Timing to Carotid Endarterectomy Affects Early and Long Term Outcomes of Symptomatic Carotid Stenosis.

BACKGROUND: The aim of this study is to evaluate early and long-term outcomes according to the timing to carotid endarterectomy (CEA) of symptomatic carotid stenosis. METHODS: Consecutive CEAs with selective shunting for symptomatic carotid stenosis ≥50% performed between 2009 and 2020. Patients had acute neurological impairment on presentation, defined as <5 points on the National Institutes of Health Stroke Scale (NIHSS). We grouped patients according to time between index event and CEA: the first group was operated between 0 and 2 days, the second group between 3 and 7 days, the third group between 8 and 14 days and the last group after 15 days. Thirty-day neurological status improvement was defined as a decrease (≥1) in the 30-day NIHSS score versus NIHSS score immediately before surgery. RESULTS: Five hundred CEAs were performed. The perioperative combined stroke and mortality rate was 3.6% (18/500), representing a perioperative mortality rate of 0.2 (n = 1) and stroke rate of 3.4% (n = 17). Overall freedom from stroke was 95% at 1 year, 89 % at 6 years, and 88% at 10 years. Annual stroke rate was 0.6% after the 30-day period. Thirty-day improvement in neurologic status occurred in 103 patients (20.6%), while in 380 (76%) neurologic status was unchanged, and 17 (3.4%) experienced worsening of their neurologic status. Patients treated within 7 days from the index event had significant benefit (OR = 2.6) in the 30-day neurological improvement versus those treated after 7 days from the index event. Timing to CEA <2 days increased significantly the risk of late stroke (OR = 9.7). CONCLUSIONS: The ideal timing for performing CEA is between 3 and 7 days from the index event if NIHSS <5 as it is associated with the best rates of improvement in neurological status and durability in the long term. Very early CEA (<48 hrs) was associated with increased late stroke occurrence.

Drugs for patients with epilepsy and excessive daytime sleepiness.

Excessive daytime sleepiness (EDS) and attentional deficits are often observed in people with epilepsy. They may be the consequence of seizures and subclinical discharges as well as of comorbid conditions as obstructive sleep apnea/hypopnea syndrome (OSAS), attention deficit hyperactivity disorder (ADHD), or other less frequent disorders. Excessive daytime sleepiness may also be caused or worsened by antiseizure medications (ASMs). Several meta-analyses suggested that lamotrigine, lacosamide, and perhaps eslicarbazepine are less sedative than other traditional and new ASMs and, in patients prone to somnolence, might be preferred over ASMs with more sedative properties. In patients with severe EDS and/or ADHD, advantages and risks of a treatment with a psychostimulant need to be considered. Methylphenidate, modafinil, armodafinil, pitolisant, and solriamfetol are authorized for use in ADHD and EDS in patients with narcolepsy and some of them also in OSAS. These agents are off-label for the treatment of EDS associated with epilepsy. They do not have proconvulsant effects, although there are several possible risks for patients with epilepsy. The risks of cardiovascular events and psychiatric symptoms should be carefully evaluated as such disorders can coexist with epilepsy and be triggered by these agents. Finally, combination of psychostimulants with ASMs may be associated with several pharmacokinetic drug-drug interactions.

Reallocation of Carotid Surgery Activity with the Support of Telemedicine in a COVID-Free Clinic during COVID-19 Pandemic.

The aim of this study is to report the reallocation of carotid surgery activity with the support of telemedicine in a COVID-free clinic during COVID-19 pandemic. Patients with symptomatic carotid stenosis or asymptomatic vulnerable plaques were reallocated to a COVID-free private clinic which began to cooperate with the National Health System during the emergency. Quick training of staff nurses was performed. Surgeons moved to the COVID-19 free clinic. Remote cerebral monitoring was performed with the support of telemedicine. Twenty-four patients underwent standard carotid endarterectomy with eversion technique. Five patients (20.8%) had recently symptomatic stenosis, and the remaining 19 patients (79.2%) had a risky asymptomatic carotid stenosis. No technical issue with remote cerebral monitoring was detected. In the early postoperative period, no neurological/systemic complication was observed. Three patients under dual antiplatelet therapy (12.5%) had neck hematoma. All patients were discharged the day after surgery. In our preliminary experience, reallocation in a COVID-free clinic allowed us to maintain a functioning carotid surgery activity during COVID-19 pandemic. A multidisciplinary approach and support of telemedicine were crucial. Training of unskilled nurse staff was necessary.

