Breast cancer resistance protein polymorphism ABCG2 c.421C>A (rs2231142) moderates the effect of valproate on lamotrigine trough concentrations in adults with epilepsy.

BACKGROUND: Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (ABCG2 c.421C>A) of the breast cancer resistance protein. METHODS: In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose-adjusted lamotrigine troughs at steady state were the outcome, and (iii) ABCG2 c.421C>A genotype (wild-type [wt] homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (UGT1A4*3 c.142T>G, rs2011425; UGT2B7-161C>T, rs7668258; ABCB1 1236C>T, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios [GMR]). RESULTS: The two studies yielded consistent results (replicated); hence, we analyzed combined data (total N = 471, 140 treated, 331 controls, 378 ABCG2 c.421C>A wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, n = 21 vs. controls, n = 72) was around 60% higher than in wt subjects (treated, n = 119 vs. controls, n = 259)-ratio of GMRs 1.61 (95%CI 1.23-2.11) (frequentist) and 1.63 (95%CrI 1.26-2.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364 µmol/L vs. no valproate; or valproate ≥364 µmol/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low. CONCLUSION: Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.

Case series of COVID-19 in patients with myasthenia gravis: a single institution experience.

Coronavirus disease 2019 (COVID-19), caused by the late 2019 outbreak of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a respiratory disease which could put myasthenia gravis patients at a greater risk of developing severe disease course. This paper presents a single-institution case series of hospitalized myasthenia gravis patients with COVID 19. We identified eight patients previously diagnosed with myasthenia gravis, four of whom presented with clear signs of myasthenia gravis symptom worsening on admission. No form of respiratory support was needed during the complete duration of stay for three patients, oxygen therapy was administered to two patients, while the remaining three patients required mechanical ventilation. Treatment was successful for seven patients, six of whom were discharged without any myasthenia gravis symptoms. One patient died after eleven days of intensive care unit treatment. Although treatment of patients with myasthenia gravis and COVID-19 patients is challenging, case series of myasthenia gravis patients with COVID-19 treated in our institution demonstrates relatively favorable treatment outcome. Our data seem to support the notion that immunosuppressive medication does not seem to result in worse outcomes. Our data also support the notion that intravenous immunoglobulin treatment is safe and should be administered to patients with myasthenia gravis and COVID-19 in case of myasthenia gravis worsening since benefits seem to greatly outweigh the risks.

INCIDENCE OF ACUTE SYMPTOMATIC SEIZURES IN PATIENTS WITH COVID-19: A SINGLE-CENTER STUDY.

The most common neurological symptoms in patients with SARS-CoV-2 infection are headache, myalgia, encephalopathy, dizziness, dysgeusia and anosmia, making more than 90 percent of neurological manifestations of COVID-19. Other neurological manifestations such as stroke, movement disorder symptoms or epileptic seizures are rare but rather devastating, with possible lethal outcome. The primary aim of this study was to estimate the prevalence of acute symptomatic seizures among COVID-19 patients, while secondary aim was to determine their possible etiology. Out of 5382 patients with COVID-19 admitted to Dubrava University Hospital from November 1, 2020 until June 1, 2021, 38 (seizure rate 0.7%) of them had acute symptomatic seizures. Of these 38 patients, 29 (76.3%) had new-onset epileptic seizures and nine (23.7%) patients with previous epilepsy history had breakthrough seizures during COVID-19. Although acute symptomatic seizures are an infrequent complication of COVID-19, seizure risk must be considered in these patients, particularly in the group of patients with a severe course of the disease. Accumulation of proinflammatory cytokines may contribute to the occurrence of seizures in patients with COVID-19, but seizures may also be secondary to primary brain pathology related to COVID-19, such as stroke or encephalitis.

DELAYED EFFECT OF VNS ON INTERICTAL EPILEPTIFORM DISCHARGES AND PHARMACORESISTANCE IN A PATIENT WITH REFRACTORY PERINATAL POSTISCHEMIC EPILEPSY.

A 20-year-old female with refractory perinatal postischemic catastrophic epilepsy and frequent daily generalized atonic, tonic, tonic-clonic and focal seizures was hospitalized in the progressive phase of illness. The diagnosis was confirmed by semiology, interictal electroencephalogram (EEG), long-term video EEG monitoring, and brain magnetic resonance imaging. Repeated interictal EEG findings showed generalized spike and slow wave complexes with a 2-3 Hz frequency. Interictal EEG showed evidence of electroclinical epileptic status on several occasions. She was treated with various antiepileptic drugs without improvement. After verification of her incompetence for normal autonomous living, which resulted in very low quality of life, this patient with refractory epilepsy underwent implantation of vagus nerve stimulator (VNS). In this case report, we present delayed effect of VNS on interictal epileptiform discharges and pharmacoresistance.

