Structural abnormalities of the optic nerve and retina in Huntington’s disease pre-clinical and clinical settings

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing Spectral Domain Optical Coherence Tomography (SD-OCT) in pre-symptomatic HD carriers of Caucasian origin. Transmission Electron Microscopy (TEM) was used to investigate ultrastructural changes in the optic nerve of the well-established R6/2 mouse model at the symptomatic stage of the disease. We found that pre-symptomatic HD carriers displayed a significant reduction in the retinal nerve fibre layer (RNFL) thickness, including specific quadrants: superior, inferior and temporal, but not nasal. There were no other significant irregularities in the GCC layer, at the macula level and in the optic disc morphology. The ultrastructural analysis of the optic nerve in R6/2 mice revealed a significant thinning of the myelin sheaths, with a lamellar separation of the myelin, and a presence of myelonoid bodies. We also found a significant reduction in the thickness of myelin sheaths in peripheral nerves within the choroids area. Those ultrastructural abnormalities were also observed in HD photoreceptor cells that contained severely damaged membrane disks, with evident vacuolisation and swelling. Moreover, the outer segment of retinal layers showed a progressive disintegration. Our study explored structural changes of the optic nerve in pre- and clinical settings and opens new avenues for the potential development of biomarkers that would be of great interest in HD gene therapies

2014 Epilepsy Benchmarks Area III: Improve Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects

The Epilepsy Benchmark goals in Area III focus on making progress in understanding and controlling seizures and related conditions as well as on developing biomarkers and new therapies that will reduce seizures and improve outcomes for individuals with epilepsy. Area III emphasizes a need to better understand the ways in which seizures start, propagate, and terminate and whether those network processes are common or unique in different forms of epilepsy. The application of that knowledge to improved seizure prediction and detection will also play a role in improving patient outcomes. Animal models of treatment-resistant epilepsy that are aligned with etiologies and clinical features of human epilepsies are especially encouraged as necessary tools to understand mechanisms and test potential therapies. Antiseizure therapies that target (either alone or in combination) novel or multiple seizure mechanisms are prioritized in this section of the Benchmarks. Area III goals also highlight validation of biomarkers of treatment response and safety risk, effective self-management, and patient-centered outcome measures as important areas of emphasis for the next five to ten years

Post-Traumatic Epilepsy Associations with Mental Health Outcomes in the First Two Years after Moderate to Severe TBI: A TBI Model Systems Analysis

Purpose Research suggests that there are reciprocal relationships between mental health (MH) disorders and epilepsy risk. However, MH relationships to post-traumatic epilepsy (PTE) have not been explored. Thus, the objective of this study was to assess associations between PTE and frequency of depression and/or anxiety in a cohort of individuals with moderate-to-severe TBI who received acute inpatient rehabilitation. Methods Multivariate regression models were developed using a recent (2010–2012) cohort (n = 867 unique participants) from the TBI Model Systems (TBIMS) National Database, a time frame during which self-reported seizures, depression [Patient Health Questionnaire (PHQ)-9], and anxiety [Generalized Anxiety Disorder (GAD-7)] follow-up measures were concurrently collected at year-1 and year-2 after injury. Results PTE did not significantly contribute to depression status in either the year-1 or year-2 cohort, nor did it contribute significantly to anxiety status in the year-1 cohort, after controlling for other known depression and anxiety predictors. However, those with PTE in year-2 had 3.34 times the odds (p = .002) of having clinically significant anxiety, even after accounting for other relevant predictors. In this model, participants who self-identified as Black were also more likely to report clinical symptoms of anxiety than those who identified as White. PTE was the only significant predictor of comorbid depression and anxiety at year-2 (Odds Ratio 2.71; p = 0.049). Conclusions Our data suggest that PTE is associated with MH outcomes 2 years after TBI, findings whose significance may reflect reciprocal, biological, psychological, and/or experiential factors contributing to and resulting from both PTE and MH status post-TBI. Future work should consider temporal and reciprocal relationships between PTE and MH as well as if/how treatment of each condition influences biosusceptibility to the other condition

Prognostic models for predicting posttraumatic seizures during acute hospitalization, and at 1 and 2 years following traumatic brain injury

