The endoscopic anterior transmaxillary temporal pole approach for mesial temporal lobe epilepsies: a feasibility study.

OBJECTIVE: In mesial temporal lobe epilepsy (MTLE), the ideal surgical approach to achieve seizure freedom and minimize morbidity is an unsolved question. Selective approaches to mesial temporal structures often result in suboptimal seizure outcomes. The authors report the results of a pilot study intended to evaluate the clinical feasibility of using an endoscopic anterior transmaxillary (eATM) approach for minimally invasive management of MTLEs. METHODS: The study is a prospectively collected case series of four consecutive patients who underwent the eATM approach for the treatment of MTLE and were followed for a minimum of 12 months. All participants underwent an epilepsy workup and surgical care at a tertiary referral comprehensive epilepsy center and had medically refractory epilepsy. The noninvasive evaluations and intracranial recordings of these patients confirmed the presence of anatomically restricted epileptogenic zones located in the mesial temporal structures. Data on seizure freedom at 1 year, neuropsychological outcomes, diffusion tractography, and adverse events were collected and analyzed. RESULTS: By applying the eATM technique and approaching the far anterior temporal lobe regions, mesial-basal resections of the temporal polar areas and mesial temporal structures were successfully achieved in all patients (2 with left-sided approaches, 2 with right-sided approaches). No neurological complications or neuropsychological declines were observed. All 4 patients achieved Engel class Ia outcome up to the end of the follow-up period (19, 15, 14, and 12 months). One patient developed hypoesthesia in the left V2 distribution but there were no other adverse events. The low degree of white matter injury from the eATM approach was analyzed using high-definition fiber tractography in 1 patient as a putative mechanism for preserving neuropsychological function. CONCLUSIONS: The described series demonstrates the feasibility and potential safety profile of a novel approach for medically refractory MTLE. The study affirms the feasibility of performing efficacious mesial temporal lobe resections through an eATM approach.

MR spectroscopic imaging at 3 T and outcomes in surgical epilepsy.

For the spectroscopic assessment of brain disorders that require large-volume coverage, the requirements of RF performance and field homogeneity are high. For epilepsy, this is also challenging given the inter-patient variation in location, severity and subtlety of anatomical identification and its tendency to involve the temporal region. We apply a targeted method to examine the utility of large-volume MR spectroscopic imaging (MRSI) in surgical epilepsy patients, implementing a two-step acquisition, comprised of a 3D acquisition to cover the fronto-parietal regions, and a contiguous parallel two-slice Hadamard-encoded acquisition to cover the temporal-occipital region, both with TR /TE = 2000/40 ms and matched acquisition times. With restricted (static, first/second-order) B0 shimming in their respective regions, the Cramér-Rao lower bounds for creatine from the temporal lobe two-slice Hadamard and frontal-parietal 3D acquisition are 8.1 ± 2.2% and 6.3 ± 1.9% respectively. The datasets are combined to provide a total 60 mm axial coverage over the frontal, parietal and superior temporal to middle temporal-occipital regions. We applied these acquisitions at a nominal 400 mm3 voxel resolution in n = 27 pre-surgical epilepsy patients and n = 20 controls. In controls, 86.6 ± 3.2% voxels with at least 50% tissue (white + gray matter, excluding CSF) survived spectral quality inclusion criteria. Since all patients were clinically followed for at least 1 year after surgery, seizure frequency outcome was available for all. The MRSI measurements of the total fractional metabolic dysfunction (characterized by the Cr/NAA metric) in FreeSurfer MRI gray matter segmented regions, in the patients compared with the controls, exhibited a significant Spearman correlation with post-surgical outcome. This finding suggests that a larger burden of metabolic dysfunction is seen in patients with poorer post-surgical seizure control.

The use of chemotherapeutic agents as prophylaxis for recurrent urinary tract infection in healthy nonpregnant women: A network meta-analysis.

