Effect of clinical features on antiseizure medication doses in patients with newly diagnosed epilepsy.

Objective: We evaluate the effect of distinct clinical features on anti-seizure medication (ASM) doses in seizure-free and not seizure-free patients aged ≥16 years with new-onset epilepsy. Materials and methods: This study included 459 patients with a validated diagnosis of epilepsy. The most prescribed ASMs were oxcarbazepine (OXC; n = 307), followed by valproic acid (VPA; n = 115), carbamazepine (CBZ; n = 81), and lamotrigine (LTG; n = 67). The seizure freedom rate with their first or subsequent ASM was 88.0%. A retrospective analysis of patient records was performed to determine any association between doses of ASMs and patient characteristics. Results: The median OXC dose in seizure-free patients aged >60 years was 600 mg compared to 900 mg in younger patients. When controlling for age but not in an unadjusted model, the median dose of OXC was lower (300 mg, p = 0.018) for seizure-free patients compared to non-seizure-free patients, and the median dose of OXC was also 300 mg lower among older patients aged >60 years (p < 0.001). The median OXC doses for men aged ≤60 years were 300 mg higher than for women aged >60 years (900 mg vs. 600 mg, p = 0.021). The median dose of VPA was 400 mg higher in men than in women (p < 0.001) and 400 mg higher in not seizure-free patients compared to seizure-free patients only when adjusting for sex (p < 0.001). Higher median doses for CBZ were registered with FAS compared with FBTCS (difference in median doses of 200 mg; p = 0.017). Conclusion: Significant OXC dose differences were detected between age groups, whereas VPA dosing was different in men and women. Moreover, CBZ doses were dependent on some seizure types. These data allow for the individualization of the initial target dosing based on key clinical characteristics.

Indications for the use of intravenous second-line antiseizure medications in an emergency room setting.

BACKGROUND: Second-line iv antiseizure medications (ASMs) are used to treat status epilepticus (SE), but in the emergency room setting, there might be other intended and unintended indications for administration. We wanted to explore these different indications and assess the actual usage of first- and second-line ASMs for SE with reference to other uses, such as for SE mimics. METHODS: In this retrospective study, we searched the electronic patient registry with the following terms: "epilepsy", "SE", and "seizure", during 2015. Patients at least 16 years old and treated with iv second-line ASMs were further analysed. We reassessed the indications for the use of iv ASMs based on clinical features and examinations performed. RESULTS: A total of 166 episodes from 136 patients with a median age of 66 years were evaluated, constituting the following indication categories: ongoing SE (48.2%), recurrent seizures (19.3%), postictal (12.1%), seizure mimics (10.2%) and prophylactic use of ASMs (10.2%). Ongoing SE included the following subgroups: convulsive SE, focal aware SE, nonconvulsive SE (NCSE) and NCSE with coma. The seizure mimics group had a preexisting epilepsy diagnosis more often than the ongoing SE group (73% vs. 44%, p = 0.039). Ischaemic stroke was the most frequent seizure mimic. EEG was performed during hospital admission in 78% of patients with ongoing SE, 50% of patients with recurrent seizures, 75% of patients with postictal state, 53% of seizure mimic episodes and 12% of the prophylactic group. In NCSE and comatose NCSE, the diagnosis was made, and treatment was initiated only after an EEG in 52% and 30% of cases, respectively. The use of newer second-line ASMs (levetiracetam and lacosamide) was frequent in our study population. Immediate side effects of ASMs were infrequent. CONCLUSIONS: Even though most of the use of ASMs was justified and administered for SE, it is a diagnostic challenge where a prior diagnosis of epilepsy can be a misleading factor, and EEG is an essential tool when clinical features are often overlapping with other acute seizure disorders. Side effects of the newer second-line ASMs after a single dose are infrequent.

Prescribed antiseizure medication doses and their relation to defined daily doses for achieving seizure freedom in newly diagnosed patients with epilepsy.

