Impaired bone health as a co-morbidity of epilepsy.

Increasing number of studies shows significant reductions in bone mineral density in patients with epilepsy treated with enzyme-inducing anti-seizure medications (EIASM), valproic acid, and newer anti-seizure medications (ASM). ASM seems to be a specific risk factor for the development of osteoporosis affecting 11%-31% of patients with epilepsy and leads to 2 to 6 times increased risk of fractures compared to the background population. Treatment with ASM clearly contributes to epilepsy-associated bone disease. Yet, the exact pathophysiological mechanism has not been established; however, several hypotheses were suggested, especially in relation to EIASM. As the long-lasting medical treatment, often in polytherapy, has shown negative effects on bone health, it indicates the need for guidelines for the prevention and management of bone disease to be included in the follow-up of patients with epilepsy. An algorithm for following bone status during the treatment has been suggested based on Danish national guidelines.

Metabolic bone disease in patients with epilepsy and the use of antiepileptic drugs - Insight from a Danish cross-sectional study.

BACKGROUND: Osteoporosis is a bone disorder defined by a decrease in bone mineral density (BMD) which can lead to an increased risk of fractures. Patients with epilepsy are more prone to having fractures. When accounting for seizure-related fractures, the epilepsy patient population still suffers from an increased risk of fractures. This can be attributed to adverse effects of antiepileptic drugs (AEDs). AIM: The aim of this study was to investigate the association between the use of AEDs and decreased BMD in a large unselected population of Danish patients with epilepsy. METHOD: The study was a cross-sectional study based on data retrieved from 835 patients visiting an outpatient Epilepsy Clinic in Glostrup, Denmark, from January 1st 2006 - January 31st 2018. The data included results from DXA-scans and demographic information. Logistic regression models and other statistical analyses were performed. RESULTS: The results showed that the odds for having osteoporosis when taking EIAEDs were 2.2 (95 % CI: 1.2-3.8, P = 0.007) times higher than those taking NEIAEDs. Furthermore, the odds for having osteoporosis increased with duration of epilepsy (OR = 1.0, 95 % CI: 1.0 - 1.0, P = 0.001) and when the patients consume two AEDs compared to one AED (OR = 2.3, 95 % CI: 1.3-4.1, P < 0.001). Additionally, consuming three AEDs compared to one lead to a 2.3 times higher risk of having osteoporosis (95 % CI: 1.2-4.4, P = 0.01). CONCLUSION: When accounted for many riskfactors, EIAEDs, polytherapy with AEDs and duration of epilepsy are correlated with osteoporosis. There is a need for using these known riskfactors as guidelines in indentifying patients at increased risk of developing osteoporosis.

The effect of normalization of sodium on bone turnover markers in patients with epilepsy. A randomized single-blinded placebo-controlled trial.

Hyponatremia [p[Na]<136 mmol/L] is an independent risk factor for decreased bone mineral density (BMD). However, whether hyponatremia represents a surrogate marker, or a direct causal relationship to bone loss remains unknown. The aim of the study was to investigate the effect of salt replacement therapy on bone turnover markers (BTM) and BMD in patients with epilepsy and chronic hyponatremia. This prospective single-blinded randomized trial investigated serum BTM and BMD, evaluated by Dual Energy X-ray Absorptiometry (DXA), in 21 patients at baseline and following three months of salt replacement therapy. Patients with two consecutive measurements of hyponatremia prior to baseline and no known osteoporosis were included from the epilepsy out-patient clinic at Rigshospitalet, Denmark. Seven patients were randomized to placebo and 14 to salt intervention. The baseline p[Na] was 134 (130.5-140) mmol/L (median (IQR)). All patients had BTM within age-specific reference ranges at baseline. Following 3 months of intervention with 3-9 g of salt daily there was no difference in levels of procollagen type 1 N-terminal propeptide (P1NP) or C-terminal cross-linking telopeptide of type 1 collagen (CTX) between placebo and intervention. Nor was there any difference in BMD evaluated at the lumbar spine (L1-L4) or at the femoral neck or total hip. In our study, salt replacement did neither affect BTM nor BMD. However, due to the small size of the study, more studies are needed to further investigate this.

