Second-line cannabis therapy in patients with epilepsy.

OBJECTIVE: Marijuana-based therapies (MBTs) have been shown to reduce seizure frequency in patients with severe and drug-resistant epilepsy (DRE). Pharmaceutical-grade CBD (EpidiolexⓇ) was approved by the FDA in 2018 for the treatments of Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS) and subsequently in 2020 for tuberous sclerosis complex (TSC). It is unclear what the utility would be in prescribing one type of MBT if a previous, alternative type failed. We conducted a retrospective study to determine if an alternative formulation of MBT reduces seizure frequency if the patient has not had a meaningful response from an initial MBT. We also investigated the clinical impact that a second MBT has on side effect profile. METHODS: We reviewed the charts of patients with DRE who were at least 2 years old and who took at least 2 different formulations of MBT, including a pharmacologic formulation of CBD (EpidiolexⓇ), artisanal marijuana, and/or a hemp-based formulation. We reviewed medical records in patients 2 years of age and older; however, subjects' historical data, such as age of first seizure onset, may be prior to the age of 2 years. We extracted data on demographics, type of epilepsy, history of epilepsy, medication history, seizure count, and drug side effects. Seizure frequency, side effect profiles, and predictors of responder status were evaluated. RESULTS: Thirty patients were identified as taking more than 1 type of MBT. Our findings suggest that seizure frequencies do not change significantly from baseline to after the first MBT and to after the second MBT (p = .4). However, we did find that patients with greater baseline seizure frequency were significantly more likely to respond to treatment after the second MBT (p = .03). To our second endpoint of side effect profile, we found that patients who experienced side effects after a second MBT had significantly greater seizure frequency compared to those who did not (p = .04). CONCLUSION: We found no significant seizure frequency reduction from baseline to after a second MBT in patients who tried at least 2 different formulations of MBT. This suggests a low probability of seizure frequency reduction with a second MBT therapy in patients with epilepsy who tried at least two different MBTs. While these findings need to be replicated in a larger sample, they suggest that clinicians should not delay care by trying alternative MBT formulations after a patient has already tried one. Instead, it may be more prudent to attempt an alternative class of therapy.

Longitudinal cognitive assessment in patients with primary CNS lymphoma treated with induction chemotherapy followed by reduced-dose whole-brain radiotherapy or autologous stem cell transplantation.

INTRODUCTION: The standard treatment for primary central nervous system lymphoma (PCNSL) involves induction methotrexate-based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). As WBRT carries a substantial risk for cognitive impairment, alternative consolidation treatments have been used to reduce neurotoxicity, including reduced-dose WBRT (rdWBRT) or high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT). In this study, we characterized cognitive functions in PCNSL patients achieving long-term remission following rdWBRT or HDC-ASCT. METHODS: PCNSL patients completed cognitive evaluations at diagnosis, post-induction chemotherapy, and yearly up to 5 years following rdWBRT or HDC-ASCT. Quality of life (QoL), white matter (WM) disease, and cortical atrophy (CA) on MRI were assessed at similar intervals. RESULTS: Performance was impaired on most cognitive tests at diagnosis. Linear mixed model analyses in each group showed statistically significant improvement from baseline up to year 3 in attention/executive functions, graphomotor speed, and memory; however, there was a decline in attention/executive functions and memory after year 3 in both groups. WM abnormalities increased over time in both groups, but more patients treated with rdWBRT developed CA and WM changes. There were no significant longitudinal group differences in cognitive performance or QoL. CONCLUSIONS: Results indicated improvement in cognitive function up to 3 years post-treatment, but a decline at later time points and an increase in brain structure abnormalities in both groups. The findings suggest that rdWBRT and HDC-ASCT may be associated with delayed neurotoxicity in progression-free patients and underscore the need for long-term follow-up to characterize cognitive dysfunction in PCNSL patients.

Genetic variants and cognitive functions in patients with brain tumors.

