Societal costs and quality of life analysis in patients undergoing resective epilepsy surgery: A one-year follow-up.

Although effectiveness of Resective Epilepsy Surgery (RES) for patients with drug-resistant epilepsy (DRE) is widely proven, research on the impact of societal costs (SC) is lacking. The aim of this study is to provide both clinical and economic outcomes of RES by offering an overview of treatment effectiveness as well as SC of RES in a cohort of 30 Dutch DRE patients. This project serves as a pilot project to offer an up-to-date model for larger cost-effectiveness studies. Medical consumption, productivity losses, disease-specific and generic health-related quality of life (QoL), and seizure frequency were assessed before and 3-, 6-, and 12-months post-surgery with validated questionnaires. Linear mixed models, ANOVAs, and logistic regressions were performed. SC for the first year after RES entailed €54,376 and decreased over time. Moreover, 50% of patients experienced a clinically important increase in disease-specific QoL and 53% of patients in generic health-related QoL. Lastly, 73% of patients reached seizure freedom 12 months postoperative. Seizure reduction was correlated with increase in disease-specific QoL. Within one year after surgery, RES leads to reduction in SC and improvements in QoL over time. Future research should encompass longer follow-up periods, larger sample size, and a cost-effectiveness analysis with a comparator.

QUality of life and Economic evaluation after neuroSTimulation for Epilepsy (QUESTE) in adolescents and adults with drug-resistant epilepsy: protocol for a multicentre, prospective observational cohort study in The Netherlands.

INTRODUCTION: Epilepsy is one of the most common chronic neurological disorders. Antiseizure medication (ASM) is the first choice of treatment, however, 30% of epilepsy patients are drug-resistant. For these patients, neuromodulation can be an option, especially when epilepsy surgery is not possible or did not lead to seizure freedom. Epilepsy is associated with reduced quality of life (QoL), which heavily depends on seizure control.The most recent Cochrane reviews have shown that vagus nerve stimulation and deep brain stimulation of the anterior nucleus of the thalamus, lead to a responder rate OR of, respectively, 1.93 and 1.20. The question arises if neuromodulation for drug-resistant epilepsy (DRE) will be more cost-effective than sole treatment with ASM. The current study aims to determine the change in QoL after neuromodulation. Secondarily, we will aim to study the cost-effectiveness of these treatments. METHODS AND ANALYSIS: This prospective cohort study aims at including 100 patients aged 16 or above who will be referred for neuromodulation, from January 2021 to January 2026. After informed consent, QoL and other relevant parameters will be assessed at baseline, 6 months, 1, 2 and 5 years after surgery. Data on seizure frequency will be derived from patient charts. We expect that DRE patients will report better QoL after neuromodulation. Even if they would still report seizures, the treatment can be seen as useful. This is especially true when patients can participate in society again to a greater extent than before treatment. ETHICS AND DISSEMINATION: The board of directors of participating centres all gave permission for this study to commence. The medical ethics committees decided that this study does not fall under the Medical Research Involving Human Subjects Act (WMO). The findings of this study will be presented at (inter)national conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL9033.

Effectiveness and tolerability of lacosamide in children with drug resistant epilepsy.

We retrospectively studied the efficacy and tolerability of lacosamide (LCM) in children with drug-resistant epilepsy in a tertiary care centre in the Netherlands, from 2013 till 2019, with a follow-up of two years. 79 children, aged < 18 years, were included. Retention rate, effectiveness, reason for termination, and side-effects were analysed. Furthermore, prognostic variables for discontinuation as well as the incidence of side-effects were determined. The LCM retention rate and effectiveness of response were analysed at three, twelve and twenty-four months. The retention rate of LCM was respectively 89.9 %, 68.4 % and 54.4 %. LCM gave an effective response in 60.5 %, 67.9 % and 71.4 % of the participants who were still using LCM at the three follow-up periods. Lack of efficacy was most frequently reported as a reason for discontinuation (58.3 %). Side-effects occurred in 50.6 % of the patients, somnolence (18.2 %) being the most common, followed by behavioural changes (15.6 %), headache (9.1 %) and dizziness (9.1 %). Use of ≥ 1 sodium channel blocker (SCB) was associated with an increased risk (OR = 4.038) of side-effects. An increasing number of anti-seizure medications (ASM) was associated with a reduced risk (OR = 0.524) of stopping LCM. To conclude, LCM is an effective ASM with acceptable side-effects in children with drug-resistant epilepsy.