Effects of carbamazepine, eslicarbazepine, valproic acid and levetiracetam on bone microarchitecture in rats.

BACKGROUND: Metabolic bone disease and fractures are a great problem for patients with epilepsy. The use of antiepileptic drugs (AEDs) is known to play an essential role in the progression of bone loss by various pathophysiological mechanisms. The aim of this study was to evaluate the effects of AEDs on bone microstructure as an additional cause of an increased fracture risk in patients with epilepsy. METHODS: Five groups of each of 12 female rats were orally dosed daily for 8 weeks with either carbamazepine (CBZ) (60 mg/kg), eslicarbazepine (ESL) (80 mg/kg), valproic acid (VPA) (300 mg/kg), levetiracetam (LEV) (50 mg/kg) or saline (control (CTL)). Following killing, dissected femurs were analyzed using X-ray micro-computed tomography (µCT), dual-energy X-ray absorptiometry (DXA) and biomechanical testing. In addition, serum bone turnover markers (BTM) were monitored throughout the experiment. RESULTS: Compared to CTL treatment, VPA decreased bone volume fraction by 19%, decreased apparent density by 14% and increased structural model index by 41%. No changes were observed in bone biomechanics nor mineral density evaluated by DXA or in levels of BTM. CONCLUSIONS: Our findings suggest that VPA affects the microarchitectural properties of the bone. The AEDs CBZ, ESL and LEV appear to have less adverse effects on bone biology and may be a better choice when treating patients with respect to bone health.

An explorative literature review of the multifactorial causes of osteoporosis in epilepsy.

PURPOSE: Patients with epilepsy have a greatly increased risk of osteoporosis and fractures. The literature is diverse and contradictory when dealing with the underlying pathophysiological mechanisms. Consequently, the purpose of this review was to shed light on the multifactorial causes behind the increased occurrence of metabolic bone disease in patients with epilepsy and to identify areas for future research. METHODS: A review of the literature was performed searching PubMed with relevant Medical Subject Headings MeSH terms. The results of the search were evaluated for relevance to the review based on the title and abstract of the publication. Publications in language other than English and publications pertaining only pediatric patients were excluded. For all studies, included reference lists were evaluated for further relevant publications. In total, 96 publications were included in this explorative review. RESULTS: The high occurrence of metabolic bone disease in patients with epilepsy is multifactorial. The causes are the socioeconomic consequences of having a chronic neurological disease but also adverse effects to antiepileptic drug treatment ranging from interference with calcium and vitamin D metabolism to hyponatremia-induced osteoporosis. CONCLUSION: The literature supports the need for awareness of bone health in patients with epilepsy. The pathophysiological mechanisms are many and various wanting for further research in the less well-characterized areas. Furthermore, great responsibility rests on the healthcare professionals in implementing comprehensive patient care and in assuring bone protective measures in clinical practice to prevent bone loss in patients with epilepsy.

Psychogenic nonepileptic seizures treated with psychotherapy: Long-term outcome on seizures and healthcare utilization.

Psychogenic nonepileptic seizures (PNES) are known to be associated with significant costs of healthcare services. Here, we report the impact of psychotherapy on behavior surrounding healthcare utilization and the potential economic benefits associated with long-term seizure control. METHODS: This retrospective study describes patients seen between 2010 and 2016 at the epilepsy clinic at Glostrup University Hospital in Denmark and offered a psychotherapeutic treatment program for PNES. Forty-two patients were interviewed about seizure outcome 12-24 months after psychotherapy, and the annual changes in healthcare utilization and associated costs of services provided in a period of 24 months before and up to 24 months after treatment were compared. RESULTS: At 12-month follow-up, 83% of the patients had achieved above 50% reduction in seizures. The 24-month pretreatment costs compared with the 24-month posttreatment costs directly associated with seizures dropped by 95.8%, and total healthcare costs were reduced by 63%. Estimation of annual savings from the program comes to 1060 € per patient. An association was found between seizure rate and number of healthcare contacts. CONCLUSION: This study adds to the evidence that psychotherapy is a cost-effective way of treating PNES. The economic benefits from this form of intervention appear not only to diminish costs directly associated with PNES, but also healthcare utilization in general.

