Morbidity and mortality risks associated with valproate withdrawal in young men and women with epilepsy.

Valproate is the most effective treatment for idiopathic generalised epilepsy. Current guidance precludes its use in women of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to men. New guidance will limit use both in men and women aged <55 years, resulting in withdrawal of valproate from men already taking it, as occurs for women. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for men or women on valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients' and clinicians' minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young men and women. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were men and women aged 16-54 years with ≥1 epilepsy disease or symptom code between 01/12/2017-01/12/2018 and ≥2 valproate prescriptions over the preceding two years (01/01/2015-30/11/2017). 5-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining on vs. withdrawn from valproate during the 01/12/2017-01/12/2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). 8,991 men and 5,243 women taking valproate were recruited. 28% of men and 36% of women were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance (HRs overall: 1.236 (CI 1.159-1.319), men: 1.181 (CI 1.083-1.288), women: 1.242 (CI 1.125-1.371)), hospital admission (HRs overall: 1.160 (CI 1.081-1.246), men: 1.132 (CI 1.027-1.249), women: 1.147 (CI 1.033-1.274)), falls (HRs overall: 1.179 (CI 1.041-1.336), men: 1.298 (CI 1.090-1.546)), injuries (HRs overall: 1.095 (CI 1.021-1.174), men: 1.129 (CI 1.029-1.239)), burns (HRs overall: 1.592 (CI 1.084-2.337)), and new-onset depression (HRs overall 1.323 (CI 1.119-1.565), women: 1.359 (CI 1.074-1.720)). The risk of these outcomes occurring was 1-7% higher in those withdrawn from valproate than in those remaining on valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.

Clinical practice guidelines on the management of status epilepticus in adults: A systematic review.

OBJECTIVE: Status epilepticus (SE) is the second most common neurological emergency in adults. Despite improvements in the management of acute neurological conditions over the last decade, mortality is still durably high. Because a gap has emerged between SE management based on clinical practice guidelines (CPGs) and actual clinical practice, we conducted a systematic review of CPGs, assessing their quality, outlining commonalities and discrepancies in recommendations, and highlighting research gaps. METHODS: We searched the PubMed and EMBASE databases and other gray literature sources (nine among guideline registries, evidence-based medicine databases, point-of-care tools; seven websites of governmental organizations and international neurologic societies) in December 2021 (updated in November 2023). The units of analysis were CPGs that included recommendations on the diagnostic and/or therapeutic management of SE in adults. The quality of the CPGs was assessed using the AGREE II tool. RESULTS: Fifteen CPGs were included. The "Applicability" domain was assigned the lowest median score of 10%. The domains "Stakeholder Involvement", "Rigor of Development," and "Editorial Independence" were as well generally underrated. Recommendations on general and diagnostic management and on organizational interventions were fragmented and scattered. Recommendations on pre-hospital and hospital treatment of early-onset and refractory SE were broadly agreed, whereas there was less agreement on the treatment model and medications for established SE and super-refractory SE. SIGNIFICANCE: The CPGs for the management of SE developed in recent years are flawed by several methodological issues and discrepancies in the coverage of important topics. The gap between CPG-based management of SE and actual clinical practice may be due in part to the inherent limitations of the CPGs produced so far.

A Comprehensive Review of Essential Oils and Their Pharmacological Activities in Neurological Disorders: Exploring Neuroprotective Potential.

Numerous studies have demonstrated essential oils' diverse chemical compositions and pharmacological properties encompassing antinociceptive, anxiolytic-like, and anticonvulsant activities, among other notable effects. The utilization of essential oils, whether inhaled, orally ingested, or applied topically, has commonly been employed as adjunctive therapy for individuals experiencing anxiety, insomnia, convulsions, pain, and cognitive impairment. The utilization of synthetic medications in the treatment of various disorders and symptoms is associated with a wide array of negative consequences. Consequently, numerous research groups across the globe have been prompted to explore the efficacy of natural alternatives such as essential oils. This review provides a comprehensive overview of the existing literature on the pharmacological properties of essential oils and their derived compounds and the underlying mechanisms responsible for these observed effects. The primary emphasis is on essential oils and their constituents, specifically targeting the nervous system and exhibiting significant potential in treating neurodegenerative disorders. The current state of research in this field is characterized by its preliminary nature, highlighting the necessity for a more comprehensive overlook of the therapeutic advantages of essential oils and their components. Integrating essential oils into conventional therapies can enhance the effectiveness of comprehensive treatment regimens for neurodegenerative diseases, offering a more holistic approach to addressing the multifaceted nature of these conditions.