OBJECTIVES: To investigate the antiseizure medication (ASM) doses required to achieve seizure freedom and their correlation with the World Health Organization's defined daily doses (DDDs) in patients aged 16 years or older with newly diagnosed epilepsy. METHODS: The study included 459 patients with a validated diagnosis of new-onset epilepsy. Patient records were retrospectively analyzed to determine the ASM doses in patients with or without seizure freedom during follow-up. The DDD of the relevant ASM was then retrieved. RESULTS: The seizure-freedom rate with first and subsequent ASMs was 88% (404/459 patients) during the follow-up. The mean prescribed doses (PDDs) and PDD/DDD ratio of the most commonly used ASMs, ie, oxcarbazepine (OXC), carbamazepine (CBZ), and valproic acid (VPA), differed significantly between seizure-free and non-seizure-free status (992 mg and 0.99 vs 1132 mg and 1.13; 547 mg and 0.55 vs 659 mg and 0.66; and 953 mg and 0.64 vs 1260 mg and 0.84, respectively). The effect of the OXC dose as the first failed ASM on the possibility of achieving seizure freedom was significant (Fisher's exact test, p = 0.002). Thirty-four of 43 patients (79%) in which an OXC dose of ≤900 mg failed became seizure-free, as compared with 24 of 54 patients (44%) with a failed OXC dose >900 mg. SIGNIFICANCE: The present study provides new insights into the doses of the commonly used ASMs such as OXC, CBZ, and VPA that can lead to seizure freedom as monotherapy or as combination therapy. The higher PDD/DDD ratio of OXC (0.99) than that of CBZ or VPA renders a generalized PDD/DDD comparison highly problematic.

Long-term effectiveness of enzyme replacement therapy in Fabry disease with the p.Arg227Ter variant: Fabry disease in Ostrobothnia (FAST) study.

Fabry disease (FD) is an X chromosome-linked, life-threatening lysosomal disease caused by one of more than 1000 currently known variants in the α-galactosidase A (GLA) gene. The follow-up part of the Fabry Disease in Ostrobothnia (FAST) study reports the long-term effect of enzyme replacement therapy (ERT) on a prospectively collected cohort of 12 patients, 4 males and 8 females, mean age 46 years (SD 16), with the classical variant c.679C > T p.Arg227Ter, which is one of the most common FD variants worldwide. In the natural history period of the FAST study, half of the patients in both sexes had at least one major event, of which 80% were of cardiac origin. During 5 years of ERT, four patients had a total of six major clinical events consisting of one silent ischemic stroke, three ventricular tachycardias and two increased left ventricular mass indexes. In addition, four patients developed minor cardiac events, four patients minor renal events, and one patient a minor neurological event. ERTs may delay but not prevent the progression of the disease in most patients with the variant Arg227Ter. This variant might be suitable for investigating the efficacy of second-generation ERTs compared to the currently used ERTs regardless of sex.

Response to subsequent antiseizure medications after first antiseizure medication failure in newly diagnosed epilepsy.

Objective: There is a lack of studies using the International League Against Epilepsy (ILAE) recommendation to define drug-resistant epilepsy (DRE). This study evaluated the seizure freedom rates of substitution or add-on and subsequent antiseizure medication (ASM) therapies using different proposed definitions of DRE or ASM trials in patients with a failed first ASM. We also identified prognostic factors for 1-year seizure freedom. Methods: This study included 459 patients with epilepsy of whom 151 were not seizure-free after the first ASM. Multilevel mixed-effects logistic regression was used to examine the correlation between observations from the same patient. Results: The overall seizure freedom rate with the first and subsequent ASMs was 88.0% (404/459). The rate of DRE when defined as the failure of two ASMs for any reason was 20.0%, and according to the ILAE definition of DRE, it was 16.3%. After failing the first ASM, 63.6% of patients (96/151) became seizure free with subsequent ASMs and tried an average of 1.9 ASMs (range 1-5). Of the patients who achieved 1-year seizure freedom, 10.1% (41/404) were taking polytherapy and there was no difference between substitution and add-on. All the patients with generalized epilepsy were seizure-free. A favorable prognostic factor was age >60 years and an EEG without epileptiform activity. The efficacies of the different ASMs were largely similar, but drugs that enhanced GABA-mediated inhibitory neurotransmission had the lowest seizure freedom rate. Significance: In adults with newly-diagnosed epilepsy, 1-year seizure freedom was achieved for almost 90% of the patients. After failing the first ASM, two-thirds of the patients responded to subsequent ASM regimens. Our results support the feasibility and applicability of the ILAE concept of an adequate ASM trial and the failure of two ASMs as a definition of DRE.

