with refractory focal epilepsy. METHODS: Clinical features before and during RTG treatment were retrospectively collected from patients treated at four German epilepsy centers in 2011 and 2012. RESULTS: A total of 195 patients were included. Daily RTG doses ranged from 100 to 1500 mg. Retigabine reduced seizure frequency or severity for 24.6% and led to seizure-freedom in 2.1% of the patients but had no apparent effect in 43.1% of the patients. Seizure aggravation occurred in 14.9%. The one-, two-, and three-year retention rates amounted to 32.6%, 7.2%, and 5.7%, respectively. Adverse events were reported by 76% of the patients and were mostly CNS-related. Blue discolorations were noted in three long-term responders. Three possible SUDEP cases occurred during the observation period, equalling an incidence rate of about 20 per 1000 patient years. CONCLUSIONS: Our results are similar to other pivotal trials with respect to the long-term, open-label extensions and recent postmarketing studies. Despite the limitations of the retrospective design, our observational study suggests that RTG leads to good seizure control in a small number of patients with treatment-refractory seizures. However, because of the rather high percentage of patients who experienced significant adverse events, we consider RTG as a drug of reserve.

Intracranial EEG correlates of implicit relational inference within the hippocampus.

Drawing inferences from past experiences enables adaptive behavior in future situations. Inference has been shown to depend on hippocampal processes. Usually, inference is considered a deliberate and effortful mental act which happens during retrieval, and requires the focus of our awareness. Recent fMRI studies hint at the possibility that some forms of hippocampus-dependent inference can also occur during encoding and possibly also outside of awareness. Here, we sought to further explore the feasibility of hippocampal implicit inference, and specifically address the temporal evolution of implicit inference using intracranial EEG. Presurgical epilepsy patients with hippocampal depth electrodes viewed a sequence of word pairs, and judged the semantic fit between two words in each pair. Some of the word pairs entailed a common word (e.g., "winter-red," "red-cat") such that an indirect relation was established in following word pairs (e.g., "winter-cat"). The behavioral results suggested that drawing inference implicitly from past experience is feasible because indirect relations seemed to foster "fit" judgments while the absence of indirect relations fostered "do not fit" judgments, even though the participants were unaware of the indirect relations. A event-related potential (ERP) difference emerging 400 ms post-stimulus was evident in the hippocampus during encoding, suggesting that indirect relations were already established automatically during encoding of the overlapping word pairs. Further ERP differences emerged later post-stimulus (1,500 ms), were modulated by the participants' responses and were evident during encoding and test. Furthermore, response-locked ERP effects were evident at test. These ERP effects could hence be a correlate of the interaction of implicit memory with decision-making. Together, the data map out a time-course in which the hippocampus automatically integrates memories from discrete but related episodes to implicitly influence future decision making.

Functional hemispherectomy: postoperative motor state and correlation to preoperative DTI.

INTRODUCTION: Functional hemispherectomy (FH) is an infrequent method to reduce seizure frequency in patients with intractable epilepsy. The risk that hemispherotomy injures brain structures involved in residual motor function is challenging to predict. Our purpose was to evaluate MR diffusion tensor imaging (DTI) to preoperatively assess residual ipsilateral motor function prior to FH. METHODS: We applied DTI in 34 patients scheduled for FH to perform fiber tracking in healthy and damaged hemispheres of the corticospinal tracts (CSTs) and of the corpus callosum. We assessed the CSTs and the commissural fibers for streamline count, for fractional anisotropy (FA), and for respective ratios (affected/unaffected side). We correlated these DTI values to post-to-prior changes of muscle strength and evaluated their diagnostic accuracy. RESULTS: FA of the affected CSTs and of commissural fibers was significantly higher in patients with postoperative loss of muscle strength compared to patients without (p = 0.014 and p = 0.008). In contrast, CST FA from healthy hemispheres was not different between both groups. Ratios of streamline counts and FA from CSTs were higher in patients with postoperative reduced muscle strength compared to those without (1.14 ± 0.22 vs. 0.58 ± 0.14, p = 0.040; 0.93 ± 0.05 vs. 0.74 ± 0.03, p = 0.003). CSTs' normalized FA ratio greater than -0.085 predicted loss of muscle strength with 80 % sensitivity and 69.6 % specificity. CONCLUSION: Preoperative tracking of the CST and of commissural fibers contributes to the prediction of postoperative motor outcome after functional hemispherectomy.

Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies.

PURPOSE: Temporal lobe epilepsy with antibodies (abs) against the glutamic acid decarboxylase 65 isoform (GAD-TLE) is known as an immune-mediated neurological syndrome. Here we evaluate the therapy response to various immunotherapies and epilepsy surgery in this syndrome. METHOD: All patients with GAD-TLE and follow-up data and stored serum and CSF samples, identified and treated at the Bonn centre from 2002 to 2010, were studied retrospectively. Seizure freedom for ≥1 year and reduction of ≥50%, i.e. therapy response, were assessed. GAD-ab titres and neuropsychological performances were documented prior and after individual interventions. RESULTS: Thirteen patients with GAD-TLE were identified with the following seizure responses: corticosteroids (5 responders out of 11 treated patients); i.v. immunoglobulins (1/5), apheresis therapy (1/8); and natalizumab (1/1), selective amygdala-hippocampectomy (2/3). None of the patients achieved sustained seizure freedom apart from one patient. This patient was on antiepileptic drug treatment after discontinuation of immunotherapy. CONCLUSION: The seizure response to immunotherapies in patients with GAD-TLE was poor. Corticosteroids were the most effective regarding seizure response. Especially the poor effects of apheresis therapies support the idea that GAD-abs are not directly pathogenic. None of three patients was seizure-free after temporal lobe surgery suggesting that GAD-TLE patients respond worse than others to this type of intervention. Our results reflect the chronic course of the disease with low likelihood for patients with GAD-TLE to attain long-term seizure freedom.

Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity.

In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab(-)). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab(+) patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen (72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab(+) patients, but in none of the CASPR-2-Ab(+) or LGI/CASPR-2-Ab(-) patients (p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab(+) patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab(+)-LE.

Temporal lobe surgery in Germany from 1988 to 2008: diverse trends in etiological subgroups.

BACKGROUND AND PURPOSE: In the epilepsy community, there is talk that the number of classical patients with early onset temporal lobe epilepsy (TLE) and Ammon's horn sclerosis (AHS) is decreasing. This is counterintuitive, considering the success story of epilepsy surgery, improved diagnostic methods and the current recommendation of early admission to surgery. In order to recognize trends, the development of temporal lobe surgery over 20 years in three major German epilepsy centers was reviewed. METHODS: Age at surgery and duration of epilepsy, which was differentiated according to histopathology (AHS, developmental, tumor, vascular), year of surgery and center, were evaluated in a cohort of 2812 patients from three German epilepsy centers who underwent temporal lobe surgery between 1988 and 2008. The analysis was carried out for the pooled cohort as well as for each center separately. RESULTS: Of all patients, 52% showed AHS. Compared with other pathologies, the AHS group had the earliest epilepsy onset and the longest duration of epilepsy. Across five time epochs, the diagnosis of AHS increased in the first epoch, remaining constant thereafter. Contrary to the trends in other pathologies, in the AHS group the mean age of patients at surgery increased by 7 years and the duration of epilepsy until surgery increased by 5 years. This trend could be replicated in all three centers. As initially hypothesized for all groups, age and duration of epilepsy in other pathology groups remained constant or indicated earlier submission to surgery. CONCLUSIONS: During the first few years studied, most probably due to progress in brain imaging, the proportion of patients with AHS increased. However, despite stable numbers over time, and contrary to the trends in other pathology groups, age and duration of epilepsy in mesial TLE with AHS (mTLE + AHS) increased over time. This supports the hypothesis of a decreasing incidence of AHS. This trend is discussed with respect to disease-modifying factors which have changed the incidence of classical mTLE + AHS or, alternatively, to recent developments in antiepileptic drug treatment, the appraisal of surgery and economic incentives for treatment options other than surgery.

