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Purpose: To evaluate risk factors for drug resistance and polypharmacy in patients with temporal lobe epilepsy., Methods: Patients with temporal lobe epilepsy, treated for more than 5 years, completed questionnaires on antiepileptic drug use and effect. Logistic regression models were used for analysis of risk factors., Results: Of 135 patients included in the study, 65% were classified as drug resistant and 41% identified as using polypharmacy. Poor effects associated with first-choice antiepileptic drug were reported by 59% of the patients, and 70% reported poor effects of second-line treatment. The most frequently used first-generation antiepileptic drugs had a similar mean effect to those of second-generation. Univariate regression analyses showed a significant association between drug resistance and mesial temporal sclerosis, seizure onset below 18 years, and lack of family history of epilepsy. However, multivariate regression analysis showed no association with any demographic or clinical features. Unsuccessful treatment with the first antiepileptic drug increased the risk of drug resistance by 18 times, and the risk of poor effect from the second antiepileptic drug by 9 times. Disease duration was associated with annual risk for drug resistance of 7% and for polypharmacy of 5%., Conclusions: A poor effect from initial pharmacotherapy is the only early risk factor for drug resistance found in this study. Long disease duration increases the risk of drug resistance and polypharmacy. Second-generation antiepileptic drugs provide no additional effect for poor responders to first-generation drugs., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Sudden unexpected death in epilepsy (SUDEP) primarily affects young adults and is the leading cause of death related directly to seizures. High frequency of generalized tonic-clonic seizures is the most important risk factor, and effective seizure protection is probably the most important measure to prevent these tragic deaths. For several years a potential role of antiepileptic drugs (AEDs) has been discussed, but at present there is wide agreement that choice of AED therapy does not influence the risk. However, although it is well known that the efficacy and safety profiles of AEDs may differ significantly when used in the treatment of genetic epilepsy compared to symptomatic or cryptogenic epilepsy, this has generally been overlooked in epidemiologic studies of possible relationships between AEDs and SUDEP. Consequently important information about drug safety may have been lost. This review challenges the current view that no AED can increase the risk of SUDEP., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The reasons why the mortality of patients with epilepsy is significantly increased, even many years after seizure onset, are not fully understood. The aim of this study was to compare the distribution of the causes of death (COD) in an epilepsy population with that in the general population and with previous findings in other epilepsy populations. In addition, we investigated the chronological relationship between the onset of epilepsy and the onset of the diseases leading to death., Methods: The COD for patients who were registered with a diagnosis of epilepsy at Stavanger University Hospital from August 1 1995-July 31 2005 and died during the same period were obtained from the Norwegian Cause of Death Registry and the hospital records were reviewed. The distribution of the corresponding COD in the general population was obtained from Statistics Norway., Results: At least 6.8% (18/266) of the deaths of epilepsy patients were directly related to seizures. Epilepsy patients who had died from brain tumors (n=46) were excluded from further analysis. Of the remaining 220 deceased epilepsy patients, 39 (17.7%) had died from heart disease, compared with 27.8% in the general population (p<0.001). No other significant differences in the distribution of COD in the epilepsy population and the general population were identified. The majority of the epilepsy patients who died from heart disease (71.8%) and cerebrovascular disease (72%) had cardiovascular disease prior to seizure onset and in at least 43% of those who died from neoplasms the onset of malignancy occurred before the first seizure., Conclusion: Comorbid diseases and underlying conditions were the major determinants of mortality in this population of epilepsy patients. Conditions that are not caused by epilepsy or its treatment may represent an important explanation for the previously documented excess mortality in people with