Assessment of Trabecular Bone Score: a 7-year follow-up study in institutionalized adults with refractory epilepsy and intellectual disability.

PURPOSE: The aim of this longitudinal study was to assess trabecular bone scores (TBS) in institutionalized adults with refractory epilepsy and intellectual disability and to study the association of TBS and incident fractures during seven years of follow-up. METHODS: In 2009 and 2016, all institutionalized adult patients of a long-stay care facility in the Netherlands (n=261) were invited to undergo a dual-energy X-ray absorptiometry (DXA) including vertebral fracture assessment (VFA) and assessment of TBS. Vertebrae T4-L4 were analyzed using quantitative morphometry. New and worsening vertebral fractures (VFs) were considered as incident VFs. Data regarding clinical fractures were extracted from the medical files. Patients were treated with anti-osteoporosis medication according to the Dutch guideline. RESULTS: Baseline and follow-up DXA, VFA and TBS could be obtained in 136 patients (83 male) aged between 18 and 79 years old (44.7±15.5). At baseline, 36 patients (26.5%) were diagnosed with osteoporosis, 68 (50.0%) with osteopenia and 32 patients (23.5%) had a normal bone mineral density (BMD). As for TBS, 26 patients (19.1%) had a partially degraded microarchitecture and 26 patients (19.1%) a degraded microarchitecture. During seven years of follow-up, 80 patients (59%) sustained at least one fracture, of which 28 patients (35%) had one or more major osteoporotic fractures. Thirty-four patients (25.0%) had at least one new or worsening morphometric VF. Compared to baseline, TBS significantly decreased over seven years of follow-up in non-treated patients (-0.039±0.064, p<.001). In patients who were treated with bisphosphonates for more than one year during follow-up, TBS did not change significantly (p=.093). In multivariate analyses, no significant associations were found between TBS at baseline and incident fractures during follow-up. CONCLUSION: In this study, we found a high incidence of fractures and TBS decreased significantly over seven years of follow-up in non-treated institutionalized adult patients with refractory epilepsy and intellectual disability, but TBS was not associated with incident fractures.

Bone mineral density and fractures in institutionalised children with epilepsy and intellectual disability.

BACKGROUND: Long-term use of antiseizure drugs is associated with a low bone mineral density (BMD) and an increased fracture risk. The literature regarding institutionalised children on chronic antiseizure drugs is limited. Therefore, the aim of this cross-sectional study is to evaluate the prevalence of low BMD and the history of fractures in institutionalised children with epilepsy and intellectual disability (ID). METHODS: A dual-energy X-ray absorptiometry of lumbar spine (L1-L4) and hip was performed in 24 children, residing in a long-stay care facility in the Netherlands. Additionally, serum concentrations of albumin, calcium and 25-hydroxyvitamin D were determined. Data on fractures were retrospectively extracted from the medical files. RESULTS: Ages of the children (14 male and 10 female) ranged from 5 to 17 years with a mean age of 13.0 (±3.2). The criteria of the International Society for Clinical Densitometry (ISCD) were used for classification of bone mineral disorders. Eight (33.3%) children had a normal BMD (Z-score > - 2.0). Of the 16 children with a low BMD (Z-score ≤ - 2.0), three were diagnosed as osteoporotic, based on their fracture history. Ten children (41.7%) were reported to have at least one fracture in their medical history. Serum concentrations of albumin-corrected calcium (2.28-2.50 mmol/L) and (supplemented) vitamin D (16-137 nmol/L) were within the normal range. CONCLUSIONS: This study demonstrated that 67% of institutionalised children with epilepsy and ID had low BMD and 42% had a history of at least one fracture, despite supplementation of calcium and vitamin D in accordance with the Dutch guidelines.

Incidence of clinical fractures: A 7-year follow-up study in institutionalized adults with epilepsy and intellectual disability.