Hyponatremia and metabolic bone disease in patients with epilepsy: A cross-sectional study.

AIM: Patients with epilepsy frequently develop hyponatremia due to the treatment with antiepileptic drugs and have an increased risk of developing metabolic bone disease. Hyponatremia is known to be associated with osteoporosis. The aim of the study was to investigate the association between hyponatremia and osteoporosis in patients with epilepsy. METHOD AND MATERIAL: This cross-sectional study included patients with epilepsy from a tertiary epilepsy out-patient clinic in Denmark, who had a Dual Energy X-ray Absorptiometry scan performed and an accompanying plasma sodium (p-Na) measured prior to or a maximum of 14 days after the scan. Information regarding the patients' health and medical conditions were obtained from their medical reports. RESULTS: A total of 695 patients (females 53.8%, age 49 (34:63) years (median (quartiles)) were included. 10.4% had hyponatremia (p-Na ≤ 135 mmol/L). The hyponatremic patients had significantly lower T-scores in the lumbar spine, femoral neck and total femur (all p < 0.023) and the odds ratio of osteoporosis (T-score < -2.5) was significantly increased (2.91 (1.61-5.27) (95% confidence interval) (p = 0.001)). When adjusting for potential confounders the patients with moderate and severe hyponatremia (p-Na < 129 mmol/L) had a significantly lower mean T-score in the lumbar spine (p = 0.030). CONCLUSION: We conclude that hyponatremia is common in patients with epilepsy and that moderate and severe hyponatremia is independently associated with decreased bone mineral density in the lumbar spine. Therefore, hyponatremia in a patient with epilepsy should warrant further examination of the patient for bone loss and osteoporosis.

Zonisamide serum concentrations during pregnancy.

PURPOSE: To investigate the change in zonisamide (ZNS) serum concentration and its consequences in pregnant women with epilepsy. METHODS: Six hospitals in Norway and Denmark screened their records for women who had been using ZNS during pregnancy. Absolute serum concentrations as well as concentration/dose (CD)-ratios were compared to non-pregnant values. Descriptive data on seizure control and obstetrical data were also collected. RESULTS: 144 serum concentrations from 23 pregnancies in 15 individual women with epilepsy were included (six on monotherapy). The mean ZNS serum concentration fell to a minimum of 58.6 ±â€¯15.1%, while the C/D-ratio fell to as low as 55.1 ±â€¯15.3% of the non-pregnant-value. The lowest values were seen in gestational months six to nine, and the individual nadir varied considerably (range: 24-81% of the non-pregnant value). Four out of ten previously seizure-free patients experienced breakthrough seizures. Gestational age, weight at birth and head circumference of the newborns were within the reference ranges. CONCLUSIONS: ZNS serum concentrations may fall by over 40% during pregnancy, with large interindividual variability. In some patients, this may lead to worsened seizure control. These findings are in line with reports on other AEDs and suggest that regular therapeutic drug monitoring and dose adjustments may be useful.

Clinical experience with eslicarbazepine acetate in adults with sub-analysis of elderly.