epilepsy., (Copyright © 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Pharmacoresistance continues to be a major challenge in Temporal Lobe Epilepsies (TLE). A key to overcome pharmacoresistance is to identify subgroups among the TLE and disclose their specific molecular pathways. This will facilitate a tailored pharmacological treatment and improve outcome. There is growing evidence in favor of the theory that TLE with childhood febrile seizures (TLE-FS) may represent one distinctive subgroup among the TLE., Material and Methods: We compared clinical features from 102 TLE-FS patients with 105 TLE patients without FS. We also conducted a logistic regression analysis to adjust for possible confounders caused by overrepresentation of patients with Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) in the TLE-FS group., Results: MTLE-HS was overrepresented in patients with TLE-FS (p=0.043). Age at epilepsy onset was lower in patients with TLE-FS (p<0.001). TLE-FS patients had a higher frequency of first grade family members with FS (p=0.003, adjusted for MTLE-HS: p=0.002). They were more frequently plagued with simple partial seizures (p=0.015, adjusted: p=0.038), and especially with vertiginous symptoms (p=0.004 adjusted: p=0.006). They also had the higher frequency of autonomic symptoms (p=0.003; adjusted: p=0.012), and more generalized tonic-clonic seizures (0.034; adjusted p=0.038)., Conclusion: We identified TLE-FS as a phenotype that can be delineated from other TLE. None of the characteristics are specific, but we disclosed a set of features also when adjusted for MTLE-HS., (Copyright © 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Neuroplasticity can be defined as the ability of the brain to adapt to environmental impacts. These adaptations include synapse formation and elimination, cortical reorganization, and neurogenesis. In epilepsy these mechanisms may become detrimental and contribute to disease progression. It has been proposed that Matrix Metalloproteinase 9 (MMP-9), a proteinase that cleaves extracellular matrix molecules, may be critically involved in aberrant synaptic formation in hippocampi of patients with Temporal Lobe Epilepsy (TLE). Here we present a case-control study designed to identify possible variants of the MMP-9 gene associated with human TLE., Material and Methods: 218 Norwegian patients with TLE and 181 ethnically matched controls were compared in our association analysis. We also studied associations within two subgroups of TLE--Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS), and Temporal Lobe Epilepsy with childhood Febrile Seizures (TLE-FS). Single nucleotide polymorphisms (SNPs) were selected from HapMap and dbSNP databases for the MMP-9 gene on chromosome 20. We used standard haplotype analysis and multivariate explorative analysis., Results: There were no statistically significant associations between the analyzed SNPs in the MMP-9 gene and TLE, nor were any significant associations found with the two examined subgroups MTLE-HS and TLE-FS, confirmed by both analyses., Conclusion: We could not identify any polymorphisms of the human MMP-9 gene that were associated with TLE, MTLE-HS or TLE-FS, in the selected SNPs. However, factors that influence MMP-9 gene expression, post-transcriptional modifications, or the balance between activation and inhibition of MMP-9 may play a role in the pathogenesis of TLE and other epileptic syndromes., (2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Most studies of quality of life (QOL) in seizure-free epilepsy patients suggest normal or near-normal function. Previous studies on QOL in well-controlled epilepsy have not investigated determinants for QOL from a database that includes a wide range of health related and epilepsy related variables, as well as demographical data, neuropsychological data, data from a comprehensive personality inventory and results from a QOL-questionnaire. Thus, the aim of this study was to analyze predictors of QOL based on such a range of variables., Methods: Adults with epilepsy on antiepileptic (AED) monotherapy and without epileptic seizures for at least 2 years (n=158) were assessed with the QOLIE-89., Results: The main findings were that QOL in well-controlled epilepsy patients was in the normal range and that presence of substantial health related concerns was a significant predictor of poor QOL., Discussion: The findings that substantial health concerns predict poor QOL may have clinical implications, as seizure-free epilepsy is a relatively benign condition, and careful information and counselling about this may alleviate health concerns and improve quality of life.

