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.
AIMTo evaluate the association between carotid intima-media thickness (CIMT) at hospital admission and unfavorable outcomes in adults without advanced vascular diseases presenting with non-severe ...COVID-19 pneumonia to assess the feasibility of evaluating CIMT as a risk stratification aid in this setting.METHODSThis proof-of-concept nested case-control study enrolled consecutive non-vaccinated adults free of advanced vascular diseases presenting with verified non-severe COVID-19 pneumonia between December 2020 and June 2021. CIMT was measured at admission, and patients were managed in line with the national Ministry of Health guidelines. Those who died or required mechanical ventilation (MV) during the index hospital stay were considered cases and were matched (entropy balancing, exact matching) on a set of covariates to survivors not requiring MV (controls). Frequentist and Bayesian logistic models were fitted to the case status.RESULTSThe study enrolled 207 patients: 27 (13%) cases and 180 controls. All were retained in the analysis after entropy balancing, while 27 cases were exactly matched to 99 controls. Higher CIMT at the proximal internal carotid artery (both left and right) was consistently associated with higher odds of being a case: all odds ratio point-estimates were ≥1.50 with lower limits of the 99% confidence intervals/credibility intervals ≥1.00 with two-sided probabilities of OR>1.00 greater than 99.5%. The susceptibility of the estimates to unmeasured confounding was low.CONCLUSIONThis study supports the feasibility of CIMT as a risk stratification aid in adults free of advanced vascular disease presenting with non-severe COVID-19 pneumonia.
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.
Seizure control with antiepileptic drugs (AEDs) as well as susceptibility to adverse drug reactions varies among individuals with epilepsy. This interindividual variability is partly determined by ...genetic factors. However, genetic testing to predict the efficacy and toxicity of AEDs is limited and genetic variability is, as yet, largely unexplainable. Accordingly, genetic testing can only be advised in a very limited number of cases in clinical routine. Currently, by applying different methodologies, many trials have been undertaken to evaluate cost benefits of preventive pharmacogenetic analysis for patients. There is significant progress in sequencing technologies, and focus is on next-generation sequencing-based methods, like exome and genome sequencing. In this review, an overview of the current scientific knowledge considering the pharmacogenetics of AEDs is given.
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.
Coronavirus disease 2019
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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.
Aim To investigate stroke characteristics in patients with concomitant coronavirus disease 2019 (COVID-19) infection in Croatia during the second wave of the COVID-19 pandemic. Methods This ...retrospective study investigated the characteristics of two groups of ischemic stroke patients: those who developed COVID-19 infection before stroke and those who developed the infection during the hospital stay after stroke onset. Stroke etiology was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Results We analyzed data from 255 stroke patients from 12 Croatian hospitals. The two groups of ischemic stroke patients differed in stroke etiology (P=0.038). Patients with COVID-19 infection before stroke had fewer cardioembolic strokes (46% vs 29.1%), more cryptogenic strokes (32.5% vs '4.3%), and more strokes in multiple vascular territories (12.4% vs 1.8%). The percentage of large-vessel occlusions was high in both groups (49.6% and 44.4%). Median modified Rankin Scale score on discharge was 4 in both groups. Mortality was 36.4% in the group with stroke after COVID-19 and 33.3% in the group with COVID-19 after stroke. Conclusion Ischemic stroke after COVID-19 differs in etiology from ischemic stroke complicated by COVID-19 infection. Both patient groups are characterized by severe disability and high mortality. Raising the awareness of prehospital stroke and optimization of clinical workflow are important if we want to improve the stroke outcomes by acute recanalization techniques.
Epilepsy is treated with a variety of anticonvulsants that are often used concomitantly. Therefore, therapeutic drug monitoring is often necessary. Along with clinical and environmental factors, ...genetic predisposition has been recognized to be relevant for interindividual variability in drug response. Polymorphic transporter proteins such as P-glycoprotein significantly influence pharmacokinetics and bioavailability of many structurally unrelated drugs. The aim of the study was to evaluate the impact of polymorphisms in the P-glycoprotein-encoding gene ABCB1 (C1236T, G2677T/A, C3435T) on antiepileptic drug disposition.
We recruited 222 patients with epilepsy who were prescribed lamotrigine in monotherapy or polytherapy. Lamotrigine plasma concentrations were analyzed and compared with ABCB1 gene variants. The ABCB1 genotyping was performed by real-time polymerase chain reaction methods. The therapeutic drug monitoring was performed by high-performance liquid chromatography-diode array detector (DAD) and immunoassay.
A significant correlation was confirmed between lamotrigine concentration and additional drugs (P < 0.001). In the whole group, statistical analysis showed correlations between lamotrigine concentrations and ABCB1 C1236T variants: 10.1 and 6.5 μmol/L for CC versus CT + TT, respectively (P = 0.021), and for dose corrected lamotrigine 0.068 and 0.053 μmol·L·mg, for CC versus CT + TT, respectively (P = 0.017). Analysis of a specific haplotype showed that 1236C-2677G-3435C carriers had higher lamotrigine concentrations than 1236T-2677G-3435T carriers (P < 0.001), followed by 1236T-2677T-3435C carriers (P < 0.001).
ABCB1 C1236T, G2677T/A, C3435T polymorphisms have an influence on lamotrigine serum concentrations.
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.
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.
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).
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.
Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.
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