Clinical utility of a video/audio-based epilepsy monitoring system Nelli.

OBJECTIVE: The aim of this study was to evaluate the clinical utility of a semi-automated hybrid video/audio-based epilepsy monitoring system (Nelli®) in a home setting. METHODS: In this retrospective study, 104 consecutive patients underwent Nelli-registration for an average of 29 days at their home. The seizure-related data obtained from the registration were assessed to investigate the utility of the Nelli-registration regarding clinical decision-making. RESULTS: Of 104 patients, Nelli® hybrid system was able to recognize clinically relevant events in 83 (80%) patients: epileptic seizures in 67 (65%) and nonepileptic events in 16 (15%). A total of 2767 epileptic seizures of different seizure types were captured and identified. These seizures included not only tonic-clonic seizures but also other complex or simple motor seizures. For the outcomes regarding clinical decision-making, a need for a new therapeutic intervention was recognized in 54 (51.9%) patients based on the number and severity of seizures captured by Nelli-registration. In 12 (11.5%) patients, the need to change the treatment plan was excluded because no evidence of suspected epileptic seizures was found. Nelli-registration aided in confirming the therapeutic efficacy of modifications of antiseizure medications (ASMs) or neuromodulation therapies in 13 (12.5%) patients. Nelli-registration enabled to determine the change in seizure classification and facilitated to reach clear diagnostic conclusions in 11 (10.6%) patients. In 14 (13.5%) patients, there was no change in clinical outcome, as Nelli-registration was unable to infer any clinical decision either due to inconclusive results or lack of typical events. Seizures detected during Nelli-registration aided in decision-making for therapeutic interventions in 71 (68%) patients. Altogether, 44 (42%) patients had adjustment of ASMs, and in 9 (9%) patients, Nelli-registrations led to the change in the settings of vagus nerve stimulation (VNS) or deep brain stimulation (DBS) treatment. Additionally, 18 (17%) patients were referred to presurgical evaluation or established a baseline seizure frequency before surgical implantation for neuromodulation treatment with VNS or DBS, while 33 (32%) patients had no change in therapy. Nine patients (8.7%) were referred to video-EEG monitoring (VEM), as Nelli-recorded events highlighted the need for presurgical evaluation in 6 patients or further diagnostic evaluation in 3 patients. CONCLUSION: This study confirms the clinical utility of the video/audio monitoring system Nelli® in home settings. Home monitoring with Nelli® hybrid system provides a new alternative for the assessment of frequency and type of epileptic seizures as well as for a recognition of nonepileptic events. Thus, Nelli-registration can facilitate the optimization of seizure monitoring and management in clinical practice, complementing existing methods such as VEM and ambulatory EEG recordings.

Raman spectroscopy combined with comprehensive gas chromatography for label-free characterization of plasma-derived extracellular vesicle subpopulations.

Raman spectroscopy together with comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GCxGC-TOFMS) was employed to characterize exomere- (<50 nm) and exosome-sized (50-80 nm) EVs isolated from human plasma by the novel on-line immunoaffinity chromatography - asymmetric flow field-flow fractionation method. CD9+, CD63+, and CD81+ EVs were selected to represent general EV subpopulations secreted into plasma, while CD61+ EVs represented the specific EV subset derived from platelets. Raman spectroscopy could distinguish EVs from non-EV particles, including apolipoprotein B-100-containing lipoproteins, signifying its potential in EV purity assessment. Moreover, platelet-derived (CD61+) EVs of both exomere and exosome sizes were discriminated from other EV subpopulations due to different biochemical compositions. Further investigations demonstrated composition differences between exomere- and exosome-sized EVs, confirming the applicability of Raman spectroscopy in distinguishing EVs, not only from different origins but also sizes. In addition, fatty acids that act as building blocks for lipids and membranes in EVs were studied by GCxGC-TOF-MS. The results achieved highlighted differences in EV fatty acid compositions in both esterified (membrane lipids) and non-esterified (free fatty acids) fractions, indicating possible differences in membrane structures, biological functions, and roles in cell-to-cell communications of EV subpopulations.