PURPOSE: To determine the incidence of clinical fractures over seven years of follow-up, in adults with epilepsy and intellectual disability, residing in a long-stay care facility. METHODS: In 2009, all institutionalized adult patients (n = 261) were invited to undergo a Dual-energy X-ray Absorptiometry (DXA) measurement and a Vertebral Fracture Assessment (VFA). Participants were followed over seven years or until date of discharge (in case of moving from the care facility) or date of death. The patients' medical files were screened for radiology reports and staff notes, to identify clinical fractures. Fracture incidence rates (IR) were determined and compared for subgroups, by calculating incidence rate ratios. Hazard ratios were calculated to identify factors associated with fracture risk, using Cox Proportional Hazards analyses. RESULTS: A total of 205 patients (124 male, 60.5%) aged between 18 and 88 years (median 48, IQR 34-60) were enrolled. At baseline, 92 patients (44.9%) were diagnosed with osteopenia and 65 (31.7%) with osteoporosis. Between 2009 and 2016, 30 patients (14.6%) deceased and 3 patients (1.5%) left the care facility. During follow-up, 156 clinical fractures were reported in 82 patients (40.0%). Thirty-eight patients (18.5%) had at least one major osteoporotic fracture. Overall, the IR was 11.6 fractures per 100 person-years. Fracture risk was significantly lower in patients who were wheelchair dependent than in patients who were able to walk (p<.001). CONCLUSION: This study demonstrated that 40% of institutionalized adults with epilepsy and intellectual disability had at least one clinical fracture during seven years of follow-up, despite adequate anti-osteoporosis treatment.

Quantitative ultrasound for monitoring bone status in institutionalized adults with refractory epilepsy and intellectual disability: A 7-year follow-up study.

PURPOSE: Long-term exposure to anti-epileptic drugs has been shown to decrease bone mineral density (BMD). The aim of this 7-year follow-up study was to explore changes in bone status, using quantitative ultrasound (QUS) and Dual-energy X-ray Absorptiometry (DXA) in adults with refractory epilepsy and intellectual disability (ID) residing at a long-term care facility. Both measurements can be challenging to conduct in this population. METHODS: In 2009 and 2016, a total of 126 patients (18-79 years) underwent QUS of the heel and DXA of lumbar spine (LS) and hip (femoral neck (FN) and total hip (TH)). Subgroup analysis was performed for patients with (group A, n = 53) and without (group B, n = 73) bisphosphonate use during follow-up. RESULTS: Overall, weak to moderate correlations between changes in DXA and QUS parameters were found. For group A, correlations varied from r = .31 to .59, whereas correlations did not exceed r = .40 in group B. Patients in group A showed a larger increase or a smaller decrease in BMD for all DXA regions during follow-up (p < .001 for ΔLS and ΔFN BMD, p = .001 for ΔTH BMD). For change in QUS parameters, no significant difference between groups was found. CONCLUSION: In this study we demonstrated the limited use of QUS in the monitoring of bone status in our study population. Although correlations between changes in QUS parameters and axial DXA are positive and mostly significant, QUS only explains little of the variability in DXA values and is inadequate for measuring treatment response in this population.

The retention of lacosamide in patients with epilepsy and intellectual disability in three specialised institutions.

PURPOSE: We describe the effectiveness of lacosamide as adjunctive therapy in patients with epilepsy and an intellectual disability. This information is relevant, as few data exist pertaining to this population with a high prevalence of (intractable) epilepsy. METHODS: We performed a retrospective study in three specialised institutions. Inclusion criteria were (1) focal onset or symptomatic generalized (2) therapy-resistant epilepsy, (3) intellectual disability and (4) residence in a care-facility for people with intellectual disabilities (PWID). The primary outcome variables were the retention rates of lacosamide, estimated through Kaplan-Meier survival analysis. Secondary outcomes were reported seizure control, side effects and clinical factors influencing discontinuation. RESULTS: One hundred and thirty-two patients were included. The median retention time of lacosamide in our cohort was four years. The estimated one-, two- and three-year retention rates of lacosamide were 64%, 57% and 56% respectively. Severity of intellectual disability and seizure type did not influence whether lacosamide was continued. In 48.5% of patients, a reduction of seizure activity was reported. Side effects were at least part of the reason for discontinuing treatment in 26.5% of all patients. Common side effects were tiredness/somnolence (in 30.3%), aggression/agitation (24.2%), and instable gait (15.2%). Five deaths during follow-up were considered unlikely to be related to the use of lacosamide. One patient died unexpectedly within two months of treatment onset, probably this was a case of SUDEP. CONCLUSION: These retention rates of lacosamide in PWID are similar to rates of previously registered anti-epileptic drugs in PWID. Behavioural side effects were noted in a high proportion compared to the general literature on lacosamide. Other side effects were in line with this literature. Lacosamide seems effective and safe for PWID and refractory epilepsy.

A randomized controlled trial of the ketogenic diet in refractory childhood epilepsy.