INTRODUCTION: The aim of this systematic review is to compare chemotherapeutic agents commonly used in treating recurrent urinary infection in nonpregnant women by their efficacy, tolerability, adverse effects, and cost employing network meta-analysis. MATERIALS AND METHODS: We used three online databases, i.e., PubMed, ScienceDirect, and Cochrane Central Registry of Clinical Trials. Randomized controlled trials (RCTs) on the use of prophylactic chemotherapeutic agents used in treating nonpregnant women with recurrent urinary tract infections (RUTIs) published between 2002 and 2016 were selected. Only published papers in English were assessed for study quality, and meta-analyses were performed using fixed-effects model with NetMetaXL. RESULTS: Six RCTs fulfilled the criteria. When all three variables, i.e., efficacy, adverse effects and cost were considered, nitrofurantoin 50 mg once daily for 6 months appears to rank high for prophylaxis against RUTI. When efficacy was the only factor, fosfomycin had the highest superiority compared to D-mannose, nitrofurantoin, estriol, trimethoprim-sulfamethoxazole, and cranberry juice, respectively. However, fosfomycin was also ranked highest by adverse events. When cost alone is considered, nitrofurantoin appeared the most cost-effective agent while placed third for efficacy alone. CONCLUSION: Selecting appropriate chemotherapeutic agents for RUTI will need to factor in effectiveness, adverse effects, and cost. While it is difficult to select an ideal drug, evaluation using network analysis may guide choice of medication for best practice.

Pilot trial of home-administered transcranial direct current stimulation for the treatment of depression.

BACKGROUND: Transcranial Direct Current Stimulation (tDCS) is a non-invasive, neuromodulation approach with promising efficacy for treating depression. To date, tDCS has been limited to clinical or research centre settings with treatment administered by staff. The aim of this study is to examine the efficacy, tolerability and feasibility of home-administered, remotely-supervised tDCS for depression. METHODS: In an open label trial, 34 participants used a Soterix 1 × 1 mini-CT device to self-administer 20-28 tDCS sessions (2 mA, 30 min, F3-anode and F8-cathode montage according to 10-20 EEG placement) over 4 weeks followed by a taper phase of 4 sessions 1 week apart. Participants were initially monitored via video link and then through completion of an online treatment diary. Mixed effects repeated measures analyses assessed change in mood scores. RESULTS: Mood improved significantly from baseline (27.47 on Montgomery-Asberg Depression Rating Scale) to 1 month after the end of acute treatment (15.48) (p < 0.001). Side effects were largely transient and minor. Outcomes were comparable to those reported in clinic-based trials. Protocol adherence was excellent with a drop-out rate of 6% and 93% of scheduled sessions completed. LIMITATIONS: The tDCS and remote monitoring procedures employed in this study require a level of manual dexterity and computer literacy, which may be challenging for some patients. This study did not have a control condition. CONCLUSIONS: This study provides initial evidence that home-based, remotely-supervised tDCS treatment may be efficacious and feasible for depressed patients and has high translational potential.

Side-effects associated with ketamine use in depression: a systematic review.

This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses. We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria. After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depresssion. Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users. We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use.

Lacosamide tolerability in adult patients with partial-onset seizures: Impact of planned reduction and mechanism of action of concomitant antiepileptic drugs.

OBJECTIVE: We evaluated the impact of planned dose reduction and mechanism of action of concomitant AEDs on tolerability in adults with partial-onset seizures undergoing lacosamide (LCM) titration. METHODS: Data were collected at baseline and 3-6 and 12-24 months post-LCM initiation. Subjects were categorized as having planned reduction of concomitant AEDs or not; AEDs were categorized as traditional sodium channel blockers (TSCB) or non-TSCB (NTSCB). Groups with/without planned reduction were compared on the presence and number of treatment-emergent adverse events (TEAEs) using chi-square tests or logistic regression and on time to LCM discontinuation with time-to-event methods controlling for standardized (STD) AED dose, a measure of concomitant AED load. Similar analyses were performed comparing subjects taking TSCB and NTSCB agents and used to identify relationships with ≥50% decreases in seizure frequency. RESULTS: One hundred six adults (mean age 41.4 ± 13.4; 50% male) underwent LCM titration from June 2009-2011 with complete data. Reduction of concomitant AEDs was planned at the time of LCM initiation in 59 (55.7%) subjects. Fewer subjects with planned reduction had TEAEs (49.2% vs. 68.1%; p=0.05), and these subjects had a lower risk of TEAEs (OR 0.36; p=0.019) after adjusting for STD AED dose. The hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction of concomitant AEDs vs. others (p=0.033) and 3.29 (1.01, 10.70) in subjects taking TSCB vs. NTSCB agents (p=0.048). Among all cases, those who ever had TEAEs had significantly higher STD dose at both follow-up visits (p=0.033 and p=0.023, respectively). Seizure outcomes were not significantly different between groups at the last follow-up assessment. SIGNIFICANCE: Planned reduction of concomitant AEDs during LCM initiation and the use of NTSCB agents only are associated with a reduced risk of TEAEs and LCM discontinuation in adults with partial-onset seizures. This study extends prior observations by considering total AED load in the assessment of tolerability and supports the benefits of early reduction of concomitant AEDs during LCM initiation.