Pulmonary manifestations and the effectiveness of enzyme replacement therapy in Fabry Disease with the p. Arg227Ter (p.R227*) mutation.

BACKGROUND: Fabry disease (FD) is caused by a defect in α-galactosidase A gene (GLA) which leads to a progressive accumulation of neutral shingolipids, mainly globotriaosylceramide and its metabolites in several organs. Pulmonary manifestations of FD mimic chronic obstructive pulmonary disease and are disproportionate to smoking status. The effect of enzyme replacement therapy (ERT) on pulmonary function is inconclusive. We studied the effect of ERT on pulmonary function in FD with a mutation p. Arg227Ter (p.R227*) which is one of the most common mutations causing classical FD in Finland and worldwide. METHODS: Patients were annually examined by multidisciplinary team. Based on the maximal pulmonary oxygen consumption at the baseline, either cardiopulmonary exercise test or combination of spirometry and 6-minute walking test were performed annually during 5-year follow-up. RESULTS: Four males and eight females met the criteria for ERT and were included in this study. Three of 12 patients had obstruction by GOLD criterion before ERT, and one had a borderline obstruction. In 5 years, five patients were classified as obstructive, although the real change in FEV1/FVC was unchanged in the whole cohort. Only one patient was an active smoker. CONCLUSION: In nonsmokers, pulmonary manifestations in classical FD are mild and might be stabilized by ERT.

Infrared and Raman spectroscopy for purity assessment of extracellular vesicles.

Extracellular vesicles (EVs) are a complex and heterogeneous population of nanoparticles involved in cell-to-cell communication. Recently, numerous studies have indicated the potential of EVs as therapeutic agents, drug carriers and diagnostic tools. However, the results of these studies are often difficult to evaluate, since different characterization methods are used to assess the purity, physical and biochemical characteristics of the EV samples. In this study, we compared four methods for the EV sample characterization and purity assessment: i) the particle-to-protein ratio based on particle analyses with nanoparticle tracking and protein concentration by bicinchoninic acid assay, ii) Western Blot analysis for specific EV biomarkers, iii) two spectroscopic lipid-to-protein ratios by either the attenuated total reflection Fourier transform infrared (ATR-FTIR) or Raman spectroscopy. The results confirm the value of Raman and ATR-FTIR spectroscopy as robust, fast and operator independent tools that require only a few microliters of EV sample. We propose that the spectroscopic lipid-to-protein (Li/Pr) ratios are reliable parameters for the purity assessment of EV preparations. Moreover, apart from determining protein concentrations, we show that ATR-FTIR spectroscopy can also be used for indirect measurements of EV concentrations. Nevertheless, the Li/Pr ratios do not represent full characterization of the EV preparations. For a complete characterization of selected EV preparations, we recommend also additional use of particle size distribution and EV biomarker analysis.

Nonresonant CARS Imaging of Porous and Solid Silicon Nanoparticles in Human Cells.