OBJECTIVE: To evaluate the efficacy and tolerability of the ketogenic diet (KD) during the first 4 months of a randomized controlled trial (RCT) in refractory epilepsy patients aged 1-18 years. METHODS: Children and adolescents with refractory epilepsy, not eligible for epilepsy surgery, were included. Following 1 month at baseline, patients were randomized to either the KD or to care as usual (CAU).Primary outcome is the proportion of patients with at least 50% reduction in seizure frequency at 4 months. Secondary outcomes are mean percentage of baseline seizures, seizure severity, and side effects. RESULTS: Fifty-seven patients were randomized; nine dropped out, leaving 48 for analysis (i.e., 26 KD, 22 CAU). In an intention-to-treat analysis, 13 patients (50%) treated with the KD and four patients (18.2%) of the CAU group were responders.Mean seizure frequency at 4 months compared to baseline, after removal of two outliers in the KD group, was significantly lower (P = 0.024) in the KD group (56%) (95% CI: 36-76) than in the CAU group (99%) (95% CI: 65-133%).Twice as many patients in the KD group had a relevant decrease in seizure severity score (P = 0.070).Patients treated with the KD had a significantly higher score for gastrointestinal symptoms (P = 0.021) without an increase in the total score of side effects. CONCLUSIONS: This trial provides class I evidence that the KD is an effective therapy in children and adolescents with refractory epilepsy compared with CAU. Most often reported side effects are gastrointestinal symptoms.The study has been registered with the Netherlands Trial Registry (NTR2498).

Cognitive effects of lacosamide as adjunctive therapy in refractory epilepsy.

BACKGROUND: Lacosamide (LCM) is a novel antiepileptic drug (AED) with potential benefit as adjunctive treatment in patients with partial-onset seizures. As yet, limited information on cognitive effects of LCM is available, especially in real-life settings. AIMS: In this open clinical prospective study, the cognitive effects of LCM were evaluated when used as adjunctive antiepileptic therapy in patients with refractory epilepsy. METHODS: We included 33 patients aged between 16 and 74 years (mean: 37 years). All patients had a localization-related epilepsy. Patients were assessed at baseline before starting LCM treatment and during follow-up when the optimal clinical dose was achieved. MATERIALS: Subjective complaints were evaluated using the SIDAED; effects on cognition were evaluated using the computerized visual searching task (CVST). RESULTS: The CVST showed significant faster information processing reaction times at the second evaluation (P = 0.013), which was not correlated with seizure control, type of epilepsy, age, gender, drug load, number of concomitant drugs, dose or duration of LCM treatment. On the SIDAED, patients complained more about their cognitive function at the second evaluation (P = 0.005). For the SIDAED, a positive correlation at follow-up was found between the total severity score and higher age (r = 0.375, P = 0.031), but not with epilepsy factors or treatment characteristics. DISCUSSION/CONLUSION: Screening of the cognitive effects of LCM showed that LCM does not have negative effects on information processing speed. As this is the most sensitive function for cognitive side effects of AEDs, LCM does not seem to induce the common negative cognitive effects. Remarkably, patients complained more, especially about their cognitive function, which is possible the 'doing better, feeling worse phenomenon'.

The effects of vagus nerve stimulation on tryptophan metabolites in children with intractable epilepsy.

BACKGROUND: The mechanism of action of vagus nerve stimulation (VNS) in intractable epilepsy is not entirely clarified. It is believed that VNS causes alterations in cytokines, which can lead to rebalancing the release of neurotoxic and neuroprotective tryptophan metabolites. We aimed to evaluate VNS effects on tryptophan metabolites and on epileptic seizures and investigated whether the antiepileptic effectiveness correlated with changes in tryptophan metabolism. METHODS: Forty-one children with intractable epilepsy were included in a randomized, active-controlled, double-blind study. After a baseline period of 12 weeks, all children underwent implantation of a vagus nerve stimulator and entered a blinded active-controlled phase of 20 weeks. Half of the children received high-output (therapeutic) stimulation (n=21), while the other half received low-output (active control) stimulation (n=20). Subsequently, all children received high-output stimulation for another 19 weeks (add-on phase). Tryptophan metabolites were assessed in plasma and cerebrospinal fluid (CSF) by use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared between high- and low-output groups and between the end of both study phases and baseline. Seizure frequency was recorded using seizure diaries. Mood was assessed using Profile of Mood States (POMS) questionnaires. RESULTS: Regarding tryptophan metabolites, anthranilic acid (AA) levels were significantly higher at the end of the add-on phase compared with baseline (p=0.002) and correlated significantly with improvement of mood (τ=-0.39, p=0.037) and seizure frequency reduction (τ=-0.33, p<0.01). No significant changes were found between high- and low-output groups regarding seizure frequency. CONCLUSION: Vagus nerve stimulation induces a consistent increase in AA, a neuroprotective and anticonvulsant tryptophan metabolite. Moreover, increased AA levels are associated with improvement in mood and reduction of seizure frequency.