Continuous positive airway pressure therapy for obstructive sleep apnea reduces interictal epileptiform discharges in adults with epilepsy.

Obstructive sleep apnea (OSA) is highly prevalent, affecting 25% of men and 10% of women. We recently reported a prevalence of OSA of 30% among 130 adults with epilepsy unselected for sleep disorder complaints, including 16% with moderate-to-severe disease, rates that markedly exceed general population estimates. Treatment of OSA with continuous positive airway pressure (CPAP) therapy or upper airway surgery reduces seizures in many cases. A single study reported a reduction in interictal spike rate with CPAP in 6 patients with OSA. We explored the effect of CPAP therapy on spike rate in 9 adults with epilepsy and OSA. Interictal epileptiform discharges were quantified during a diagnostic polysomnogram (PSG) and a second PSG using therapeutic CPAP. Spike rates were calculated for each recording during wake and sleep stages. Continuous positive airway pressure therapy was associated with significant reductions in median (quartiles) spike rate overall (77.9 [59.7-90.7] %), in wakefulness (38.5 [0.3-55] %), and in sleep (77.7 [54.8-94.7] %) but not in REM sleep. Continuous positive airway pressure therapy also produced a significant improvement in oxygen saturation and arousals. Our work extends a single prior observation demonstrating beneficial effects of CPAP therapy on interictal EEG in patients with epilepsy with comorbid OSA and supports the hypothesis that sleep fragmentation due to OSA contributes to epileptogenicity.

Pathologic findings associated with invasive EEG monitoring for medically intractable epilepsy.

Invasive electroencephalography (EEG) monitoring is often needed for presurgical evaluation in patients with medically intractable epilepsy (MIE). This study retrospectively reviews the pathologic changes associated with EEG monitoring. Two hundred twenty-six patients who underwent invasive monitoring (53.5% males; mean age, 29.8 years) and 55 controls without EEG monitoring (52.7% males; mean age, 25.6 years) were evaluated. Median length of invasive EEG monitoring was 7.0 days. Compared with controls, patients who were monitored had more pathologic changes related to invasive EEG monitoring (n = 171 [75.7%] vs n = 12 [21.8%]; P < .0001) including meningeal or parenchymal chronic inflammation (n = 128 [56.4%] vs n = 11 [20.4%]; P < .0001) and acute contusion and/or acute/subacute infarct (n = 110 [48.5%] vs n = 0; P < .0001). Histologic evidence of pathologic changes typically associated with invasive monitoring and/or craniotomy occurred in 76% of our patients with invasive monitoring compared with 19% in patients without prior invasive EEG evaluation. The most common pathologic changes related to invasive monitoring were chronic inflammation and contusion/infarct.

Seizure outcome and its predictors after temporal lobe epilepsy surgery in patients with normal MRI.

PURPOSE: To characterize seizure outcomes following temporal lobe epilepsy (TLE) surgery in patients with normal preoperative brain magnetic resonance imaging (MRI). METHODS: We reviewed adult patients with pharmacoresistant epilepsy and normal MRI who underwent TLE surgery (1996-2009). Seizure outcomes were analyzed using survival and multivariate regression with Cox proportional hazard modeling. Two analyses were performed using two favorable outcome definitions: complete seizure freedom and Engel classification. KEY FINDINGS: Sixty-four patients were analyzed (mean follow-up 4.1 years; range 1-14.5 years). Most had a standard anterior temporal lobectomy (84%) and unremarkable pathology (45%). At 1 year, the chance of complete seizure freedom was 76% [95% confidence interval (CI) 71-81%] comparable to an 81% (95% CI 76-86%) chance of Engel score of 1. With longer follow-up, a progressively broadening significant discrepancy between the two outcome measures was observed. The chance of complete seizure freedom was 66% (95% CI 61-71%) at 2 years, and 47% (95% CI 40-54%) at 7 years and beyond, whereas the respective chances of achieving an Engel 1 classification were 76% (95% CI 70-82%), and 69% (95% CI 63-75%) at similar time points. Seizure outcome as defined by either measure was worse in patients with higher baseline seizure frequency (adjusted risk-ratio 2.7 when >12 seizures/month; p = 0.01) and with preoperative generalized tonic-clonic seizures (adjusted risk ratio 10.8; p = 0.0006). Memory measures declined with dominant hippocampus resections. SIGNIFICANCE: A normal MRI should not prevent presurgical evaluations in patients with suspected TLE, as favorable long-term postoperative seizure outcomes are possible. Proposed mechanisms of epileptogenicity and seizure recurrence in this group are discussed.