BACKGROUND: Patients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer's disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this population. METHODS: One hundred and fifty brain tumor patients treated with RT ± CT or CT alone completed a neurocognitive assessment and provided a blood sample for genotyping. We genotyped genes/SNPs in these pathways: (i) LOAD risk/inflammation/cholesterol transport, (ii) dopamine regulation, (iii) myelin regulation, (iv) DNA repair, (v) blood-brain barrier disruption, (vi) cell cycle regulation, and (vii) response to oxidative stress. White matter (WM) abnormalities were rated on brain MRIs. RESULTS: Multivariable linear regression analysis with Bayesian shrinkage estimation of SNP effects, adjusting for relevant demographic, disease, and treatment variables, indicated strong associations (posterior association summary [PAS] ≥ 0.95) among tests of attention, executive functions, and memory and 33 SNPs in genes involved in: LOAD/inflammation/cholesterol transport (eg, PDE7A, IL-6), dopamine regulation (eg, DRD1, COMT), myelin repair (eg, TCF4), DNA repair (eg, RAD51), cell cycle regulation (eg, SESN1), and response to oxidative stress (eg, GSTP1). The SNPs were not significantly associated with WM abnormalities. CONCLUSION: This novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors.

Fluoroscopy of spontaneous breathing is more sensitive than phrenic nerve stimulation for detection of right phrenic nerve injury during cryoballoon ablation of atrial fibrillation.

INTRODUCTION: Right phrenic nerve palsy (PNP) is a typical complication of cryoballoon ablation of the right-sided pulmonary veins (PVs). Phrenic nerve function can be monitored by palpating the abdomen during phrenic nerve pacing from the superior vena cava (SVC pacing) or by fluoroscopy of spontaneous breathing. We sought to compare the sensitivity of these 2 techniques during cryoballoon ablation for detection of PNP. METHODS AND RESULTS: A total of 133 patients undergoing cryoballoon ablation were monitored with both SVC pacing and fluoroscopy of spontaneous breathing during ablation of the right superior PV. PNP occurred in 27/133 patients (20.0%). Most patients (89%) had spontaneous recovery of phrenic nerve function at the end of the procedure or on the following day. Three patients were discharged with persistent PNP. All PNP were detected first by fluoroscopic observation of diaphragm movement during spontaneous breathing, while diaphragm could still be stimulated by SVC pacing. In patients with no recovery until discharge, PNP occurred at a significantly earlier time (86 ± 34 seconds vs. 296 ± 159 seconds, P < 0.001). No recovery occurred in 2/4 patients who were ablated with a 23 mm cryoballoon as opposed to 1/23 patients with a 28 mm cryoballoon (P = 0.049). CONCLUSION: Fluoroscopic assessment of diaphragm movement during spontaneous breathing is more sensitive for detection PNP as compared to SVC pacing. PNP as assessed by fluoroscopy is frequent (20.0%) and carries a high rate of recovery (89%) until discharge. Early onset of PNP and use of 23 mm cryoballoon are associated with PNP persisting beyond hospital discharge.

Impact of pulmonary vein isolation on obstructive sleep apnea in patients with atrial fibrillation.

BACKGROUND: Obstructive sleep apnea (OSA) has been identified as associated with the onset and propagation of atrial fibrillation (AF) and predicts recurrences of AF after pulmonary vein isolation (PVI). Vice versa, it has never been investigated whether PVI influences OSA. However, it has been controversial whether a restored atrial function can affect the course of OSA. There-fore, we have assessed whether PVI procedure modulates the prevalence and severity of OSA. METHODS AND RESULTS: We included 23 individuals with AF that were assigned to undergo PVI into this study. Patients were 65 ± 7 years old, obese (BMI 29.9 ± 5.4 kg/m²), white (100%) and had a normal left ventricular function (LVEF 64 ± 9%). Polygraphic assessment was carried out before and 6 months after PVI. The prevalence of OSA, defined as an apnea-hypopnea index (AHI) ≥ 5 per hour of sleep, was 74% before PVI compared to 70% 6 months after the procedure (p > 0.05). Severity of OSA did not differ (AHI before vs. after: 18 ± 18/h vs. 15 ± 17/h, p > 0.05) as well as further polygraphic parameters did not differ before and after the procedure. CONCLUSIONS: Prevalence and severity of OSA are not affected by PVI in patients suffering from AF.