Objective Posttraumatic seizures (PTS) are well-recognized acute and chronic complications of traumatic brain injury (TBI). Risk factors have been identified, but considerable variability in who develops PTS remains. Existing PTS prognostic models are not widely adopted for clinical use and do not reflect current trends in injury, diagnosis, or care. We aimed to develop and internally validate preliminary prognostic regression models to predict PTS during acute care hospitalization, and at year 1 and year 2 postinjury. Methods Prognostic models predicting PTS during acute care hospitalization and year 1 and year 2 post-injury were developed using a recent (2011–2014) cohort from the TBI Model Systems National Database. Potential PTS predictors were selected based on previous literature and biologic plausibility. Bivariable logistic regression identified variables with a p-value < 0.20 that were used to fit initial prognostic models. Multivariable logistic regression modeling with backward-stepwise elimination was used to determine reduced prognostic models and to internally validate using 1,000 bootstrap samples. Fit statistics were calculated, correcting for overfitting (optimism). Results The prognostic models identified sex, craniotomy, contusion load, and pre-injury limitation in learning/remembering/concentrating as significant PTS predictors during acute hospitalization. Significant predictors of PTS at year 1 were subdural hematoma (SDH), contusion load, craniotomy, craniectomy, seizure during acute hospitalization, duration of posttraumatic amnesia, preinjury mental health treatment/psychiatric hospitalization, and preinjury incarceration. Year 2 significant predictors were similar to those of year 1: SDH, intraparenchymal fragment, craniotomy, craniectomy, seizure during acute hospitalization, and preinjury incarceration. Corrected concordance (C) statistics were 0.599, 0.747, and 0.716 for acute hospitalization, year 1, and year 2 models, respectively. Significance The prognostic model for PTS during acute hospitalization did not discriminate well. Year 1 and year 2 models showed fair to good predictive validity for PTS. Cranial surgery, although medically necessary, requires ongoing research regarding potential benefits of increased monitoring for signs of epileptogenesis, PTS prophylaxis, and/or rehabilitation/social support. Future studies should externally validate models and determine clinical utility

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

Objective Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate-to-severe TBI requiring rehabilitation and surviving at least 5 years. Methods Using the prospective TBI Model Systems National Database, we calculated PTS incidence during acute hospitalization, and at years 1, 2, and 5 postinjury in a continuously followed cohort enrolled from 1989 to 2000 (n = 795). Incidence rates were stratified by risk factors, and adjusted relative risk (RR) was calculated. Late PTS associations with immediate (7 day) versus no seizure prior to discharge from acute hospitalization was also examined. Results PTS incidence during acute hospitalization was highest immediately (<24 h) post-TBI (8.9%). New onset PTS incidence was greatest between discharge from inpatient rehabilitation and year 1 (9.2%). Late PTS cumulative incidence from injury to year 1 was 11.9%, and reached 20.5% by year 5. Immediate/early PTS RR (2.04) was increased for those undergoing surgical evacuation procedures. Late PTS RR was significantly greater for individuals who self-identified as a race other than black/white (year 1 RR = 2.22), and for black individuals (year 5 RR = 3.02) versus white individuals. Late PTS was greater for individuals with subarachnoid hemorrhage (year 1 RR = 2.06) and individuals age 23–32 (year 5 RR = 2.43) and 33–44 (year 5 RR = 3.02). Late PTS RR years 1 and 5 was significantly higher for those undergoing surgical evacuation procedures (RR: 3.05 and 2.72, respectively). Significance In this prospective, longitudinal, observational study, PTS incidence was similar to that in studies published previously. Individuals with immediate/late seizures during acute hospitalization have increased late PTS risk. Race, intracranial pathologies, and neurosurgical procedures also influenced PTS RR. Further studies are needed to examine the impact of seizure prophylaxis in high-risk subgroups and to delineate contributors to race/age associations on long-term seizure outcomes

Driving a motor vehicle and psychogenic nonepileptic seizures: ILAE Report by the Task Force on Psychogenic Nonepileptic Seizures

Objectives This International League Against Epilepsy (ILAE) Report: (a) summarizes the literature about “driving and psychogenic nonepileptic seizures (PNES)”; (b) presents the views of international experts; and (c) proposes an approach to assessing the ability of persons with PNES (PwPNES) to drive. Methods Phase 1: Systematic literature review. Phase 2: Collection of international expert opinion using SurveyMonkey®. Experts included the members of the ILAE PNES Task Force and individuals with relevant publications since 2000. Phase 3: Joint analysis of the findings and refinement of conclusions by all participants using email. As an ILAE Report, the resulting text was reviewed by the Psychiatry Commission, the ILAE Task Force on Driving Guidelines, and Executive Committee. Results Eight studies identified by the systematic review process failed to provide a firm evidence base for PNES‐related driving regulations, but suggest that most health professionals think restrictions are appropriate. Twenty‐six experts responded to the survey. Most held the view that decisions about driving privileges should consider individual patient and PNES characteristics and take account of whether permits are sought for private or commercial driving. Most felt that those with active PNES should not be allowed to drive unless certain criteria were met and that PNES should be thought of as “active” if the last psychogenic seizure had occurred within 6 months. Significance Recommendations on whether PwPNES can drive should be made at the individual patient level. Until future research has determined the risk of accidents in PwPNES a proposed algorithm may guide decisions about driving advice

Phenytoin versus Leviteracetam for seizure prophylaxis after brain injury - A meta analysis