Anticonvulsants in the Treatment of Behavioral and Psychological Symptoms in Dementia: A Systematic Review.

OBJECTIVES: Behavioral and psychological symptoms of dementia (BPSD) are common and impart a significant burden to patients, caregivers, and the health system. However, there are few pharmacological options for treating BPSD. We conducted a systematic review of clinical trials examining the efficacy of anticonvulsants in BPSD. METHODS: We searched five electronic databases through January 2023, for randomized controlled trials and systematic reviews evaluating the efficacy of non-benzodiazepine anticonvulsants for the treatment of BPSD. We used the Cochrane risk of bias tool to ascertain the risk of bias in included trials. Because statistical pooling of results using meta-analysis was not feasible, we synthesized findings using the Cochrane Synthesis Without Meta-analysis reporting guidelines. RESULTS: We identified 12 studies, including randomized controlled trials (RCTs) and 1 systematic review. Five RCTs evaluating valproic acid were synthesized by a recent Cochrane review which concluded that this drug is likely ineffective for BPSD. We extracted data from 6 trials involving 248 individuals comparing non-benzodiazepine anticonvulsants to either placebo or risperidone. Four trials (n = 97 participants) evaluated carbamazepine, only one of which demonstrated an improvement in the Brief Psychiatric Rating Scale measuring agitation, hostility, psychosis, and withdrawal/depression (effect size: 1.13; 95% confidence interval [CI]: 0.54-1.73) relative to placebo. Adverse effects were more common in patients receiving carbamazepine (20/27; 74%) relative to placebo (5/24; 21%). There is low quality evidence that oxcarbazepine is likely ineffective and that topiramate may be comparable to risperidone. CONCLUSION: Anticonvulsants are unlikely to be effective in BPSD, although the quality of existing evidence is low.

Anti-seizure medication response and the glymphatic system in patients with focal epilepsy.

BACKGROUND AND PURPOSE: We aimed to evaluate (i) glymphatic system function in patients with focal epilepsy in comparison with healthy controls, and (ii) the association between anti-seizure medication (ASM) response and glymphatic system function by using diffusion tensor image analysis along the perivascular space (DTI-ALPS). METHODS: We retrospectively enrolled 100 patients with focal epilepsy who had normal brain magnetic resonance imaging (MRI) findings, and classified them as "poor" or "good" ASM responders according to their seizure control at the time of brain MRI. We also included 79 age- and sex-matched healthy controls. All patients and healthy controls underwent conventional brain MRI and diffusion tensor imaging. The DTI-ALPS index was calculated using the DSI studio program. RESULTS: Of the 100 patients with focal epilepsy, 38 and 62 were poor and good ASM responders, respectively. The DTI-ALPS index differed significantly between patients with focal epilepsy and healthy controls and was significantly lower in patients with focal epilepsy (1.55 vs. 1.70; p < 0.001). The DTI-ALPS index also differed significantly according to ASM response and was lower in poor ASM responders (1.48 vs. 1.59; p = 0.047). Furthermore, the DTI-ALPS index was negatively correlated with age (r = -0.234, p = 0.019) and duration of epilepsy (r = -0.240, p = 0.016) in patients with focal epilepsy. CONCLUSION: Our study is the first to identify, in focal epilepsy patients, a greater reduction in glymphatic system function among poor ASM responders compared to good responders. To confirm our results, further prospective multicenter studies with large sample sizes are needed.

Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage-gated calcium channel ligand drugs.