Left atrial pressure as predictor for recurrence of atrial fibrillation after pulmonary vein isolation.

PURPOSE: Identification of reliable risk factors for recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI) has important implications. Left atrial (LA) pressure is a largely observator-independent parameter that can easily be determined after transseptal puncture. The purpose of this study was to investigate the predictive value of LA pressure for AF recurrence after PVI. METHODS: Two hundred five consecutive patients with paroxysmal or persistent AF scheduled for first PVI were included. Baseline clinical data were collected. During PVI, LA pressure was determined invasively after transseptal puncture. PVI was performed with radiofrequency or cryoenergy, and patients were followed for 25 ± 7 months. RESULTS: One hundred five (51 %) patients had AF recurrence. Patients with persistent AF prior to ablation had significantly more recurrences than patients with paroxysmal AF (70.1 vs. 42.0 %, p < 0.001). Mean LA pressure was significantly higher in patients with recurrence of AF (13.4 ± 7.1 vs. 11.0 ± 5.2 mmHg, p = 0.007), as was mean LA volume index (40.1 ± 18.5 vs. 33.0 ± 11.2 mL/m(2), p < 0.001). In the multivariate analysis, mean LA pressure was predictive in patients with normal or mildly enlarged LA, while AF type was not predictive. For each 1-mmHg increase in LA pressure, the risk of AF recurrence increased by 11 % in this subgroup. In patients with moderately or severely enlarged LA, AF type was predictive whereas LA pressure was not. CONCLUSION: LA pressure, AF type, and LA volume index are independent predictors for recurrence of AF after PVI. LA pressure may be helpful especially in patients with small atria, where AF type is not predictive.

Differences in clinical and echocardiographic parameters between paroxysmal and persistent atrial flutter in the AURUM 8 study: targets for prevention of persistent arrhythmia?

PURPOSE: Cavotricuspid isthmus-dependent atrial flutter (AFL) can occur in a paroxysmal or persistent pattern. The aim of this study was to identify clinical, echocardiographic, and electrophysiological risk factors independently associated with persistence of AFL. METHODS: Patients of the recently published AURUM 8 study with paroxysmal versus persistent AFL were compared with respect to clinical and echocardiographic baseline characteristics as well as procedural parameters. The AURUM 8 study is a randomized, multicenter clinical trial comparing the efficacy and safety of gold versus platinum-iridium 8-mm-tip ablation. AFL was paroxysmal in 218 patients and persistent in 210 patients. RESULTS: Univariate analysis revealed that patients with persistent AFL had higher New York Heart Association class (P = 0.002), shorter time since 1st AFL episode (median 0.18 vs 0.34, P = 0.037), a higher prevalence of previous coronary artery bypass grafting surgery (17% vs 9%, P = 0.02), left ventricular hypertrophy (17% vs 8%, P = 0.005), dyspnea during AFL (P < 0.001), mitral regurgitation (P = 0.002), tricuspid regurgitation (P = 0.049), and pulmonary hypertension (P = 0.01). Palpitations during AFL were less frequent in patients with persistent AFL (P = 0.001). Multivariate analysis revealed that age, weight, AFL diagnosis after initiation of class IC or III antiarrhythmic drugs for atrial fibrillation, history of left ventricular hypertrophy, dyspnea during AFL and mitral regurgitation on echocardiography were significant independent variables associated with persistent AFL. A history of atrial fibrillation and palpitations during AFL were independently associated with paroxysmal AFL. CONCLUSIONS: We were able to identify clinical and echocardiographic risk factors associated with persistence of typical AFL. Treatment of these risk factors can potentially not only prevent the transition from paroxysmal to persistent AFL, but maybe also the development or initiation of AFL in general.