Predictors of biochemical aspirin and clopidogrel resistance in patients with ischemic stroke.

Variable platelet response to aspirin and clopidogrel is a well-established phenomenon in patients with coronary artery disease. We sought to determine the predictors of an impaired biochemical response to aspirin and clopidogrel in patients with ischemic stroke. Patients with established cerebrovascular disease who underwent an aspirin/clopidogrel response panel (ie, light transmittance aggregometry) between June 2003 and March 2007 were identified through an electronic database. The medical records of these patients were retrospectively reviewed, and demographic characteristics, medical history, and laboratory results were recorded. Univariate and multivariate logistic regression analyses were performed to assess for factors associated with antiplatelet resistance. Of the 465 patients included in this study, 120 (28%) were biochemical aspirin nonresponders and 83 (28%) were biochemical clopidogrel nonresponders. Of the 270 patients on dual antiplatelet therapy, 25 (9.3%) were dual biochemical nonresponders. In binary logistic regression modeling, patients with congestive heart failure (odds ratio [OR] = 4.54; 95% confidence interval [CI] = 1.33-15.5; P = .02) and those with higher hemoglobin A1c values (OR = 1.41; 95% CI = 1.12-1.79; P = .004) had a significantly greater likelihood of having a biochemical nonresponse to aspirin therapy. African-American patients (OR = 2.19; 95% CI = 1.23-3.91; P < .007) were significantly more likely to be nonresponders to clopidogrel. This preliminary study shows that aspirin and clopidogrel biochemical nonresponse frequently occurs in ischemic stroke patients. In addition, some associated variables may affect the biochemical response to antiplatelet therapy. Further study is needed to explore whether this nonresponse has an impact on clinical outcomes.

De novo sustained refractory status epilepticus and encephalopathy: a retrospective case series.

Refractory status epilepticus is a devastating persistent seizure state with a poor prognosis that requires emergency medical management. Recent studies have reported de novo, idiopathic refractory status epilepticus of unclear etiology in healthy young patients followed by severe neurologic sequelae. We present a series of 7 cases of de novo sustained refractory status epilepticus. We found that all patients were young and previously healthy and that, prior to the onset of refractory status epilepticus, all had prodromal viral-like symptoms. The onset of refractory status epilepticus was explosive and intractable, resulting in prolonged hospital stay and dependence on multiple antiepileptic medications. Clinical outcome was poor in all 7 patients. The laboratory findings suggest a possible immune activation that can have persisted in the nervous system after a nonspecific infection. We report on these patients so as to raise awareness of this unique entity to facilitate early diagnosis and treatment.

Coexistent pathology in chronic epilepsy patients with neoplasms.

Neoplasms are a well-established cause of medically intractable or chronic epilepsy. Certain tumors, including gangliogliomas and dysembryoplastic neuroepithelial tumors, are well known to be associated with cortical dysplasia. This study retrospectively examines the incidence of coexistent pathology in patients with tumors and chronic epilepsy. This study is a retrospective review of 270 tumors arising in patients with medically intractable epilepsy encountered during a 20-year period (1989-2009). Coexistent pathology was noted in 50 of 270 (17.8%) patients, including 27 males (54%) with a mean age at surgery of 18 years (range 1-52 years). The vast majority of lesions (n=40) (80%) were located in the temporal lobe and less commonly in the parietal lobe (n=4) and the occipital lobe (n=3). Tumor diagnoses included ganglioglioma (n=29), dysembryoplastic neuroepithelial tumor (n=10), low-grade glial/glioneuronal neoplasm (n=5), low-grade astrocytoma (n=2), angiocentric glioma (n=1), low-grade mixed glioma (n=1), dysembryoplastic neuroepithelial tumor/ganglioglioma mixed tumor (n=1), and meningioangiomatosis (n=1). Forty-one (82%) tumors represented WHO grade-I neoplasms. Concomitant pathology included malformation of cortical development (cortical dysplasia) in 40 patients (80%) (Palmini et al type-I: n=37; Palmini et al type-II: n=3). Hamartias were identified in 10 patients (20%), hippocampal sclerosis in four patients (8%), and nodular heterotopia in one patient (2%). The true incidence of coexistent pathology (17.8% in this study) was likely underrepresented, given the limited extent of adjacent non-tumoral tissue sampling in cases of resected tumor. Coexistent pathology may account for the incidence of recurrent or residual epilepsy in patients who undergo tumor resection.