Coherent anti-Stokes Raman scattering (CARS), a nonlinear optical method for rapid visualization of biological objects, represents a progressive tool in biology and medicine to explore cells and tissue structures in living systems and biopsies. In this study, we report efficient nonresonant CARS imaging of silicon nanoparticles (SiNPs) in human cells as a proof of concept. As both bulk and porous silicon exhibit a high third-order nonlinear susceptibility, χ(3), which is responsible for the CARS intensity, it is possible to visualize the SiNPs without specific labels. Porous and solid SiNPs were obtained from layers of porous and nonporous silicon nanowires and mesoporous silicon. Electron microscopy and Raman spectroscopy showed that porous SiNPs consisted of ∼3 nm silicon nanocrystals (nc-Si) and pores, whereas solid nanoparticles comprised ∼30 nm nc-Si. All types of SiNPs were nontoxic at concentrations up to 500 µg/mL after 24 h of incubation with cells. We demonstrated that although nc-Si possesses a distinguished narrow Raman band of about 520 cm-1, it is possible to detect a high CARS signal from SiNPs in the epi-direction even in a nonresonant regime. 3D CARS images showed that all types of studied SiNPs were visualized as bright spots inside the cytoplasm of cells after 3-6 h of incubation because of the contrast provided by the high third-order nonlinear susceptibility of SiNPs, which is 1 × 104 to 1 × 105 times higher than that of water and typical biological media. Overall, CARS microscopy can provide localization of SiNPs within biological structures at the cellular level and can be a powerful tool for in vitro monitoring of silicon-based drug delivery systems or use SiNPs as labels to monitor various bioprocesses inside living cells.

Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients.

BACKGROUND: Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. OBJECTIVES: To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. METHODS: In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. RESULTS: Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. CONCLUSIONS: SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

Response to first antiseizure medication in patients diagnosed with epilepsy.

OBJECTIVES: To investigate the interaction among the efficacy, tolerability and overall effectiveness of the first antiseizure medication in patients 16 years or older with newly diagnosed epilepsy. MATERIALS AND METHODS: The study included 584 patients who were referred to the Tampere University Hospital between 1 January 1995 and 31 December 2005 and were diagnosed with epilepsy. All individuals were retrospectively followed up until 31 December 2006, until reaching at least one year of seizure freedom, or until death if before the cut-off date. RESULTS: Overall, after thorough validation of the epilepsy diagnosis 459 patients comprised the study cohort; among these patients, 73% of males and 60% of females became seizure-free for at least one year with the first antiseizure medication. The seizure freedom rate for focal epilepsy was 67%. There was no significant difference in focal epilepsy to achieve seizure freedom between oxcarbazepine, carbamazepine or valproic acid. The seizure freedom rate among patients above 60 years of age was 67%. For patients with structural and unknown aetiology, seizure freedom rates were 61.5% and 75.3%, respectively. Additionally, epileptiform activity on EEG in patients with focal epilepsy decreased odds of seizure freedom in adjusted logistic regression models (OR 0.55, p=0.036). CONCLUSIONS: This study provides a more positive prediction of seizure freedom compared with previous studies with the onset of epilepsy at 16 years or older with an overall estimation that two-thirds of patients with new-onset epilepsy obtain seizure freedom with the first antiseizure medication.

Natural course of Fabry disease with the p. Arg227Ter (p.R227*) mutation in Finland: Fast study.

BACKGROUND: Fabry disease is caused by a deficient or an absent alfa-galactosidase A activity and is an X-linked disorder that results in organ damage and a shortened life span, especially in males. The severity of the disease depends on the type of mutation, gender, skewed X-chromosome inactivation, and other still unknown factors. METHODS: In this article, we describe the natural course of a common classic Fabry disease mutation, p.Arg227Ter or p.R227*, in Finland. RESULTS: Four males and ten females belonged to two extended families. The mean age was 46 years (SD 18.4). Six patients (43%) had cardiac hypertrophy, three patients (21%) had ischemic stroke, and none had severe kidney dysfunction. Three patients had atrial fibrillation; two patients who had atrial fibrillation also had pacemakers. All males over 30 years of age had at least one of the following manifestations: cardiac hypertrophy, stroke, or proteinuria. In females, the severity of Fabry disease varied from classic multiorgan disease to a condition that mimicked the attenuated cardiac variant. No one was totally asymptomatic without any signs of Fabry disease. Cardiac magnetic resonance imaging was performed on nine of 14 patients was the most sensitive for detecting early cardiac manifestations. Five patients (55%) had late gadolinium enhancement-positive segments. CONCLUSION: Cardiac involvement should be effectively detected in females before considering them asymptomatic mutation carriers.

Cell-Nanoparticle Interactions at (Sub)-Nanometer Resolution Analyzed by Electron Microscopy and Correlative Coherent Anti-Stokes Raman Scattering.