Superiority of gold versus platinum irrigated tip catheter ablation of the pulmonary veins and the cavotricuspid isthmus: a randomized study comparing tip temperatures and cooling flow requirements.

INTRODUCTION: In order to optimize power delivery into the myocardium during radiofrequency ablation (RFA) without overheating the electrode tip, active cooling of the tip electrode as well as electrode tips made of gold have evolved. Recently, an externally irrigated gold tip electrode ablation catheter has been developed to combine the advantages of these 2 technologies. We sought to investigate the procedural parameters tip temperature, delivered power and cooling flow requirements of the irrigated gold tip catheter in comparison to the conventional irrigated platinum iridium (Pt) tip catheter in pulmonary vein isolation (PVI) and cavotricuspid isthmus (CTI) ablation. METHODS AND RESULTS: Sixty patients referred for first PVI were randomized into ablation with irrigated gold tip catheter versus irrigated Pt tip catheter. Forty-nine patients received ablation of CTI following PVI. Mean and standard deviation from all measurements were calculated for each patient. During RFA of pulmonary veins, mean catheter tip temperature was significantly lower in the gold group (35.4 ± 0.9 °C vs 38.2 ± 0.8 °C, P < 0.001), and total amount of delivered energy was higher (1303.1 ± 81.1 W vs 1223.7 ± 115.6 W, P = 0.004). During CTI ablation, necessary saline flow was almost 2.5-fold lower in the gold group (22.5 ± 5.9 mL/min vs 52.5 ± 9.7 mL/min, P < 0.001), accompanied by significantly lower tip temperature (39.1 ± 0.6 °C vs 40.5 ± 1.4 °C, P < 0.001). CONCLUSION: The irrigated gold tip electrode allows to deliver significantly more energy at a lower electrode tip temperature in RFA of PV and CTI in comparison to the irrigated Pt tip electrode. The required saline flow during CTI ablation is much lower than in Pt.

Left atrial deformation imaging with ultrasound based two-dimensional speckle-tracking predicts the rate of recurrence of paroxysmal and persistent atrial fibrillation after successful ablation procedures.

OBJECTIVE: Since predictors of recurrence of atrial fibrillation (AF) after ablation procedures are poorly defined, this prospective study was conducted to assess the value of left atrial (LA) deformation imaging with two-dimensional speckle-tracking (2D-ST) to predict AF recurrences after successful ablation procedures. METHODS AND RESULTS: One hundred and three consecutive patients (age 58.1 ± 16.6 years, 72.8% male) with AF (76 paroxysmal, 27 persistent) and 30 matched controls underwent transthoracic echocardiography and 2D-ST-LA-deformation analysis with assessment of LA-radial and LA-longitudinal strain (Sr, Sl), and velocities derived from the apical 4- and 2-chamber views (4CV, 2CV). AF recurrence was assessed during 6 months of follow-up. For determination of AF-related LA changes, AF patients were compared to controls and patients with AF recurrences after ablation procedures (n = 30, 29.1%) were compared with patients who maintained sinus rhythm (n = 73, 70.9%). Atrial deformation capabilities were significantly reduced (P < 0.0005) in patients with AF (4CVSl 17.8 ± 13.5%; 4CVSr 22.3 ± 14.9%; 4CV-velocities 2.53 ± 0.97 seconds) when compared with controls (4CVSl 31.3 ± 12.4%; 4CVSr 30.3 ± 9.1%; 4CV-velocities 3.48 ± 1.01 cm/s). Independent predictors for AF recurrence after ablation procedures were 2CV-LA-global-strain (Sr, P = 0.03; Sl, P = 0.003), 4CV-LA-gobal-strain (Sr, P = 0.03; Sl, P = 0.02), and regional LA-septal wall-Sl (P = 0.008). LA-global-strain parameters were superior to regional LA function analysis for the prediction of AF recurrences, with cutoff values (cov), hazard ratios (HR), positive and negative predictive values (PPV, NPV) were: 4CVSl cov, 10.79% (HR 27.8, P < 0.0005; PPV 78.8%, NPV 93.9%), 4CVSr cov, -16.65% (HR 24.8, P < 0.0005; PPV 69.4%, NPV 96.6%), 2CVSl cov, 12.31% (HR 22.7, P < 0.0005; PPV 75.8%, NPV 95.3%), and 2CVSr cov, -14.9% (HR 12.9, P < 0.0005; PPV 64.3%, NPV 93.2%). CONCLUSION: Compared with controls, AF itself seems to decrease LA deformation capabilities. The assessment of global LA strain with 2D-ST identifies patients with high risk for AF recurrence after ablation procedures. This imaging technique may help to improve therapeutic guiding for patients with AF.