Intracranial atherosclerosis as a risk factor for ischemic stroke during open heart surgery.

BACKGROUND: Embolic stroke is a feared complication after open heart surgery. Many patients undergo testing of the carotid arteries before surgery, but intracranial atherosclerosis is not commonly assessed as a mechanism. METHODS: We reviewed a prospectively maintained database of all open heart surgeries at our institution from 2005 to 2007 for patients who developed a periprocedural ischemic stroke. These patients were assessed for the mechanism of stroke through radiographic imaging of the intracranial circulation to determine the frequency of intracranial atherosclerosis as a mechanism for perioperative stroke. RESULTS: A total of 10,367 patients underwent open heart surgery from 2005 to 2007 and 180 (1.74%) patients were noted to have an ischemic stroke. Of the 180 patients, 98 (55%) underwent intracranial imaging and 29 (30%) were noted to have narrowing of an intracranial vessel. Seventeen (17.4%) patients were found to have infarct ipsilateral to the stenosis, but 8 (8.1%) of these patients were also noted to have infarcts in other vascular territories. Thus, 9 (9.1%) patients were thought to have a stroke solely related to the intracranial stenosis. CONCLUSIONS: Intracranial atherosclerosis may be an underreported mechanism for perioperative stroke after open heart surgery. Further study is required to better understand the prevalence of the disease in this population and subsequent risk of stroke.

Neurodegeneration and neuroprotective agents in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune/ inflammatory disease of the central nervous system (CNS). MS affects more than two million people worldwide and has been recognized as the leading cause of neurological disability in young adults. MS has long been considered as a CNS disease of demyelination and inflammation. Axonal degeneration has however been increasingly accepted as a key pathogenetic element. Certain noninvasive tests such as optic coherence tomography (OCT), magnetization transfer imaging (MTI), and proton magnetic resonance spectroscopy (MRS) might be superior in early detection of axonal loss and neurodegeneration as compared to conventional neuroimaging studies. New therapeutic strategies targeting the neurodegenerative process in MS provide hope to the MS community. A number of phase II or III clinical trials that are designed to target such specific pathogenetic mechanisms include sodium channel blockers, matrix metalloproteinases (MMP) inhibitors, c-AMP selective phosphodiesterase inhibitors, NMDA receptor antagonists, amongst others. In the current review, we will discuss the current understanding of the mechanisms of neurodegeneration in MS, agents with neuroprotective properties, patents currently available and, their possible application in the treatment of MS.

Emotional problems and prevalence of medication overuse in pediatric chronic daily headache.

Chronic daily headaches are an increasingly recognized neurologic issue in children. Frequent headaches can be a source of significant disability and family discord with work/school absenteeism. Medication overuse and emotional disorder would significantly impact treatment and progression. This study examined the frequency of emotional and behavioral problems in children and adolescents with chronic daily headache compared with age-related healthy controls. Prevalence of medication overuse in this chronic daily headache group was evaluated. Otherwise healthy children and adolescents with chronic daily headache (according to International Classification of Headache Disorders-II criteria) were enrolled from the Headache Clinic. Healthy controls were prospectively enrolled from physician offices. Multiple psychological rating scales, headache diaries, presence of medication overuse, and disability surveys (Pediatric Migraine Disability Assessment Survey) were completed. A total of 57 healthy controls and 70 patients were studied. The sample consisted largely of females, many of whom (60%) had medication overuse before medical treatment. Headache patients had significantly more symptoms of anxiety, depression, and somatization compared with controls. Patients with chronic daily headache were at higher risk for emotional disorders, and medication overuse was a significant occurrence, suggesting a need for multisystem treatment approach.