Neuropsychological course of voltage-gated potassium channel and glutamic acid decarboxylase antibody related limbic encephalitis.

BACKGROUND AND PURPOSE: Autoantibodies (abs) to glutamic acid decarboxylase (GAD) and to voltage-gated potassium channels (VGKC) induce distinct courses of limbic encephalitis, related to MRI findings, seizure outcome and cognition. METHODS: A detailed analysis of the cognitive course of the two forms is presented, spanning a median time interval of 28 months, including parameters of attention, learning and memory in 15 VGKC-ab-positive and 16 GAD-ab-positive patients. RESULTS: In both groups, the initially significantly impaired attention performance recovered to a putatively premorbid level. In VGKC patients the partially severely impaired learning and memory performance improved under treatment but remained subnormal at last follow-up. By contrast, GAD-ab-positive patients had initially less impaired learning and memory scores but did not show an improvement under treatment. CONCLUSIONS: The results provide evidence of distinct relations between inductive processes and cognitive outcome in VGKC-ab-positive and GAD-ab-positive subforms of limbic encephalitis, which possibly depend on differences in pathogenic molecular mechanisms and affected cerebral loci.

Intrinsic connectivity networks and personality: the temperament dimension harm avoidance moderates functional connectivity in the resting brain.

Recent functional imaging studies that examined functional connectivity in the resting brain have demonstrated various intrinsic connectivity networks (ICNs). Certain patterns of over- and underactivity in various ICNs have been hypothesized to form the neural basis of psychiatric disorders. Furthermore, activity in the ICNs does not reflect ongoing mental activity but the maintenance of neural circuits in a ready state suggesting not only relationships between ICNs and disorders but also correlations between ICNs and personality. In the present study, we assess the relationship between trait anxiety, a well established endophenotype of anxiety disorders, and functional connectivities within the insular salience ICN in a sample of healthy female subjects. Based on a previous study that demonstrated the functional relevance of the insular salience ICN for state anxiety, we used the harm avoidance scale from the Temperament and Character Inventory (TCI) as a trait marker to demonstrate increased functional connectivity within the insular salience ICN. Specifically, the functional connectivity between the anterior insula and the anterior cingulate and between the anterior insula and the dorsolateral prefrontal cortex were positively correlated with individual harm avoidance scores. The results fit into previous work, provide evidence for a potential biomarker of anxiety disorders and, most importantly, demonstrate a direct neural correlate of the personality trait harm avoidance in the absence of external stimulation.

Impaired verbal fluency under topiramate--evidence for synergistic negative effects of epilepsy, topiramate, and polytherapy.

BACKGROUND AND PURPOSE: Treatment with topiramate (TPM) is known to negatively affect executive functions and verbal fluency in particular. However, judgments of cognitive side effects under TPM rarely consider clinical conditions and possible effects of epilepsy, treatment, and drug load. METHODS: This retrospective cross-sectional study in large cohorts of patients with epilepsy evaluated the impact of TPM mono- and polytherapy on verbal fluency. To isolate TPM-induced effects from those of epilepsy and antiepileptic medication in general, verbal fluency under TPM (N = 421) was compared to the performance of a matched sample of patients with an antiepileptic medication other than TPM (N = 351), untreated patients (N = 108), and healthy controls (N = 100). RESULTS: Impaired verbal fluency performance was seen in 77% of the patients treated with TPM. Compared to healthy controls, verbal fluency in untreated patients was reduced by 22%, under monotherapy without TPM by 31% and under TPM monotherapy by 45%. With and without TPM, verbal fluency performance linearly decreased with each additional drug in polytherapy. On each level, performance under TPM was 21-28% worse than in the respective condition without TPM. Unimpaired performance under TPM was primarily associated with lower dose, higher education, and a later onset of epilepsy. CONCLUSIONS: The majority of patients under TPM shows reduced verbal fluency. However, when taking the cumulative negative effects of epilepsy, and the concomitant drug regimen into account, TPM is associated with a 21-28% poorer performance as compared with other drugs. Additionally, the data indicate an impact of dose and reserve capacity on the occurrence of impairments.