The influence of neuropathology on brain inflammation in human and experimental temporal lobe epilepsy.

It is unclear to what extent neuropathological changes contribute to brain inflammation observed in temporal lobe epilepsy (TLE). Here, we compared cytokine levels between histopathologically-confirmed sclerotic hippocampi and histopathologically-confirmed normal hippocampi from TLE patients. We analyzed a similar cytokine panel in the hippocampi of amygdala-kindled rats and we evaluated neuropathological changes by immunohistochemistry. In TLE patients, cytokine levels were not significantly different between sclerotic and non-sclerotic hippocampi. Though kindling resulted in increased astrocyte activation, cytokine levels and microglia activation were unchanged. These results suggest that the chronic epileptic state in TLE can also occur in the absence of intracerebral inflammation. Highlights.

Rat vagus nerve stimulation model of seizure suppression: nNOS and ΔFos B changes in the brainstem.

Vagus nerve stimulation (VNS) is a moderately effective treatment for intractable epilepsy. However, the mechanism of action is poorly understood. The effect of left VNS in amygdala kindled rats was investigated by studying changes in nNOS and ΔFos B expression in primary and secondary vagus nerve projection nuclei: the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve (DMV), parabrachial nucleus (PBN) and locus coeruleus (LC). Rats were fully kindled by stimulation of the amygdala. Subsequently, when the fully kindled state was reached and then maintained for ten days, rats received a single 3-min train of VNS starting 1min prior to the kindling stimulus and lasting for 2min afterwards. In control animals the vagus nerve was not stimulated. Animals were sacrificed 48h later. The brainstems were stained for neuronal nitric oxide synthase (nNOS) and ΔFos B. VNS decreased seizure duration with more than 25% in 21% of rats. No VNS associated changes in nNOS immunoreactivity were observed in the NTS and no changes in ΔFos B were observed in the NTS, PBN, or LC. High nNOS immunopositive cell densities of >300cells/mm(2) were significantly more frequent in the left DMV than in the right (χ(2)(1)=26.2, p<0.01), independent of whether the vagus nerve was stimulated. We conclude that the observed nNOS immunoreactivity in the DMV suggests surgery-induced axonal damage. A 3-min train of VNS in fully kindled rats does not affect ΔFos B expression in primary and secondary projection nuclei of the vagus nerve.

Vagus nerve stimulation has a positive effect on mood in patients with refractory epilepsy.

BACKGROUND: Preliminary research on the efficacy of vagus nerve stimulation (VNS) indicated additional effects on neuropsychological variables like mood and quality of life (QOL). OBJECTIVES: The objectives of this prospective longitudinal observational cohort study were to assess the effects of VNS on mood, QOL and cognition in patients with refractory epilepsy and to determine whether these effects occur dependent of seizure control. METHODS: We included 41 patients with refractory epilepsy; treated with VNS as part of usual patient care. A neuropsychological battery was performed during baseline and repeated after 6 months of VNS in order to compare neuropsychological variables before and after VNS. All patients completed seizure diaries. RESULTS: Significant improvements were observed for both mood and QOL after 6 months of VNS; based on the results in the POMS and QOLIE-89 questionnaires (p<0.05). There was no significant change in cognition. Mean percentage change in seizure frequency was -9.0%, while 20% of the patients achieved a seizure frequency reduction of 50% or more. No significant correlation was found between changes in seizure frequency and improvements in mood or QOL. CONCLUSIONS: VNS is associated with improvements in both mood and QOL in patients with refractory epilepsy. Since these improvements appeared to be independent of seizure control, the results of this study indicate an additional antidepressant effect of VNS, which can be of extra value in view of the high co-morbidity of mood disturbances in patients with epilepsy.

Loss of network efficiency associated with cognitive decline in chronic epilepsy.