Gold vs. platinum-iridium tip catheter for cavotricuspid isthmus ablation: the AURUM 8 study.

AIMS: Gold electrodes have the theoretical advantage of creating bigger lesions than platinum-iridium (Pt-Ir) electrodes. We performed a prospective randomized study to compare the clinical efficacy of standard 8 mm Pt-Ir tip catheter (control) and 8 mm gold-tip catheters in the ablation of the cavotricuspid isthmus (CTI)-dependent atrial flutter. METHODS AND RESULTS: A total of 463 patients undergoing CTI ablation in 19 clinical centres were randomized to receive the treatment by gold-tip or control catheter. The primary endpoint was cumulative radiofrequency (RF) application duration until achieving bidirectional CTI block. It did not differ significantly for the two catheters. The gold-tip catheter was, however, associated with a higher ablation success rate (94.3 vs. 89.0%, P = 0.042) and a substantially lower incidence of char and coagulum formation (4.8 vs. 37.9%, P < 0.001), which required exchange of 1 gold-tip (0.4%) and 10 control catheters (4.6%, P = 0.005). The gold-tip catheter delivered more mean power (52 ± 12 W) than the control catheter (48 ± 13 W, P < 0.001). Both mean and maximum temperatures measured by the thermocouple integrated in the catheter tip were statistically significantly lower in the gold (mean: 53.2 ± 4.7°C, max: 68.7 ± 6.6°C) than in the control catheter (54.3 ± 5.2 and 70.2 ± 7.0°C, respectively, P < 0.05). Fluoroscopy time, procedure duration, procedural-related complications, and arrhythmia recurrence during 6 months of follow-up did not differ between the two catheters. CONCLUSION: Owing to a higher primary ablation success rate and reduced incidence of char/coagulum formation, gold may be preferred over Pt-Ir as electrode material for 8 mm tip catheters for CTI ablation. ClinicalTrials.gov: NCT00326001 (http://clinicaltrials.gov/ct2/show/NCT00326001).

High prevalence of obstructive sleep apnea in patients with resistant paroxysmal atrial fibrillation after pulmonary vein isolation.