Cranial nerve injury is associated with dual antiplatelet therapy use and cervical hematoma after carotid endarterectomy.

OBJECTIVE: To determine predictors of cranial nerve injury (CNI) after carotid endarterectomy (CEA). METHODS: Consecutive CEAs performed over a 5-year period were enrolled in this study. Outcomes analyzed included 30-day major adverse event rate (composite of stroke, death, and myocardial infarction), death, stroke, disabling stroke, myocardial infarction, cervical hematoma and CNI rate, reoperation, and hospital readmission at 30 days. RESULTS: There were 1258 CEAs were included in the study, 1168 (93%) were performed using an eversion technique. Patients with symptoms comprised 27% of the cohort (n = 340). At 30 days, there were no deaths, 23 major adverse events (1.8%), 11 strokes (0.9%: nine minor, two major), 12 myocardial infarctions (0.9%), 41 cervical hematomas (3.3%), 9 reoperations (0.7%) and 10 hospital readmissions (0.8%). Median duration of stay was 1 day (interquartile range, 1-2 days). CNI rate at discharge was 2.3% (n = 29). Two patients (9%) had more than one cranial nerve affected. The marginal mandibular branch of the facial nerve was most frequently involved (n = 16; 52%), followed by the hypoglossal (n = 9; 29%), the vagus (n = 4; 13%), and the spinal accessory nerve (n = 2; 6%). Horner's syndrome, consistent with an injury to the cervical sympathetic chain, occurred in 13 patients (1%) who had a true cranial nerve affected as well. The vast majority (94%) of these CNIs and all Horner's syndrome neurapraxias were transient; only the two accessory lesions persisted at their follow-up visit (median, 32 months; range, 8-72 months). Significant predictors for CNI included diabetes (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.0-6.2; P = .048), cervical hematoma (OR, 41.7; 95% CI, 13.8-125.4; P < .001), and dual antiplatelet therapy (OR, 4.4; 95% CI, 1.7-11.4; P = .002). CONCLUSIONS: CNI is predominantly a transient complication, but is associated significantly with dual antiplatelet therapy use and the occurrence of a postoperative cervical hematoma. Scrupulous attention to hemostasis might reduce the incidence of CNI.

"Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients".

BACKGROUND: Neurologic outcome after early or delayed carotid endarterectomy (CEA) has yet to be fully elucidated. The aim of this study was to determine 30-day neurologic improvement with respect to the timing of CEA in symptomatic patients. METHODS: Single-institution review of consecutive patients who underwent CEA for symptomatic carotid stenosis ≥60% in the period between January 2009 and November 2013. Patients recruited had acute neurologic impairment on presentation, defined as <5 points on the National Institutes of Health Stroke Scale (NIHSS). Patients were grouped according to time between the qualifying event and surgery (0-14 days, early CEA and 15-30 days, delayed CEA). Thirty-day neurologic status improvement was defined as a decrease (≥1) in the 30-day NIHSS score versus NIHSS score immediately before surgery. RESULTS: There were 100 and 222 patients in the early and delayed CEA groups, respectively. The type of qualifying symptoms (stroke versus transient ischemic attack rate) was similar and there were no significant differences in 30-day adverse outcome rates between the 2 cohorts. There were no deaths, 4 strokes (1.2%, 3 vs. 1; P = 0.091), and 4 myocardial infarcts (1.2%, 0 vs. 4; P = 0.315). Thirty-day improvement in neurologic status was associated with early CEA, very early CEA (48 hours), and NIHSS >2 before surgery, with an odds ratio of 4.9 (confidence interval [CI], 0.9-25.7; P = 0.03), 12.9 (CI, 1.4-115.7; P = 0.02), and 2.6 (CI, 1.7-4.1; P < 0.001), respectively. CONCLUSIONS: Our results suggest that reducing the time to intervention in selected (NIHSS <5) symptomatic patients is safe and associated with improved neurologic status.