PURPOSE: Eslicarbazepine acetate (ESL) is indicated for treatment of focal epilepsy. Our aim was to evaluate the effect and tolerability of ESL in elderly and younger adults. The primary objective was to measure changes in seizure frequency before and after at least six months of treatment. Secondary objective was to analyse the safety profile. Sub-analysis was performed in patients previously treated with oxcarbamazepine. METHOD: A single-centre, retrospective study of patients with focal epilepsy treated with ESL. Data were collected by reviewing the clinical and laboratory files. Seventy-two patients received ESL, of which 14 were ≥60 years old, and were analysed for adverse effects. Fifty-nine patients received treatment for ≥6 months and were included in the evaluation of seizure frequency; in this group 12 were ≥60 years old. RESULTS: Seizure frequency (n=59) was reduced for both young adults (< 60years) and elderly adults (≥60); both groups achieved better seizure control from an average of 2 to 0.5 (p-value: 0.002) and 3.5 to 0.65 (p-value:<0.05) seizures per month, respectively. Adverse effects leading to treatment discontinuation (n=72) were more frequent in elderly (42.9%) than in young adults (17.2%) (p-value 0.04). There was no significant difference in mild adverse effects between young (15.5%) and elderly adults (14.3%). Most common adverse effects were somnolence, gastrointestinal disturbances and dizziness. CONCLUSIONS: The study indicates that ESL has an advantageous profile in relation to seizure control. The discontinuation rate might be higher in elderly than in younger adults. Further prospective studies are needed to confirm these conclusions.

Automated differentiation between epileptic and nonepileptic convulsive seizures.

Our objective was the clinical validation of an automated algorithm based on surface electromyography (EMG) for differentiation between convulsive epileptic and psychogenic nonepileptic seizures (PNESs). Forty-four consecutive episodes with convulsive events were automatically analyzed with the algorithm: 25 generalized tonic-clonic seizures (GTCSs) from 11 patients, and 19 episodes of convulsive PNES from 13 patients. The gold standard was the interpretation of the video-electroencephalographic recordings by experts blinded to the EMG results. The algorithm correctly classified 24 GTCSs (96%) and 18 PNESs (95%). The overall diagnostic accuracy was 95%. This algorithm is useful for distinguishing between epileptic and psychogenic convulsive seizures.

Quantitative analysis of surface electromyography during epileptic and nonepileptic convulsive seizures.

OBJECTIVE: To investigate the characteristics of sustained muscle activation during convulsive epileptic and psychogenic nonepileptic seizures (PNES), as compared to voluntary muscle activation. The main goal was to find surface electromyography (EMG) features that can distinguish between convulsive epileptic seizures and convulsive PNES. METHODS: In this case-control study, surface EMG was recorded from the deltoid muscles during long-term video-electroencephalography (EEG) monitoring in 25 patients and in 21 healthy controls. A total of 46 clinical episodes were recorded: 28 generalized tonic-clonic seizures (GTCS) from 14 patients with epilepsy, and 18 convulsive PNES from 12 patients (one patient had both GTCS and PNES). The healthy controls were simulating GTCS. To quantitatively characterize the signals we calculated the following parameters: root mean square (RMS) of the amplitude, median frequency (MF), coherence, and duration of the seizures, of the clonic EMG discharges, and of the silent periods between the cloni. Based on wavelet analysis, we distinguished between a low-frequency component (LF 2-8 Hz) and a high-frequency component (HF 64-256 Hz). RESULTS: Duration of the seizure, and separation between the tonic and the clonic phases distinguished at group-level but not at individual level between convulsive PNES and GTCS. RMS, temporal dynamics of the HF/LF ratio, and the evolution of the silent periods differentiated between epileptic and nonepileptic convulsive seizures at the individual level. A combination between HF/LF ratio and RMS separated all PNES from the GTCS. A blinded review of the EMG features distinguished correctly between GTCS and convulsive PNES in all cases. The HF/LF ratio and the RMS of the PNES were smaller compared to the simulated seizures. SIGNIFICANCE: In addition to providing insight into the mechanism of muscle activation during convulsive PNES, these results have diagnostic significance, at the individual level. Surface EMG features can accurately distinguish convulsive epileptic from nonepileptic psychogenic seizures, even in PNES cases without rhythmic clonic movements.

Seizure semiology inferred from clinical descriptions and from video recordings. How accurate are they?