FALSE PHARMACORESISTANCE - A TRUE PROBLEM.

Pharmacoresistant epilepsy poses a great burden to patients, their families, and the whole healthcare system, with numerous social, economic, physical, and psychical consequences. Hence, it is a diagnosis that has to be made only in cases of high certainty, after all potential causes of epilepsy have been evaluated. One of the important causes of pharmacoresistant epilepsy is false pharmacoresistance, an entity that implies a condition in which poor disease control is not a consequence of the biology of the disease itself, antiepileptic drug inefficacy, and/or patient specificity. It is a consequence of human error and strongly depends on the experience of the treating physician, as well as on the attitude of the patient. Despite its 'falseness', this entity is accompanied by real consequences for the patient and his family, and at the same time, it delays appropriate treatment of the actual disease from which the patient is suffering. In order to introduce appropriate treatment and avoid unnecessary and harmful diagnostic procedures, false pharmacoresistance is a condition that has to be ruled out in any patient with difficult-to-treat seizures.

Paroxismal non-kinesigenic dyskinesia and hemidystonia associated with silent celiac disease.

Paroxismal non-kinesigenic dyskinesia (PNKD) is a rare movement disorder manifesting as choreatic/dystonic movements, usually lasting from minutes to up to 4 h, with perserved consciousness during attacks. Primary PNKD are idiopathic or genetic disorders while secondary PNKD are associated with various neurologic and medical conditions. We present a case with PNKD and right sided hemidystonia in association with celiac disease, responsive to gluten-free diet, not previously reported in available literature. In conclusion, diagnostic tests for celiac disease should be a part of etiological investigations in patients with otherwise unexplained movement disorders including PKND. Gluten free diet could produce a favorable clinical response in those patients.

Dynamics of inflammatory factors expression in ischemic brain tissue injury.

Ischemic stroke is one of the most common cause of mortality and disability in the modern world. Still, therapeutic options remain modest. Aim of the study was to present dynamics of inflammatory factors expression (C reactive protein, procalcitonin, interleukin 10) in patients after ischemic stroke. Our study included 101 patients divided in thrombolised and nonthrombolised groups. Inflammatory factors concentration in serum was determinate at admission, 24, 48 hours and seven days after the initial onset, while neurological assessment was measured at the admission, 24 hours, seven days and three months after the initial onset using National Institute of Health Stroke Scale and Rankin Scale. Certain pattern was observed in dynamics of inflammatory factors: intensive increase in first and second day after the stroke, followed by decrease till day seven in both groups. Additionally, thrombolised group showed significant neurological improvement. Although well investigated, the role of inflammatory factors in the ischemic stroke still stays controversial. High association of C reactive protein and interleukin 10 values suggest potential prognostic role in patient's follow-up, while the role of procalcitonin values still remains unclear.

Lack of association of SCN2A rs17183814 polymorphism with the efficacy of lamotrigine monotherapy in patients with focal epilepsy from Herzegovina area, Bosnia and Herzegovina.

OBJECTIVE: We assessed the influence of the SCN2A gene polymorphism c.56 G > A rs17183814 on the response to lamotrigine monotherapy in patients with focal epilepsy in Herzegovina area, Bosnia and Herzegovina. MATERIAL AND METHODS: For SCN2A polymorphism c.56 G > A rs17183814, one hundred patients with epilepsy who were receiving lamotrigine in monotherapy and seventy-one age and sex matched healthy controls were genotyped using TaqMan assay. All patients were Caucasians from the region of Herzegovina, Bosnia and Herzegovina. Genotyping was conducted using a polymerase chain reaction in real time. Patients were divided into two groups: responders and non-responders. RESULTS: Of all patients with epilepsy, 33% were non-responders, and 67% were responders. The mean age of non-responders was 38.8 vs. group of responders in which it was 35.2. Mean age of onset of seizures in epilepsy patients was 26.7 for non-responders and 25.4 for responders. In patients with epilepsy, the mean age of seizure onset was 26.7 for non-responders and 25.4 for responders. For SCN2A c.56 G > A gene polymorphism, we did not observe any significant differences in genotypic or allelic frequency between patients with epilepsy and healthy controls. Genotype or allelic frequencies of SCN2A c.56 G > A gene polymorphism did not significantly differ for AG or GG genotypes in the non-responders vs. responders. CONCLUSION: There was no significant association in patients with focal epilepsy between studied genotypes and response to lamotrigine monotherapy in Herzegovina patients with focal epilepsy. However, we need studies in a bigger cohort of patients with epilepsy to be assessed in the future.