Comprehensive educational plan for patients with epilepsy and comorbidity (EDU-COM): a pragmatic randomised trial.

BACKGROUND: The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined. OBJECTIVE: The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity. METHODS: 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care. The primary endpoint was the number of patients becoming free from adverse treatment events and/or drug interactions after a 6-month follow-up. The number of adverse treatment events and drug interactions, health-related quality of life (HRQOL) summary score changes and the monetary costs of medical contacts and drugs were assessed as secondary outcomes. RESULTS: The primary endpoint was met by 44.0% of patients receiving the educational plan versus 28.9% of those on usual care (p=0.0399). The control group reported a significantly higher risk not to meet successfully the primary endpoint at the end of the study: OR (95% CI) of 2.29 (1.03 to 5.09). A separate analysis on drug adverse effects and drug interactions showed that the latter were more sensitive to the effect of educational treatment. Quality of life and costs were not significantly different in the two groups. CONCLUSIONS: A patient-tailored educational strategy is effective in reducing drug-related problems (particularly drug interactions) in epilepsy patients with chronic comorbidities, without adding significant monetary costs. Registered at ClinicalTrials.gov, identifier NCT01804322, (http://www.clinicaltrials.gov).

Efficacy of Tocilizumab in Limbic Encephalitis with Anti-CASPR2 Antibodies.

We report the case of a 64-year-old man who presented with subacute memory, balance impairment, behavioral and mood changes, and epileptic seizures. Magnetic resonance imaging (MRI) showed bilateral hippocampal abnormalities. Brain [18F]-FDG fluorodeoxyglucose positron emission tomography (PET) revealed hypometabolism in both the temporal lobe as well as in the left insular and parietal regions. The clinical and neuroradiological picture and the detection of anti-CASPR2 antibodies in serum oriented the diagnosis towards autoimmune limbic encephalitis. Intravenous high-dose steroid and immunoglobulin treatments were ineffective. We did not use rituximab for the presence of antibodies to HbcAg positivity. Tocilizumab given intravenously 8 mg/kg once a month for six months and then subcutaneously 162 mg every week for six months resulted in clinical and neuroradiological improvement. These data support the efficacy of tocilizumab in autoimmune limbic encephalitis associated with anti-CASPR2 antibodies, which has been sporadically reported in the literature.

Challenges in the treatment of convulsive status epilepticus.

Convulsive status epilepticus (CSE) is a medical emergency associated with high mortality and morbidity. The most recent definition of CSE is a convulsive seizure lasting more than 5min or consecutive seizures without recovery of consciousness. In adults, for the treatment of the early stages of CSE, diazepam, lorazepam or midazolam are the most common treatments, although the choice of agent seems less important than rapid treatment. Midazolam, when administered intramuscularly (best evidence), buccally, or nasally, is effective and safe in the pre-hospital setting. The antiepileptic drugs, phenytoin, valproate, levetiracetam and, more recently lacosamide, are used in CSE that persists after first-line treatments (established CSE). Phenytoin is more difficult to administer and is less well tolerated. Evidence of the efficacy of lacosamide is scarce. Anaesthetics are the drugs of choice for the treatment of refractory CSE (not responding to second-line drugs). Midazolam seems to be the best tolerated and is the most often used drug, followed by propofol and thiopental (pentobarbital in the USA). A few studies indicate that ketamine is effective with the possible advantage that it can be co-administered with other anaesthetics, such as midazolam or propofol. CSE becomes super-refractory after more than 24h of appropriate treatments and may last weeks. Several anaesthetics have been proposed but evidence is scarce. Autoimmune refractory CSE has been recently identified, and early treatment with immuno-modulatory agents (corticosteroids and IV immunoglobulins and also second-line agents such as cyclophosphamide and rituximab followed by chronic immunosuppressive treatment) is now recommended by many experts.

A Meta-analysis of the Cortical Silent Period in Epilepsies.