Many idiopathic epilepsies have been shown to be caused by ion channel dysfunction. Channelopathies also cause the long QT syndrome (LQTS) which is associated with syncopes and sudden cardiac death. It has been postulated that the same channelopathy may be associated with both epilepsy and LQTS. We report a patient with idiopathic epilepsy who died in sudden unexpected death in epilepsy (SUDEP) at the age of 25. A post mortem DNA sequencing of the LQTS-associated genes revealed a novel missense mutation in the SCN5A gene coding for the cardiac sodium channel, voltage gated, type V, alpha subunit. The possibility that the mutation may explain both the epilepsy and the sudden death is discussed. However, the patient was treated with lamotrigine which may interfere with cardiac ion channels and may also have played a part in inducing a terminal cardiac arrhythmia.

Purpose: Risk of depression, anxiety, and reduced quality of life is elevated in epilepsy patients, due to a range of factors including aetiology, structural brain lesions, seizure worry, epilepsy surgery, hereditary factors, psychosocial factors, and possible adverse effects of antiepileptic drugs (AEDs). Studies on the relationships between epilepsy-related variables and behavioural adjustment have been mainly conducted on patients with persisting seizures, whereas the present study investigated behavioural function in epilepsy patients seizure-free for more than 2 years on monotherapy., Methods: Adults with epilepsy on AED monotherapy and without epileptic seizures for at least 2 years (n=126) were assessed with the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), in addition to MRI and EEG., Results: Group analysis found mean MMPI-2 scores on all the clinical and content scales to be within the normal range. Abnormally elevated scores on scales measuring aspects of depression, health-related concerns, low self-esteem, negative treatment indicators, and physical complaints were recorded in a higher proportion of patients than would normally be expected. Multiple regression analysis showed that MRI pathology was a significant predictor for an abnormally poor score on the low self-esteem scale, and that epilepsy onset

Hormonal fluctuations in the menstrual cycle have been shown to have an impact on the epilepsy in women with catamenial epilepsy. The epilepsy frequency is higher in the elderly, and this part of the population is steadily increasing. It is therefore of interest whether the hormonal changes in the menopausal transition affects the epilepsy. The perimenopause is associated with hormonal fluctuations and may worsen the epilepsy in women with catamenial epilepsy. It has been suggested that seizures may improve after menopause, particularly in the women with catamenial epilepsy. There is still however, limited data on the effects of menopause on the epilepsy. Prospective studies imply a long time span, and research in this field is scarce. More research on the relationship between hormonal fluctuations and seizures may enable us to predict the effect on the epilepsy. Special awareness should be given to a woman with epilepsy in the menopausal transition.

Purpose: Several antiepileptic drugs (AEDs) induce changes in endocrine function in women with epilepsy. Levetiracetam (LEV) is one of the newer AEDs, and to date no endocrine side-effects have been reported in humans. However, a recent study on ovarian follicular cells from prepubertal pigs showed that LEV affected basal steroid hormone secretion. The aim of the present study was to investigate possible effects of the drug on endocrine function and ovarian morphology in non-epileptic rats., Methods: Thirty female Wistar rats were fed per-orally with either 50mg/kg LEV (n=15) or 150 mg/kg LEV (n=15) twice daily for 90-95 days. Twenty rats received a control solution. The rats were killed in the dioestrus phase of the oestrous cycle. Serum concentrations of testosterone, 17beta-oestradiol, progesterone, follicle stimulating hormone (FSH), luteinizing hormone (LH) and LEV were measured, and the ovaries examined histologically., Results: Mean ovarian weight showed a significant, dose-dependent increase after LEV treatment. Mean numbers of ovarian follicular cysts were not changed, but the numbers of corpora lutea and secondary follicles were significantly higher in the treated animals. Serum testosterone was significantly increased in treated animals (0.50 nmol/l versus 0.16 nmol/l in controls, p<0.05), while oestradiol was reduced (67.4 compared to 257.5 pmol/l in controls, p<0.05). The low-dose group had significantly lower serum progesterone concentrations than the control group (56.8 nmol/l versus 34.7 nmol/l, respectively, p<0.05). FSH was reduced in the treated animals (3.3 ng/ml versus 5.5 ng/ml, p<0.05) while LH was unaffected., Conclusion: Our findings indicate a possible effect of LEV on the hypothalamic-pituitary-gonadal (HPG) axis and ovarian morphology in non-epileptic rats. The effects differ from those previously described for other AEDs. Caution must be taken before these results can be applied to humans.

Patients with epilepsy, treated with antiepileptic drugs (AEDs) are at increased risk of fractures. Although several commonly used AEDs reduce bone mass in patients, the mechanisms are only scarcely known. In this review, we focus on the usefulness of animal models to explore the skeletal effects of AEDs. Moreover, we report our findings from a recent study comparing the effect of levetiracetam (LEV), phenytoin (PHT) and valproate (VPA) on various aspects of bone health in actively growing female rats. Our data indicate that these AEDs act differently on bone mass, structure and metabolism. A novel finding is that LEV reduces bone strength and bone formation without altering bone mass. Based on these results we propose that epidemiological fracture studies of patients treated with LEV are needed, and that these patients should be evaluated regularly to identify possible bone-related side effects.