AIMS: Gabapentin and pregabalin bind to α2-δ subunit of voltage-gated calcium channels (Cav ). Other drugs targeting Cav include cardiovascular calcium channel blockers (CCBs) and anticonvulsants (levetiracetam, ethosuximide and zonisamide). In addition to pharmacodynamics, the safety profile of gabapentinoids seems to overlap with the one of cardiovascular CCBs (oedema) and Cav -blocking anticonvulsants (suicide and ataxia). The objective of this study was to cluster the safety profile of different Cav -ligand drugs by focusing on whether gabapentinoids present a distinct adverse drug reaction (ADR) signature from cardiovascular CCBs and anticonvulsants. METHODS: We extracted all ADRs with at least one significant disproportionate reporting (reporting odds ratio) related to gabapentinoids, CCBs or anticonvulsants in VigiBase. After principal component analysis preprocessing, a hierarchical ascendent classification was performed to cluster gabapentinoids and other Cav -ligand drugs that share a similar ADR signature. The robustness of the results was determined through four sensitivity analyses, varying on the dataset or the clustering method. RESULTS: A total of 16 drugs and 65 ADRs were included. Gabapentinoids were in Cluster #1, which included eight other drugs (isradipine, nicardipine, lacidipine, lercanidipine, ethosuximide, levetiracetam, zonisamide and nimodipine). Cluster #2 contained two drugs (diltiazem and verapamil) and Cluster #3 contained four drugs (amlodipine, felodipine, nifedipine and nitrendipine). The clustering results were consistent in all sensitivity analyses. CONCLUSIONS: The safety profile of gabapentinoids overlaps with those of some dihydropyridine CCBs and Cav -blocking anticonvulsants. These results could be used to anticipate some unidentified ADRs of gabapentinoids from information accumulated with older drugs and sharing a common molecular target and ADR signature.

Short-Term Impact of Seizures and Mitigation Opportunities.

PURPOSE OF REVIEW: The burden of epilepsy is complex and consists of elements directly related to acute seizures as well as those associated with living with a chronic neurologic disorder. The purpose of this systematic review was to characterize short-term burdens of seizures and to explore the potential value of acute treatments to mitigate these burdens apart from reducing the risk of status epilepticus. RECENT FINDINGS: A systematic literature search was conducted using PubMed to identify articles published from January 1, 2017, to June 22, 2023, that described short-term burdens and acute treatments of seizures. Primary outcomes included those related to short-term burdens of seizures and the benefits of acute treatments to reduce short-term burdens. Of the 1332 articles identified through PubMed and 17 through other sources, 27 had relevant outcomes and were included in the qualitative synthesis. Seizure emergencies negatively affected short-term quality of life and the ability to conduct normal daily living activities and were associated with physical (injury) and financial (emergency transport, hospitalization) burdens. The use of acute treatment was associated with a rapid return (≤ 1 h) to normal function/self for both patients and caregivers and potentially lower healthcare utilization and costs. Seizure action plans may improve knowledge and comfort with seizure care, empowering patients and caregivers. The short-term burden of seizures can create a substantial negative impact on patients and caregivers. Acute treatments may reduce the short-term burdens of seizures in addition to their well-described role to reduce seizure activity and the risk for status epilepticus.

Prevalence of and factors associated with the early prescription of antiseizure medications in adults newly diagnosed with epilepsy in Germany.

BACKGROUND: There is little information on prescription patterns of antiseizure medications (ASMs) during the early management of patients with epilepsy in Germany. Therefore, this study investigated the prevalence of and the factors associated with ASM prescription in patients newly diagnosed with epilepsy in this country. METHODS: Adults diagnosed for the first time with epilepsy in one of 128 neurology practices in Germany between 2005 and 2021 were included (Disease Analyzer database, IQVIA). The prescription of ASMs was assessed within 30 days, six months, and 12 months of the diagnosis. Covariates were demographic factors, epilepsy sub-diagnoses, and co-diagnoses frequently associated with epilepsy. RESULTS: This study included 55,962 participants (mean [SD] age 52.5 [20.0] years; 50.5 % men). The prevalence of ASM prescription ranged from 45.0 % within 30 days to 66.0 % within 12 months of the diagnosis. Men were less likely to receive ASMs within six and 12 months of epilepsy diagnosis than women. In addition, epilepsy sub-diagnoses of symptomatic, complex, or generalized nature were associated with increased odds of ASM prescription compared with epilepsy of unspecified nature. Finally, there was an inverse and significant association between multiple co-diagnoses (e.g., diabetes, mental and behavioral disorders due to use of alcohol, and traumatic brain injury) and ASM prescribing. CONCLUSIONS: A substantial proportion of participants were prescribed ASMs in the year following epilepsy diagnosis, highlighting that the early prescription of ASMs was necessary for these patients. Further research is warranted to corroborate the present findings in other countries and settings.