OBJECTIVE: To study the relation between possibly altered whole brain topology and intellectual decline in chronic epilepsy, a combined study of neurocognitive assessment and graph theoretical network analysis of fMRI was performed. METHODS: Forty-one adult patients with cryptogenic localization-related epilepsy and 23 healthy controls underwent an intelligence test and fMRI with a silent-word generation paradigm. A set of undirected graphs was constructed by cross-correlating the signal time series of 893 cortical and subcortical regions. Possible changes in cerebral network efficiency were assessed by performing graph theoretical network analysis. RESULTS: Healthy subjects displayed efficient small world properties, characterized by high clustering and short path lengths. On the contrary, in patients with epilepsy a disruption of both local segregation and global integration was found. An association of more pronounced intellectual decline with more disturbed local segregation was observed in the patient group. The effect of antiepileptic drug use on cognitive decline was mediated by decreased clustering. CONCLUSIONS: These findings support the hypothesis that chronic localization-related epilepsy causes cognitive deficits by inducing global cerebral network changes instead of a localized disruption only. Whether this is the result of epilepsy per se or the use of antiepileptic drugs remains to be elucidated. For application in clinical practice, future studies should address the relevance of altered cerebral network topology in prediction of cognitive deficits and monitoring of therapeutic interventions.

Vagus nerve stimulation in refractory epilepsy: effects on pro- and anti-inflammatory cytokines in peripheral blood.

OBJECTIVE: The vagus nerve has important immunological functions that may be relevant for its anticonvulsive action. We postulate that this anticonvulsive action is activated by a shift in the immune system resulting in a reduction of neurotoxic and an increase of neuroprotective tryptophan metabolites. METHODS: Eleven patients with refractory epilepsy and 11 controls matched for age and gender were included in this study. The primary outcome measure was a 50% seizure reduction. Other variables were pro-inflammatory cytokines IL-6 and TNF-α, anti-inflammatory cytokine IL-10, cortisol, and the tryptophan metabolites 3-hydroxykynurenine (3-OH-KYN), kynurenic acid (KYNA), kynurenine, serotonin (5-HT) and 5-hydroxyindol acetic acid (5-HIAA). Blood samples were scheduled during baseline, and in week 28 of add-on treatment. RESULTS: IL-6 levels were higher in the responders than in the control group, and decreased after vagus nerve stimulation (VNS), whereas IL-10 was low and increased after VNS. In nonresponders, VNS resulted in an increase of IL-6 plasma levels and in a decrease of IL-10. Cortisol concentrations are higher in the epilepsy group than in the control group. After VNS, these concentrations decreased. The concentrations of the tryptophan metabolites were lower in the epilepsy group than in the control group. The KYNA ratios are defined as the ratio of neuroprotective KYNA versus neurotoxic 3-OH-KYN and KYNA versus neurotoxic kynurenine: these ratios were lower in epilepsy patients than in controls, and they both moderately increased after VNS. CONCLUSION: The outcome of this preliminary study indicates that VNS causes a rebalancing of the immune system. This results in: (1) a reduction of neurotoxic and an increase of neuroprotective kynurenine metabolites and (2) in the normalization of cortisol levels.

Functional connectivity and language impairment in cryptogenic localization-related epilepsy.

BACKGROUND: An often underestimated cognitive morbidity in patients with epilepsy is language dysfunction. To investigate the neuronal mechanisms underlying neuropsychological language impairment, activation maps and functional connectivity networks were studied by fMRI of language. METHOD: Fifty-two patients with cryptogenic localization-related epilepsy and 27 healthy controls underwent neuropsychological assessment of IQ, word fluency, and text reading. fMRI was performed with a standard covert word-generation and text-reading paradigm. Functional connectivity analysis comprised cross-correlation of signal time series of the characteristic and most strongly activated regions involved in the language tasks. RESULTS: After careful selection, 34 patients and 20 healthy controls were found eligible for analysis. Patients displayed lower IQ, lower fluency word count, and lower number of words correctly read compared to controls. fMRI activation maps did not differ significantly between patients and controls. For the word-generation paradigm, patients with epilepsy had significantly lower functional connectivity than controls in the prefrontal network. Patients performing worse on the word-fluency test demonstrated a significantly lower mean functional connectivity than controls. Text reading demonstrated lower functional connectivity in patients with epilepsy in the frontotemporal network. Similarly, lower mean functional connectivity was observed in patients with lowest reading performance compared to controls. A relation between reduced functional connectivity and performance on word-fluency and text-reading tests was demonstrated in epilepsy patients. CONCLUSION: Impaired performance on language assessment in epilepsy patients is associated with loss of functional connectivity in the cognitive language networks.