To assess how accurate the interpretation of seizure semiology is when inferred from witnessed seizure descriptions and from video recordings, five epileptologists analyzed 41 seizures from 30 consecutive patients who had clinical episodes in the epilepsy monitoring unit. For each clinical episode, the consensus conclusions (at least 3 identical choices) based on the descriptions and, separately, of the video recordings were compared with the clinical conclusions at the end of the diagnostic work-up, including data from the video-EEG recordings (reference standard). Consensus conclusion was reached in significantly more cases based on the interpretation of video recordings (88%) than on the descriptions (66%), and the overall accuracy was higher for the video recordings (85%) than for the descriptions (54%). When consensus was reached, the concordance with the reference standard was substantial for the descriptions (k=0.67) and almost perfect for the video recordings (k=0.95). Video recordings significantly increase the accuracy of seizure interpretation.

Bone mineral density in adult patients treated with various antiepileptic drugs.

There is considerable evidence suggesting, that older antiepileptic drugs (AEDs) and some of the newer ones decrease bone mineral density (BMD). However, there is only limited and conflicting data concerning the effect of levetiracetam on BMD. In this cross-sectional study we analysed data from 168 adult consecutive outpatients treated with AEDs for more than 2 years, and who underwent measurement of the BMD. We compared the incidence of decreased BMD among the patients treated with 6 different AEDs: carbamazepine (CBZ), oxcarbazepine (OXC), valproic acid (VPA), lamotrigine (LTG), topiramate (TPM) and levetiracetam (LEV). Among the patients on monotherapy, reduced BMD was present significantly most often in patients treated with LEV and those treated with OXC. In the group of patients on polytherapy there was no significant difference in the incidence of low BMD among patients treated with various AEDs. Our data suggest that patients on long-term treatment with LEV have a higher risk for affection of bone density.

Postictal inhibition of the somatosensory cortex.

Transient suppression of the motor cortex and of the speech areas cause well-described postictal phenomena following seizures involving the respective cortical areas. Pain is a rare symptom in epileptic seizures. We present a patient with painful tonic seizures in the left leg. The amplitude of the cortical component of the somatosensory evoked potential following stimulation of the left tibial nerve was reduced immediately after the seizure. Our findings suggest that the excitability of the sensory cortex is transiently reduced following a seizure involving the somatosensory area.

Deletion of 7q34-q36.2 in two siblings with mental retardation, language delay, primary amenorrhea, and dysmorphic features.

We describe a chromosome rearrangement, ins(7;13)(q32q34;q32), which segregates in a three generation family, giving rise to three individuals with an unbalanced rearrangement. Two of the individuals, a sister and a brother, were investigated further in this study. They had minor facial dysmorphism and neuropsychiatric disorders including mental retardation, language delay and epilepsy. The sister had primary amenorrhea. Array CGH revealed a 12.2 Mb deletion at 7q34-q36.2 including more than 60 genes where CNTNAP2 and NOBOX are of special interest. Comparison of the clinical and cytogenetic findings of our patients with previously reported patients, supports that haploinsuffiency of CNTNAP2 can result in language delay and/or autism spectrum disorder. Furthermore, we report on the second women with a deletion involving NOBOX who is affected by primary amenorrhea.

Effect of medication withdrawal on the interictal epileptiform EEG discharges in presurgical evaluation.

Medication withdrawal (MW) is an important method of provoking seizures and activating epileptiform EEG activity during the diagnostic work-up of patients evaluated for epilepsy surgery. Previously it was suggested that MW might influence the seizure-type and activate cortical areas otherwise not producing epileptiform discharges, leading to a false localization of the irritative zone. In order to investigate this we reviewed 42 consecutive cases of MW, of 36 patients, during a 3-year period. We compared seizure frequency, seizure-types and the localization of interictal epileptiform discharges before and after MW. Seizure frequency was significantly higher after MW. In the whole group we found an increase in seizure propagation: the proportion of the complex partial seizures and secondarily generalised seizures increased, while the proportion of the simple partial seizures decreased following MW. In one-third of the patients the interictal EEGs after the MW were different from those recorded before the MW. However, in these discordant cases the EEG findings after the MW (and not before the MW) were concordant with the seizure onset zone and the lesional zone. We conclude that MW is an effective and reliable seizure provoking method, and it does not lead to false localization of the irritative zone.