Several animal studies have shown that both the epilepsy itself and many antiepileptic drugs (AEDs) affect reproductive endocrine function in both males and females. Epileptic activity may lead to arrested ovarian cyclicity, anovulatory cycles, polycystic ovaries, and endocrine changes in female animals. In males, seizures disturb normal reproductive physiology by inducing endocrine changes, alterations in gonadal size, and hyposexuality. Several AEDs also affect endocrine function, fertility, and gonadal morphology in both sexes. This paper reviews the literature regarding animal studies related to reproductive disorders in epilepsy. Although care should always be taken when applying data from animal experiments to the human situation, animal models provide a unique possibility for investigating the independent effects of the epilepsy itself and the effects of AEDs in isolation, without confounding factors. By constantly comparing results from clinical and animal studies, and by developing appropriate animal models, several mechanistic questions regarding the complex interplay between epilepsy, hormones, and AEDs can be explored. Animal experiments should play an integral part in the study of reproductive endocrine disorders in epilepsy.

Purpose: Women with epilepsy have increased frequency of reproductive health problems compared to women without epilepsy. In puberty, reproductive hormonal changes during sexual maturation may affect epilepsy and induce the debut of seizures as indicated in some studies. On the other hand, epileptic activity affects sex hormone function, which may induce alterations in pubertal endocrine maturation and thereby menarche age. We wanted to investigate the relation between epilepsy and menarche age in a larger population of female epilepsy patients., Methods: A retrospective, questionnaire study of a cohort of 265 female outpatients from three Norwegian hospitals and 142 controls, aged 18-45 years was conducted. Parameters regarding epilepsy and reproductive health issues were registered. Perimenarche was defined as 2 years before and 2 years after the year of menarche., Results: There was a significantly higher frequency of patients with epilepsy debut between 10 and 18 year compared to 0-9 years (p<0.01). There was, however, no significant difference in occurrence of epilepsy debut in the perimenarche period compared to the 5 year periods before and after perimenarche, and no significant difference in epilepsy debut in the year of menarche compared to the 5 years before or after. Menarche age was not significantly different in those with epilepsy debut before or after menarche. Epilepsy type (idiopathic generalised or partial) did not influence the menarche age., Conclusions: The study did not confirm the former observations of clustering of epilepsy debut at menarche or in the perimenarche period or alterations in menarche age in girls with epilepsy. However, onset of epilepsy is more frequent in the adolescent years (10-18), than in childhood (0-9).

Problem: Menstrual disorders, reduced fertility and sexual problems seem to be more frequent in women with epilepsy than in the general population. Most investigations concerning menstrual disturbances in epilepsy patients, however, are small and based on selected materials. We therefore wanted to investigate the frequency of menstrual disturbances in a large, unselected population of epilepsy patients., Methods: A retrospective, questionnaire study of a cohort of female outpatients, aged 18-45 was conducted. Each patient chose a close female friend who served as control, to optimise matching regarding age and lifestyle., Results: Answers were received from 265 patients and 142 controls. Menstrual disturbances were more frequent in patients with epilepsy (48.0%) than in controls (30.7%) (P=0.004). Menstrual disturbances were more frequent in patients on polytherapy versus monotherapy (P=0.049) and more frequent in patients with high seizure frequency (>5seizures/year) compared to patients with a lower seizure frequency or those seizure free (P=0.006). The frequency of menstrual disturbances was higher in patients on valproate compared to carbamazepine monotherapy (P=0.045)., Conclusion: This investigation confirms that women with epilepsy have an increased frequency of menstrual disturbances compared to women without epilepsy. In women with high seizure frequency and in those on polytherapy, the frequency of menstrual disturbances are further increased. The highest frequency of menstrual disturbances occurred in women using valproate.