Ketamine reduces seizure and interictal continuum activity in refractory status epilepticus: a multicenter in-person and teleneurocritical care study.

BACKGROUND: There is not a preferred medication for treating refractory status epilepticus (RSE) and intravenous ketamine is increasingly used. Ketamine efficacy, safety, dosage, and influence of other variables on seizure cessation while on ketamine infusions are not well studied. We aimed to characterize ketamine effect on RSE, including interictal activity on electroencephalogram (EEG) and when done by Teleneurocritical care (TNCC). METHODS: We conducted a multicenter, retrospective study from August 2017 to October 2022. Patients 18 years or older who had RSE and received ketamine were included. The primary outcome was effect of ketamine on RSE including interictal activity; secondary outcomes were effect of other variables on RSE, care by TNCC, ketamine infusion dynamics, adverse events, and discharge outcomes. Logistic regression was used. RESULTS: Fifty-one patients from five hospitals met inclusion criteria; 30 patients had RSE and interictal activity on EEG. Median age was 56.8 years (IQR 18.2) and 26% had previously diagnosed epilepsy. Sixteen (31%) patients were treated virtually by TNCC. In those with RSE on EEG, ketamine was added as the fourth antiseizure medication (mean 4.4, SD 1.6). An initial bolus of ketamine was used in 24% of patients (95 mg, IQR 47.5), the median infusion rate was 30.8 mcg/kg/min (IQR 40.4), and median infusion duration was 40 h (IQR 37). Ketamine was associated with 50% cessation of RSE and interictal activity at 24 h in 84% of patients, and complete seizure cessation in 43% of patients. In linear regression, ASMs prior to ketamine were associated with seizure cessation (OR 2.6, 95% CI 0.9-6.9, p = 0.05), while the inverse was seen with propofol infusions (OR 0.02, 95% CI 0.001-0.43, p = 0.01). RSE management by in-person NCC versus virtual by TNCC did not affect rates of seizure cessation. CONCLUSIONS: Ketamine infusions for RSE were associated with reduced seizure burden at 24 h, with 84% of patients having 50% seizure reduction. Similar efficacy and safety was observed irrespective of underlying RSE etiology or when done via TNCC vs in-person NCC.

Teratogenicity is more likely a function of primary and secondary pharmacology than caused by chemically reactive metabolites: a critical evaluation of 40 years of scientific research.

The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.

Pharmacological Treatment of Fibromyalgia Syndrome: A Practice-Based Review.

PURPOSE OF REVIEW: Fibromyalgia Syndrome (FMS) is a complex chronic pain condition characterized by widespread musculoskeletal pain and numerous other debilitating symptoms. The purpose of this review is to provide a comprehensive overview, based on everyday clinical practice, of the drugs presently employed in the treatment of FMS. RECENT FINDINGS: The treatment of FMS is based on a multimodal approach, with pharmacologic treatment being an essential pillar. The drugs used include tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, other antidepressants, anticonvulsants, myorelaxants, and analgesics. The effectiveness of these medications varies, and the choice of drug often depends on the specific symptoms presented by the patient. Many drugs tend to either address only some domains of the complex FMS symptomatology or have a limited effect on pain. Each treatment option comes with potential side effects and risks that necessitate careful consideration. It may be beneficial to divide patients into clinical subpopulations, such as FMS with comorbid depression, for more effective treatment. Despite the complexities and challenges, the pharmacological treatment remains a crucial part for the management of FMS. This review aims to guide clinicians in prescribing pharmacological treatment to individuals with FMS.

Efficacy of second-line anticonvulsant agents with adult status epilepticus: A systematic review and network meta-analysis.