The lack of influence of IVS5-91 G>A polymorphism of the SCN1A gene on efficacy of lamotrigine in patients with focal epilepsy.

Background: IVS5-91G>A (rs3812718) polymorphism of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene has been associated with inadequate responsiveness to common antiepileptic drugs which act as sodium channel blockers. This study was performed to investigate the effect of IVS5-91G>A (rs3812718) polymorphism on lamotrigine (LTG) efficacy in a cohort of patients with non-lesional focal epilepsy taking LTG as monotherapy. Methods: A total of 100 of patients with non-lesional focal epilepsy on LTG monotherapy was included in this prospective interventional study. After reaching a stable dose of LTG patients were followed-up for 12 consecutive months. LTG responsiveness was defined as a 75% or more reduction in seizure frequency on a stable dose of LTG. Genotyping was performed at the end of the study using standard procedures and data were correlated with clinical data. Results: There were no significant differences in the prevalence of responsiveness to LTG between carriers of different genotypes. Average maintenance LTG doses in the responder group differed by genotype in the order AA>GA>GG, but these differences did not reach statistical significance. Conclusion: Our data suggest lack of association between SCN1A IVS5-91G>A (rs3812718) polymorphism and response to LTG.

Efficacy of repetitive transcranial magnetic stimulation using a figure-8-coil or an H1-Coil in treatment of major depressive disorder; A randomized clinical trial.

Repetitive transcranial magnetic stimulation (rTMS) is an evidence-based treatment option for major depressive disorder (MDD). However, comparisons of efficacy between the two FDA-approved protocols of rTMS modalities are lacking. The aim of this industry-independent, randomized-controlled, single-blind trial was to evaluate clinical outcome of the two FDA-approved rTMS protocols delivered by H1-coil and the figure-8-coil, in MDD patients. A total of 228 MDD patients were randomized to 20 sessions of H1-coil or 8-coil as an adjunct to standard-of-care pharmacotherapy, or standard-of-care pharmacotherapy alone. Baseline MDD symptom severity was almost the same in the three groups. Hamilton depression rating scale (HAM-D17) mean score was 17 (5.3) in H1-coil, 17 (5.4) in 8-coil, and 19 (6.1) in control group. The primary outcome was the proportion of patients achieving remission defined as HAM-D17 score ≤7 at end-of-treatment at week-4. In the intention-to-treat analysis odds ratio for remission was 1.74 (CI95% 0.79-3.83) in H1-coil compared to the 8-coil group. The difference between two rTMS protocols was not significant. Remission rate was significantly greater in both HF-rTMS groups compared to the control: 60% (CI95% 48-71%), 43% (CI95% 31-55%) and 11% (CI95% 5-20%) respectively. The response was significantly better in H1-coil, than in 8-coil group OR = 2.33; CI95% 1.04-5.21 (P = 0.040). The HAM-D17 was lowered by 59% in the H1-coil, 41% in the 8-coil (P = 0.048), and 17% in the control group (P < 0.001 vs H1-coil; P = 0.003 vs 8-coil). Safety, tolerability, and the changes in quality of life were comparable. We confirmed the safety and efficacy of both FDA-approved protocols as adjunctive treatments of MDD. Better response rate and greater reduction of depression severity were observed in the H1-coil group, but without a significant difference in the remission rate between the two rTMS modalities. CLINICAL TRIALS REGISTRATION: Clinicaltrials.govNCT02917499.

Effect of clonidine on the cutaneous silent period during spinal anesthesia.