OBJECTIVE: The cortical silent period (CSP) following transcranial magnetic stimulation reflects GABAB-mediated inhibition in the primary motor cortex (M1) and could contribute to understand the pathophysiological substrates of epileptic conditions. Increased CSP duration has been reported in idiopathic generalized epilepsy (IGE) and in partial epilepsy (PE) involving the M1, although other studies yielded discordant findings. We used meta-analysis to systematically assess the consistency of CSP changes in untreated patients with epilepsies. METHODS: Databases were searched for controlled studies evaluating the CSP in drug-naïve or drug-free patients with IGE or PE. For each study, the mean difference with 95% confidence intervals (CIs) between CSP duration obtained in patients and controls was calculated. The effect of motor threshold (MT) on the CSP duration has also been explored by meta-analysis and meta-regression. RESULTS: Fourteen studies (267 patients and 234 controls) were included. A significant mean difference (14.16 ms, 95% CI, 1.20, 27.11 ms) was found, with longer CSP in patients than in controls. The mean difference was still greater (18.05 ms) if only the 202 IGE patients were analyzed. No MT difference emerged between patients and controls. Meta-regression showed no relationship between MT and CSP duration. CONCLUSION: Meta-analysis confirms CSP modifications in epilepsies, with enhancement of this cortical inhibitory measure at least in most IGE patients. This provides rationale for further investigations aiming to verify the hypotheses that increased CSP reflects compensatory neural phenomena counteracting transition from the interictal to ictal state and that CSP variability reflects the pathophysiological heterogeneity of epileptic syndromes.

Adverse events, placebo and nocebo effects in placebo-treated paediatric patients with refractory focal epilepsies. Analysis of double-blind studies.

BACKGROUND AND PURPOSE: Assessment of placebo and nocebo effects and evaluation of background incidence of some predefined adverse effects (AEs) of antiepileptic drugs (AEDs) in placebo-treated paediatric patients recruited in randomized controlled studies (RCTs) of refractory focal epilepsies. METHODS: We searched all add-on, double-blind, placebo-controlled trials investigating any AED in paediatric patients with focal epilepsies and extracted both for patients treated with placebo and for those treated with the active drug, number of patients, number of responders (≥50% reduction of seizure frequency) number of patients withdrawing because of AEs, number of patients with AEs, and number of patients with 11 predefined AEs. The association between placebo and active treatment AEs was also explored. RESULTS: Seven RCTs were included in our study with a total of 668 children treated with the experimental drug and 634 with placebo. In placebo-treated patients, overall responder rate was 19.7% [(95% CI), (16.0, 23.4)], proportion of placebo-treated patients withdrawing because of AEs was 3.6% (2.1, 5.1%), and proportions of patients with any AE was 81.3% (68.5, 94.1%). The three most frequently reported AEs were headache (PR=11.4%, 6.4,16.3%) somnolence (PR=9.6%, 4.9, 14.3%), and ataxia (PR=4.6, -1.1, 10.2). A significant correlation between placebo-treated patients and those treated with the active drug was found for the outcome measure any AE and the AEs somnolence, headache and fatigue. CONCLUSIONS: Both placebo and nocebo effects assessed in this paediatric population did not differ from findings reported in adults. This is in partial contrast to what has been previously reported and with observations in other diseases. Also specific AEs, which are at least in part, caused by the background treatment, failed to show significant differences from what previously observed in adult RCTs.

Drug safety evaluation of zonisamide for the treatment of epilepsy.

INTRODUCTION: Zonisamide is a broad spectrum antiepileptic drug with multiple mechanisms of action which has been recently approved in the US and Europe as an adjunctive therapy for refractory partial seizures in adults. AREAS COVERED: The adverse effect profile of this drug from controlled, randomized studies and open and long-term studies and case reports is described herein. EXPERT OPINION: Zonisamide has several CNS dose-dependent, metabolic and idiosyncratic adverse effects. Knowledge of these effects is essential for the prevention or minimization of several of them. For example, treatment-emergent adverse events may be prevented by slow titration; incidence of kidney stones may be reduced through an increase in fluid intake and avoidance of concomitant treatment with topiramate and/or ketogenic diet; and oligohydrosis may be prevented by hydratation and avoidance of hot temperatures. An accurate selection of patients can be useful for the prevention of some adverse effects. Psychiatric disturbances are mainly observed in predisposed subjects and patients with a previous allergic episode to sulfonamide-containing drugs are at a higher risk for developing a skin rash.