BACKGROUND: Status epilepticus (SE) is potentially life-threatening, however, it is unclear which antiepileptic drugs (AEDs) should be used as second-line AEDs. OBJECTIVE: We conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing multiple second-line AEDs for SE to investigate the efficacy of AEDs. METHODS: We searched MEDLINE, CENTRAL, ClinicalTrials.gov, and World Health Organization International Clinical Trials Platform Search Portal and included RCTs for patients aged ≥15 years with SE on December 31, 2023. We compared multiple second-line AEDs for SE including fosphenytoin (fPHT), lacosamide (LCM), levetiracetam (LEV), phenytoin (PHT), phenobarbital (PHB), and valproate (VPA). The primary and secondly outcomes were termination of seizures integrating the absence of seizure recurrence at 30 min and 60 min, and adverse events associated with AEDs, respectively, with expressing as relative risk (RR) with a 95% confidence interval (CI). We conducted a NMA using frequentist-based approach with multivariate random effects, and assessed the certainty based on the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: Seven RCTs (n = 780) were included, and statistically significant difference was detected between VPA vs. PHB (RR, 0.67; 95% CI, 0.53-0.85; very low certainty), fPHT vs. PHB (RR, 0.66; 95% CI, 0.48-0.90; very low certainty), LCM vs. PHB (RR, 0.62; 95% CI, 0.41-0.93; very low certainty), and LEV vs. PHB (RR, 0.69; 95% CI, 0.51-0.94; very low certainty). Moreover, PHB was the highest in the ranking for termination of seizures. For adverse events, no significant reduction was observed owing to the selection of AEDs, although the ranking of PHB was the lowest. CONCLUSIONS: PHB may have been the most effective for seizure termination as second-line AEDs in adult patients with SE. However, the certainty of almost all comparisons was "very low", and careful interpretation is essential.

Synthesis, Theoretical Study, and Anticonvulsant Evaluation of N-Arylenaminones.

N-Arylenaminones are highly versatile compounds which can be synthesized in relatively simple ways. In this work we explored the synthesis of the four monosubstituted N-(4-R-phenyl)enaminones 3 a (R=NO2), 3 b (R=F), 3 c (R=H), and 3 d (R=OMe) with the goal of determining the influence of the substituents' electronic effects on tautomer stability and biological activity. These compounds were analyzed by means of Density Functional Theory calculations (DFT), to evaluate the relative stability of the possible tautomers. We found that the enaminone structure is the most stable with respect to the ketoimine and iminoenol forms. In addition, all four compounds display anticonvulsant activity, with 3 d being the one that mostly increased latency and mostly decreased the number of convulsions with respect to the control group. The suggested mechanism of action involves blockage of the voltage-dependent Na+ channels, considering that these molecules meet the structural characteristics needed to block the receptor, as is the case of the positive control molecules phenytoin (PHT) and valproic acid (VPA).

Preconception counselling in women with epilepsy.

Pregnancy and the postpartum period are potentially high-risk periods for women with epilepsy and their babies. All women with epilepsy should have the opportunity for preconception counselling with the aim of reducing risk, optimising outcomes for the potentially developing fetus and enabling informed decision-making. This article provides an evidence-based framework for preconception counselling discussion, including the review of diagnosis and of current antiseizure medication, the risk to the fetus in relation to antiseizure medication and maternal seizures, maternal morbidity, SUDEP risk, folic acid supplements, contraception, breastfeeding and safety advice.

Sexual dysfunction and commonly used drugs in neurology.

Sexual dysfunction is common in men and women with neurological diseases. Medications used in neurology can cause sexual dysfunction independently of the disease process and this may adversely affect patients' quality of life. This review focuses on medications commonly prescribed to neurological patients that may contribute to altered sexual function, and discusses how they may differ in men and women.

Comparative Effectiveness and Safety of Seizure Prophylaxis Among Adults After Acute Ischemic Stroke.