A wide variety of nanoparticles are playing an increasingly important role in drug delivery. Label-free imaging techniques are especially desirable to follow the cellular uptake and intracellular fate of nanoparticles. The combined correlative use of different techniques, each with unique advantages, facilitates more detailed investigation about such interactions. The synergistic use of correlative coherent anti-Stokes Raman scattering and electron microscopy (C-CARS-EM) imaging offers label-free, chemically-specific, and (sub)-nanometer spatial resolution for studying nanoparticle uptake into cells as demonstrated in the current study. Coherent anti-Stokes Raman scattering (CARS) microscopy offers chemically-specific (sub)micron spatial resolution imaging without fluorescent labels while transmission electron microscopy (TEM) offers (sub)-nanometer scale spatial resolution and thus visualization of precise nanoparticle localization at the sub-cellular level. This proof-of-concept imaging platform with unlabeled drug nanocrystals and macrophage cells revealed good colocalization between the CARS signal and electron dense nanocrystals in TEM images. The correlative TEM images revealed subcellular localization of nanocrystals inside membrane bound vesicles, showing multivesicular body (MVB)-like morphology typical for late endosomes (LEs), endolysosomes, and phagolysosomes. C-CARS-EM imaging has much potential to study the interactions between a wide range of nanoparticles and cells with high precision and confidence.

Preparation and characterization of multi-component tablets containing co-amorphous salts: Combining multimodal non-linear optical imaging with established analytical methods.

Co-amorphous mixtures have rarely been formulated as oral dosage forms, even though they have been shown to stabilize amorphous drugs in the solid state and enhance the dissolution properties of poorly soluble drugs. In the present study we formulated tablets consisting of either spray dried co-amorphous ibuprofen-arginine or indomethacin-arginine, mannitol or xylitol and polyvinylpyrrolidone K30 (PVP). Experimental design was used for the selection of tablet compositions, and the effect of tablet composition on tablet characteristics was modelled. Multimodal non-linear imaging, including coherent anti-Stokes Raman scattering (CARS) and sum frequency/second harmonic generation (SFG/SHG) microscopies, as well as scanning electron microscopy, X-ray diffractometry and Fourier-transform infrared spectroscopy were utilized to characterize the tablets. The tablets possessed sufficient strength, but modelling produced no clear evidence about the compaction characteristics of co-amorphous salts. However, co-amorphous drug-arginine mixtures resulted in enhanced dissolution behaviour, and the PVP in the tableting mixture stabilized the supersaturation. The co-amorphous mixtures were physically stable during compaction, but the excipient selection affected the long term stability of the ibuprofen-arginine mixture. CARS and SFG/SHG proved feasible techniques in imaging the component distribution on the tablet surfaces, but possibly due to the limited imaging area, recrystallization detected with x-ray diffraction was not detected.

Discontinuation of carbamazepine due to concerns of long-term consequences of enzyme induction.

OBJECTIVE: Treatment with carbamazepine (CBZ), a potent enzyme inducer, is known to affect the lipid profile, steroid, and vitamin D metabolism. Consequently, it has been postulated that patients on CBZ should be switched to noninducing antiepileptic drugs (AEDs). However, little is known about the seizure outcome following a CBZ switch in seizure-free patients. We aimed to address this issue using a controlled observational study design. METHODS: Fifty-eight patients taking CBZ for focal epilepsy were assessed for discontinuing CBZ treatment due to concerns of long-term adverse-effects; 34 discontinued its therapy and 24 continued with CBZ. Six-month seizure freedom was the primary end point. Furthermore, serum samples (total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, sex hormone-binding globulin (SHBG), free testosterone, and 25-hydroxyvitamin D levels from before and at least 3 months after discontinuation or continuation were obtained from all patients. RESULTS: Seizure-free patients had a 5-fold elevated odds of seizure recurrence if CBZ was discontinued (95% confidence interval [CI 0.51-49.3; p = 0.17). A significant decrease in serum levels of TC, LDL, HDL, and SHBG as well as a significant increase in that of free testosterone were found in the discontinuation group compared with those who continued CBZ. Nonsignificant changes in triglycerides and vitamin D levels were detected. SIGNIFICANCE: Discontinuation of CBZ in seizure-free patients seems to carry a moderate, but legitimate, risk of relapse. Conversely, our results indicate that CBZ might have unfavorable effects on serum levels of TC, LDL, HDL, SHBG, and free testosterone.