AIM: To investigate the effect of clonidine on the cutaneous silent period (CSP) during spinal anesthesia. METHODS: A total of 67 adult patients were included in this randomized, prospective, single-center, double-blind trial. They did not have neurological disorders and were scheduled for inguinal hernia repair surgery. This trial was registered on ClinicalTrials.gov (NTC03121261). The patients were randomized into two groups with regards to the intrathecally administered solution: (1) 15 mg of 0.5% levobupivacaine with 50 µg of 0.015% clonidine, or (2) 15 mg of 0.5% levobupivacaine alone. There were 34 patients in the levobupivacaine-clonidine (LC) group and 33 patients in the levobupivacaine (L) group. CSP and its latency were measured four times: prior to the subarachnoid block (SAB), after motor block regression to the 0 level of the Bromage scale, with ongoing sensory blockade, and both 6 and 24 h after SAB. RESULTS: Only data from 30 patients in each group were analyzed. There were no significant differences between the groups investigated preoperatively and after 24 h. The CSP of the L group at the time point when the Bromage scale was 0 was 44.8 ± 8.1 ms, while in the LC group it measured 40.2 ± 3.8 ms (P = 0.007). The latency in the L group at the time point when the Bromage scale was 0 was 130.3 ± 10.2 ms, and in the LC group it was 144.7 ± 8.3 ms (P < 0.001). The CSP of the L group after 6 h was 59.6 ± 9.8 ms, while in the LC group it was 44.5 ± 5.0 ms (P < 0.001). The latency in the L group after 6 h was 110.4 ± 10.6 ms, while in LC group it was 132.3 ± 9.7 ms (P < 0.001). CONCLUSION: Intrathecal addition of clonidine to levobupivacaine for SAB in comparison with levobupivacaine alone results in a diminished inhibitory tonus and shortened CSP.

Is Apolipoprotein E ε2 Associated with Delayed Onset of Non-Lesional Temporal Lobe Epilepsy?

The aim of the study was to evaluate the possible association between Apo E polymorphisms and age at seizure onset in patients with non-lesional temporal lobe epilepsy. Eighty patients with non-lesional temporal lobe epilepsy with or without bilateral tonic-clonic propagation were analyzed. Age at seizure onset was defined as age at the first unequivocal seizure (excluding febrile convulsions). ApoE alleles were determined by a procedure where genome DNA was amplified by chain reaction along with polymerase, using the LightCycler kit (Roche) for ApoE mutations on codons 112 and 158. There was a statistically significant difference between the groups of patients with ApoE ε2/3 and ε3/4 genotypes (p=0.03), but not between patients with ApoE, ε2/3 and ε3/3, and those with ApoE ε3/4 and ε3/3. In conclusion, the results of our study suggested positive association of a specific ApoE genotype and onset of non-lesional temporal lobe epilepsy.

The Croatian Model of Integrative Prospective Management of Epilepsy and Pregnancy

Epilepsy is the most common neurological complication in pregnancy. Women with epilepsy have a higher risk of complications in pregnancy. In Croatia, women with epilepsy are treated by neurologists at tertiary centers according to the place of residence. We prospectively followed-up pregnancies in women with epilepsy and healthy controls, and analyzed the factors responsible for their delivery outcomes and development of their babies. Healthy pregnant women had a higher level of education and economic status, but pregnant women with epilepsy took folic acid in a higher proportion than controls, possibly due to timely preconception counseling. Complications during pregnancy depended on the number of antiepileptic drugs and epilepsy control. We noticed some behavioral and cognitive aspects in children exposed in utero to valproic acid, which required follow up. The rate of congenital malformations was not increased. In conclusion, women with epilepsy should receive preconception counseling about the risk for pregnancy, but also about the possibilities to minimize that risk. We have introduced a model of integrative management of pregnancy and epilepsy based on close collaboration among different clinical experts in Croatia, in order to provide prompt counseling and timely intervention.

General recommendations for the management of aneurysmal subarachnoid hemorrhage.

Subarachnoid hemorrhage is a neurologic emergency and a detrimental cerebrovascular event with a high rate of death and complications. Recommendations have been developed and based on literature search, evaluation of the results of large international clinical trials, collective experience of the authors, and endorsed by the Croatian Society of Neurovascular Disorders, Croatian Society of Neurology including Section for Neurocritical Care, Croatian Neurosurgical Society, Croatian Society for Difficult Airway Management and Croatian Medical Association. The aim of these guidelines is to provide current and comprehensive recommendations and to assist physicians in making appropriate decisions in the management of subarachnoid hemorrhage. Evidence based information on the epidemiology, risk factors and prognosis, as well as recommendations on diagnostic work up, monitoring and management are provided, with regard to treatment possibilities in Croatia.

Recommendations for the management of medical complications in patients following aneurysmal subarachnoid hemorrhage.

These are evidence based guidelines for the management of medical complications in patients following aneurysmal subarachnoid hemorrhage, developed and endorsed by the Croatian Society of Neurovascular Disorders, Croatian Society of Neurology including Section for Neurocritical Care, Croatian Neurosurgical Society, Croatian Society for Difficult Airway Management and Croatian Medical Association. They consist of recommendations for best monitoring, medical treatment and interventions based on the literature, evaluation of the results of large international clinical trials, and collective experience of the authors.