BACKGROUND: Older adults occasionally receive seizure prophylaxis in an acute ischemic stroke (AIS) setting, despite safety concerns. There are no trial data available about the net impact of early seizure prophylaxis on post-AIS survival. METHODS: Using a stroke registry (American Heart Association's Get With The Guidelines) individually linked to electronic health records, we examined the effect of initiating seizure prophylaxis (ie, epilepsy-specific antiseizure drugs) within 7 days of an AIS admission versus not initiating in patients ≥65 years admitted for a new, nonsevere AIS (National Institutes of Health Stroke Severity score ≤20) between 2014 and 2021 with no recorded use of epilepsy-specific antiseizure drugs in the previous 3 months. We addressed confounding by using inverse-probability weights. We performed standardization accounting for pertinent clinical and health care factors (eg, National Institutes of Health Stroke Severity scale, prescription counts, seizure-like events). RESULTS: The study sample included 151 patients who received antiseizure drugs and 3020 who did not. The crude 30-day mortality risks were 219 deaths per 1000 patients among epilepsy-specific antiseizure drugs initiators and 120 deaths per 1000 among noninitiators. After standardization, the estimated mortality was 251 (95% CI, 190-307) deaths per 1000 among initiators and 120 (95% CI, 86-144) deaths per 1000 among noninitiators, corresponding to a risk difference of 131 (95% CI, 65-200) excess deaths per 1000 patients. In the prespecified subgroup analyses, the risk difference was 52 (95% CI, 11-72) among patients with minor AIS and 138 (95% CI, 52-222) among moderate-to-severe AIS patients. Similarly, the risk differences were 86 (95% CI, 18-118) and 157 (95% CI, 57-219) among patients aged 65 to 74 years and ≥75 years, respectively. CONCLUSIONS: There was a higher risk of 30-day mortality associated with initiating versus not initiating seizure prophylaxis within 7 days post-AIS. This study does not support the role of seizure prophylaxis in reducing 30-day poststroke mortality.

Blocking channels to metastasis: targeting sodium transport in breast cancer.

The development of therapies that can suppress invasion and prevent metastasis, 'anti-metastatic drugs', is an important area of unmet therapeutic need. The new results of a recent open-label, multicentre randomised trial published in J Clin Oncol showed a significant disease-free survival (DFS) benefit for breast cancer patients receiving presurgical, peritumoral injection of lidocaine, an amide local anaesthetic, which blocks voltage-gated sodium channels (VGSCs). VGSCs are expressed on electrically excitable cells, including neurons and cardiomyocytes, where they sustain rapid membrane depolarisation during action potential firing. As a result of this key biophysical function, VGSCs are important drug targets for excitability-related disorders, including epilepsy, neuropathic pain, affective disorders and cardiac arrhythmia. A growing body of preclinical evidence highlights VGSCs as key protagonists in regulating altered sodium influx in breast cancer cells, thus driving invasion and metastasis. Furthermore, prescription of certain VGSC-inhibiting medications has been associated with reduced cancer incidence and improved survival in several observational studies. Thus, VGSC-inhibiting drugs already in clinical use may be ideal candidates for repurposing as possible anti-metastatic therapies. While these results are promising, further work is required to establish whether other VGSC inhibitors may afford superior metastasis suppression. Finally, increasing preclinical evidence suggests that several other ion channels are also key drivers of cancer hallmarks; thus, there are undoubtedly further opportunities to harness ion transport inhibition that should also be explored.

Risk-conferring HLA variants in an epilepsy cohort: benefits of multifaceted use of whole genome sequencing in clinical practice.

BACKGROUND: Whole genome sequencing is increasingly used in healthcare, particularly for diagnostics. However, its clinically multifaceted potential for individually customised diagnostic and therapeutic care remains largely unexploited. We used existing whole genome sequencing data to screen for pharmacogenomic risk factors related to antiseizure medication-induced cutaneous adverse drug reactions (cADRs), such as human leucocyte antigen HLA-B*15:02, HLA-A*31:01 variants. METHODS: Genotyping results, generated from the Genomics England UK 100 000 Genomes Project primarily for identification of disease-causing variants, were used to additionally screen for relevant HLA variants and other pharmacogenomic variants. Medical records were retrospectively reviewed for clinical and cADR phenotypes for HLA variant carriers. Descriptive statistics and the χ2 test were used to analyse phenotype/genotype data for HLA carriers and compare frequencies of additional pharmacogenomic variants between HLA carriers with and without cADRs, respectively. RESULTS: 1043 people with epilepsy were included. Four HLA-B*15:02 and 86 HLA-A*31:01 carriers were identified. One out of the four identified HLA-B*15:02 carriers had suffered antiseizure medication-induced cADRs; the point prevalence of cADRs was 16.9% for HLA-A*31:01 carriers of European origin (n=46) and 14.4% for HLA-A*31:01 carriers irrespective of ancestry (n=83). CONCLUSIONS: Comprehensive utilisation of genetic data spreads beyond the search for causal variants alone and can be extended to additional clinical benefits such as identifying pharmacogenomic biomarkers, which can guide pharmacotherapy for genetically-susceptible individuals.