Invasive treatment of superficial veins of the lower extremities.

Modern invasive treatment of superficial venous insufficiency of the lower extremities is largely based on the use of intravenous procedures under ultrasound guidance. The first-line treatment is thermoablation, in which the insufficient superficial vein, typically vena saphena magna or parva, is constricted by using laser or radio frequency energy under ultrasound guidance. The procedure is nearly always successful under local anesthesia and can be performed as an outpatient operation. When necessary, visible collateral varices can be treated with foam sclerotherapy or by surgical excision. The need for associated medication or longer follow-up is limited and recovery is fast. The patients can be mobilized immediately, and only a couple of days of sick leave are usually required.

Internal Carotid Artery and the Proximal M1 Segment Are Optimal Targets for Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) is an established treatment of acute anterior circulation stroke caused by large vessel occlusion (LVO). We compared the clinical outcome (3-month modified Rankin Scale, mRS) in hyperacute (<3h from the onset of symptoms) ischemic stroke between an MT and an intravenous thrombolysis (IVT) cohort in proximal (ICA and the proximal M1 segment of the middle cerebral artery) and distal (the distal M1 and the M2 segment) LVOs. METHODS: We prospectively reviewed 67 patients who underwent MT with newer-generation stent retrievers. The IVT cohort consisted of 98 patients who received IVT without MT. We recorded baseline clinical, procedural and imaging variables, technical outcome, 24-h imaging outcome, and the clinical outcome. Differences between the groups were studied with theoretically appropriate statistical tests and binary logistic regression analysis. RESULTS: The proportion of patients who had a proximal LVO and experienced good (mRS ≤2) or excellent (mRS ≤1) clinical outcome was significantly larger in the MT group (62 vs. 7%, p < 0.001; 47 vs. 3%, p < 0.001, respectively). In a regression model including relevant confounding variables, good clinical outcome was seen significantly more often among patients with proximal occlusions (OR = 6.0, CI 95% 1.9-18.3, p = 0.002). In a similar model, no statistically significant differences were observed in patients with more distal occlusions. CONCLUSIONS: MT is superior to IVT in achieving good clinical outcome in hyperacute anterior circulation stroke in the most proximal occlusions (ICA and proximal M1 segment). In the distal M1 and M2 segments neither of these therapies clearly outperforms the other.

Multimodal Nonlinear Optical Imaging for Sensitive Detection of Multiple Pharmaceutical Solid-State Forms and Surface Transformations.

Two nonlinear imaging modalities, coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG), were successfully combined for sensitive multimodal imaging of multiple solid-state forms and their changes on drug tablet surfaces. Two imaging approaches were used and compared: (i) hyperspectral CARS combined with principal component analysis (PCA) and SFG imaging and (ii) simultaneous narrowband CARS and SFG imaging. Three different solid-state forms of indomethacin-the crystalline gamma and alpha forms, as well as the amorphous form-were clearly distinguished using both approaches. Simultaneous narrowband CARS and SFG imaging was faster, but hyperspectral CARS and SFG imaging has the potential to be applied to a wider variety of more complex samples. These methodologies were further used to follow crystallization of indomethacin on tablet surfaces under two storage conditions: 30 °C/23% RH and 30 °C/75% RH. Imaging with (sub)micron resolution showed that the approach allowed detection of very early stage surface crystallization. The surfaces progressively crystallized to predominantly (but not exclusively) the gamma form at lower humidity and the alpha form at higher humidity. Overall, this study suggests that multimodal nonlinear imaging is a highly sensitive, solid-state (and chemically) specific, rapid, and versatile imaging technique for understanding and hence controlling (surface) solid-state forms and their complex changes in pharmaceuticals.