OBJECTIVES: To address the question whether obstructive sleep apnea (OSA) is associated with the recurrence of paroxysmal atrial fibrillation (AF) in patients treated with ≥2 pulmonary vein isolation procedures. PATIENTS AND METHODS: In this study, we included adults with therapy-resistant symptomatic paroxysmal AF, defined as AF recurring after ≥2 PV-isolation procedures (n = 23). For comparison, we selected another cohort of patients being successfully treated by one PV isolation without AF recurrence within 6 months (n = 23). PV isolation was performed by radiofrequency with an open irrigated tip catheter. Each of the 46 participants completed an overnight polygraphic study. The two groups were matched for age, gender, and ejection fraction. Patients were late middle-aged (65 ± 7 vs 63 ± 10 years, P = 0.23), white (100%), and overweight (BMI 27.3 ± 3.6 vs. 27.2 ± 4.6 kg/m(2), P = 0.97). RESULTS: The prevalence of sleep apnea, defined as an apnea-hypopnea index (AHI) of >5 per hour of sleep, was 87% in patients with therapy-resistant AF compared to 48% in the control cohort (P = 0.005). In addition, OSA was more severe in the resistant AF group indicated by a significantly higher AHI (27 ± 22 vs 12 ± 16, P = 0.01). CONCLUSION: The extraordinarily high prevalence of sleep apnea in patients with recurrent paroxysmal AF supports its presumable role in the pathogenesis of AF and demands further controlled prospective trials. Moreover, OSA should inherently be considered in patients with therapy-resistant AF.

Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation.

AIMS: Left atrial catheter ablation of the pulmonary veins (PV) has evolved as an important therapeutic option for the treatment of atrial fibrillation (AF). We aimed to investigate the incidence and predictors of silent cerebral embolism associated with PV catheter ablation, detected by diffusion-weighted magnetic resonance imaging (DW-MRI). METHODS AND RESULTS: We performed a prospective analysis of 53 consecutive patients with persistent or paroxysmal AF that underwent PV ablation and post-procedural cerebral MRI 1 day after lasso catheter-guided ostial PV ablation. Patients were analysed for possible demographical, medical, echocardiographical, and procedural predictors of embolic events. A mean of 3.5 +/- 0.5 PVs were ablated per patient. In six patients, DW-MRI depicted new clinically silent microembolism after PV ablation (11%). The number of ineffective medical antiarrhythmic agents prior to ablation procedure was significantly higher in the embolism group (3.3 +/- 0.5 vs. 2.2 +/- 1.4, P = 0.014). Coronary heart disease (CAD) was more frequent in patients with cerebral embolisms (33 vs. 2%, P = 0.031); left ventricular volume (130 +/- 12 vs. 103 +/- 26 mL, P = 0.002), and septal wall thickness (13.0 +/- 1.4 vs. 7.9 +/- 4.8 mm, P = 0.025) were significantly increased. CONCLUSION: This study shows a high incidence of silent micro-embolic events after PV ablation. CAD, left ventricular dilatation, and hypertrophy were potential predictors of this complication.

Comparison of cryoballoon and radiofrequency ablation of pulmonary veins in 40 patients with paroxysmal atrial fibrillation: a case-control study.

INTRODUCTION: Ablation of pulmonary veins (PV) is an established therapeutic option for patients with symptomatic drug-refractory paroxysmal atrial fibrillation (AF). Radiofrequency (RF) is currently the most widespread energy source for PV ablation. Cryothermal energy applied with a cryoballoon technique as an alternative has recently evolved. METHODS AND RESULTS: In a case-control setting, we compared 20 patients with paroxysmal AF who underwent their first PV ablation with the cryoballoon technique to 20 matched patients with conventional RF ablation. In the case of persistent electrical potentials after cryoballoon ablation, it was combined with ablation with a conventional cryocatheter. All patients performed daily event recording for 3 months after ablation procedure. Ablation parameters and success rate after 3 and 6 months were compared. In the cryoballoon group, the overall success rate was 55% (50% in the cryoballoon only group [14 patients] and 66% in the combination group [6 patients]), as opposed to the RF group with 45%. AF episode burden was lower after cryoballoon ablation. There was no significant difference between cryoballoon and RF ablation regarding procedure parameters. In the cryoballoon group, 3 phrenic nerve palsies occurred using the 23 mm balloon that resolved spontaneously. CONCLUSION: PV ablation with the cryoballoon technique is feasible and seems to have a similar success rate in comparison to RF ablation. Procedure- and fluoroscopy duration are not longer than in conventional RF ablation.