Drug-induced disturbances in reproductive hormones and gonadal morphology have been observed both in patients with epilepsy and in non-epileptic animals. Less is known about the influence of newer antiepileptic drugs including lamotrigine on reproduction. Lamotrigine is now increasingly used both in epilepsy and psychiatric disorders. Sixty-five Wistar rats were fed by gastric tube either 5 mg kg(-1) lamotrigine solution (males=15, females=20) or 0 (vehicle control, males=15, females=15) twice daily for 90 days. In males, no significant differences were found in body or testicular weight. Testicular atrophy was observed in one control animal and in two of the rats receiving lamotrigine. No morphological changes were seen in the other organs investigated (liver, kidney, pancreas, brain, lymphatic tissue, heart). None of the animals showed over-expression of p53. No significant differences were observed between the control rats and the male rats receiving lamotrigine regarding testosterone, FSH and LH. In females, no changes in ovarian morphology or alterations in other tissues were observed. Serum testosterone, FSH, LH, insulin and progesterone remained unchanged in the lamotrigine treated animals, while serum estrogen was significantly reduced.

Uncertainty exists about the effect of antiepileptic drugs on gonadal function. In females, long-term valproate treatment has been shown to induce endocrine disturbances and an increased number of ovarian cysts. The aim of the present study was to investigate whether valproate can also induce morphological changes in the testis of male animals. In addition, possible morphological changes in the liver, heart, lungs, lymphatic nodes, pancreas, kidney or brain were studied. The carcinogenic implications were evaluated by the measurement of p53. Male Wistar rats were fed perorally with valproate mixture 200 mg kg(-1)(n= 15) or 400 mg kg(-1)(n= 20), or control solution (n= 15) twice daily for 90 days. Serum concentrations measured 4-6 hours after the last dose were 105 and 404 micromol l(-1)in low- and high-dose valproate treated animals respectively. There was a highly significant, 51% decrease (P< 0.001) in testicular weight in the high-dose treated valproate rats with no changes in the other groups. There was widespread testicular atrophy with histologically verified spermatogenic arrest in 15/20 of the high-dose valproate treated animals. No changes in the testis were seen in the low-dose valproate treated rats, nor in the control rats. There were no morphological changes in the other investigated organs. None of the groups showed over-expression of p53. In conclusion, a dose-dependent effect of chronic valproate treatment was found on testicular morphology in rats. Caution must be taken before these results can be applied to humans., (Copyright 2001 BEA Trading Ltd.)

Long-term valproate treatment is associated with polycystic ovaries and endocrine disorders in women with epilepsy. The mechanisms responsible for these effects are unknown, but both the epilepsy itself and the drug per se may be of importance. The aim of this study was to investigate possible effects of the drug on gonadal structure and function in animals with no epileptic disorders. Three groups, each of 15 female Wistar rats, were fed perorally with a valproate mixture (50 mg / kg or 200 mg / kg) or control solution once daily for 90 days, giving mean valproate concentrations within the normal human range. A significant, 20% increase in ovary weight was found in both low- (P = 0.027) and high- (P < 0.001) dose animals together with a significantly increased number of ovarian follicular cysts. Mean serum testosterone concentration was significantly reduced in both low- and high-dose animals. There was a non-significant trend towards reduced estrogen levels, while progesterone levels were unchanged. Even if the hormonal changes are somewhat different from those in humans, the findings demonstrate that changes in gonadal structure and endocrine function also occur in intact animals indicating a drug-specific effect. Our findings encourages further studies using animal models to elucidate possible mechanisms involved in the endocrine side-effects of antiepileptic drugs., (Copyright 1999 BEA Trading Ltd.)

The aim of our study was to identify predictors for recurrence of epileptic seizures in a large county hospital population. We identified 956 patients (18-67 years) with ICD 9 code 345 as primary diagnosis, seen at the Central Hospital of Akershus over 7 years (1987-1994). The diagnosis of epilepsy was confirmed for 696 of the patients. These were divided into two groups: (1) no seizures during the previous year (n = 485) and (2) seizures during the previous year (n = 184). To identify predictors for recurrence of seizures, we used neurologic deficit, number of AEDs used, CT-scan findings, EEG findings, aetiology, gender, age below and above 50 years and comorbidity as independent variables in a logistic regression model. In a univariate analysis, the strongest predictors for recurrence of seizures were: age above 50 years (OR = 5.2;P < 0.0001), known aetiology (OR = 1.4;P = 0.04) and use of two or more AEDs (OR = 5. 7;P < 0.0001). In the multivariate analysis age, more than 50 years (OR = 1.7;P = 0.0216) and use of two or more AEDs (OR = 5.6;P < 0.0001) were the only predictors for recurrence of epileptic seizures., (Copyright 1999 BEA Trading Ltd.)