Pharmacological treatment of bipolar disorder and risk of diabetes mellitus: A nationwide study of 30,451 patients.

OBJECTIVE: While treatment with antipsychotics and antiepileptics have been associated with an increased risk of diabetes mellitus (DM), lithium may have the opposite effect via inhibition of glycogen synthase kinase-3. The aim of this study was to investigate whether treatment of bipolar disorder with lithium, antipsychotics, or antiepileptics is associated with the risk of DM in a real-world clinical setting. METHODS: Using nationwide registers, we identified all patients diagnosed with bipolar disorder in Danish Psychiatric Services from January 1, 1996, to January 1, 2019 (N = 30,451). The risk of developing DM was operationalized via hospital diagnoses and redeemed prescriptions for glucose-lowering drugs. For lithium, antipsychotics, valproate, and lamotrigine, we calculated hazard rate ratios (HRR) for developing DM via adjusted Cox proportional hazards models. Potential cumulative dose-response-like associations were examined using the log-rank test. RESULTS: During follow-up (245,181 person-years), 2107 (6.9%) patients developed DM. Compared with non-users of the respective drugs, we found no clinically or statistically significant difference in the risk of developing DM among patients receiving lithium (n = 11,690; incidence rate of DM/1000 person-years (IR) = 8.87, 95% CI: 8.02-9.90; HRR = 0.94, 95% CI: 0.84-1.06) or lamotrigine (n = 11,785; IR = 7.58, 95% CI: 6.69-8.59; HRR = 0.89, 95% CI: 0.77-1.02), respectively. Conversely, for patients receiving valproate (n = 5171; IR = 12.68, 95% CI: 10.87-14.80; HRR = 1.34, 95% CI: 1.14-1.58) and antipsychotics (n = 22,719; IR = 12.00, 95% CI: 11.14-12.94; HRR = 1.65, 95% CI: 1.45-1.88), respectively, there was increased risk of developing DM. For antipsychotics, we observed a clear cumulative dose-response-like association with the risk of DM. CONCLUSIONS: Treatment with valproate and antipsychotics-but not with lithium and lamotrigine-was associated with increased risk of DM in a real-world cohort of patients with bipolar disorder.

Supply problems of antiseizure medication are common among epilepsy patients in Germany.

OBJECTIVE: To evaluate the frequency of reported antiseizure medication (ASM) supply problems among patients with epilepsy (PWE) in Germany. METHODS: The Epi2020 study was a multicenter study focusing on different healthcare aspects of adult PWE in Germany. In addition to basic clinical and demographic characteristics, PWE were asked to answer a questionnaire regarding supply difficulties regarding their ASM, and if they had to discontinue ASM treatment due to supply problems. Generic switch of medication was recorded, and adverse effects were measured using the Liverpool Adverse Events Profile (LAEP) scale. Data were analyzed to detect predictors of supply problems. RESULTS: In total, 434 PWE with a mean age of 40 years (median 37 years, SD = 15.5, range: 18-83 years, 254 female) participated in this study. 53.7% of PWE (n = 233) reported that at least once in the past 12 months their ASM was not available at the pharmacy, and 24.9% (n = 108) reported having experienced ASM supply problems three times or more during the past 12 months. Patients with epilepsy treated with carbamazepine and zonisamide reported frequent problems with availability in 45.8% and 44.8% respectively, whereas those treated with lacosamide and valproate reported supply problems less frequently (17.0% and 16.4%, respectively). Nine patients (2.1%) were unable to take their ASM as prescribed at least once in the past 12 months due to supply problems. Forty-nine patients (11.3%) reported having to switch ASM due to supply difficulties with generic replacement occurring in 39.4% (n = 171) of patients. Those with supply problems were more likely to be treated with more ASMs and scored higher on the LAEP. CONCLUSION: Supply problems with ASM are frequent among PWE in Germany and are reported for older and newer ASMs. Supply problems contribute to ASM nonadherence and are positively correlated with the number of ASM taken and adverse events.