Background: Current standard therapy for seizure prophylaxis in Neuro-surgical patients involves the use of Phenytoin (PHY). However, a new drug Levetiracetam (LEV) is emerging as an alternate treatment choice. We aimed to conduct a meta-analysis to compare these two drugs in patients with brain injury.Methods: An electronic search was performed in using Pubmed, Embase, and CENTRAL. We included studies that compared the use of LEV vs. PHY for seizure prophylaxis for brain injured patients (Traumatic brain injury, intracranial hemorrhage, intracranial neoplasms, and craniotomy). Data of all eligible studies was extracted on to a standardized abstraction sheet. Data about baseline population characteristics, type of intervention, study design and outcome was extracted. Our primary outcome was seizures.Results: The literature search identified 2489 unduplicated papers. Of these 2456 papers were excluded by reading the abstracts and titles. Another 25 papers were excluded after reading their complete text. We selected 8 papers which comprised of 2 RCTs and 6 observational studies. The pooled estimate\u27s Odds Ratio 1.12 (95% CI = 0.34, 3.64) demonstrated no superiority of either drug at preventing the occurrence of early seizures. In a subset analysis of studies in which follow up for seizures lasted either 3 or 7 days, the effect estimate remained insignificant with an odds ratio of 0.96 (95% CI = 0.34, 2.76). Similarly, 2 trials reporting seizure incidence at 6 months also had insignificant pooled results while comparing drug efficacy. The pooled odds ratio was 0.96 (95% CI = 0.24, 3.79).Conclusions: Levetiracetam and Phenytoin demonstrate equal efficacy in seizure prevention after brain injury. However, very few randomized controlled trials (RCTs) on the subject were found. Further evidence through a high quality RCT is highly recommended

Maturation of the Language Network: From Inter- to Intrahemispheric Connectivities

Language development must go hand-in-hand with brain maturation. Little is known about how the brain develops to serve language processing, in particular, the processing of complex syntax, a capacity unique to humans. Behavioral reports indicate that the ability to process complex syntax is not yet adult-like by the age of seven years. Here, we apply a novel method to demonstrate that the basic neural basis of language, as revealed by low frequency fluctuation stemming from functional MRI data, differs between six-year-old children and adults in crucial aspects. Although the classical language regions are actively in place by the age of six, the functional connectivity between these regions clearly is not. In contrast to adults who show strong connectivities between frontal and temporal language regions within the left hemisphere, children's default language network is characterized by a strong functional interhemispheric connectivity, mainly between the superior temporal regions. These data indicate a functional reorganization of the neural network underlying language development towards a system that allows a close interplay between frontal and temporal regions within the left hemisphere

Effectiveness and tolerability of 12-Month Brivaracetam in the real world: EXPERIENCE, an international pooled analysis of individual patient records

Background and Objective Real-world evidence studies of brivaracetam (BRV) have been restricted in scope, location, and patient numbers. The objective of this pooled analysis was to assess effectiveness and tolerability of brivaracetam (BRV) in routine practice in a large international population. Methods EXPERIENCE/EPD332 was a pooled analysis of individual patient records from multiple independent non-interventional studies of patients with epilepsy initiating BRV in Australia, Europe, and the United States. Eligible study cohorts were identified via a literature review and engagement with country lead investigators, clinical experts, and local UCB Pharma scientific/medical teams. Included patients initiated BRV no earlier than January 2016 and no later than December 2019, and had ≥ 6 months of follow-up data. The databases for each cohort were reformatted and standardised to ensure information collected was consistent. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within 3 months before timepoint), continuous seizure freedom (no seizures from baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were considered non-responders/not seizure free. Analyses were performed for all adult patients (≥ 16 years), and for subgroups by seizure type recorded at baseline; by number of prior antiseizure medications (ASMs) at index; by use of BRV as monotherapy versus polytherapy at index; for patients who switched from levetiracetam to BRV versus patients who switched from other ASMs to BRV; and for patients with focal-onset seizures and a BRV dose of ≤ 200 mg/day used as add-on at index. Analysis populations included the full analysis set (FAS; all patients who received at least one BRV dose and had seizure type and age documented at baseline) and the modified FAS (all FAS patients who had at least one seizure recorded during baseline). The FAS was used for all outcomes other than ≥ 50% seizure reduction. All outcomes were summarised using descriptive statistics. Results Analyses included 1644 adults. At baseline, 72.0% were 16–49 years of age and 92.2% had focal-onset seizures. Patients had a median (Q1, Q3) of 5.0 (2.0, 8.0) prior antiseizure medications at index. At 3, 6, and 12 months, respectively, ≥ 50% seizure reduction was achieved by 32.1% (n = 619), 36.7% (n = 867), and 36.9% (n = 822) of patients; seizure freedom rates were 22.4% (n = 923), 17.9% (n = 1165), and 14.9% (n = 1111); and continuous seizure freedom rates were 22.4% (n = 923), 15.7% (n = 1165), and 11.7% (n = 1111). During the whole study follow-up, 551/1639 (33.6%) patients discontinued BRV. TEAEs since prior visit were reported in 25.6% (n = 1542), 14.2% (n = 1376), and 9.3% (n = 1232) of patients at 3, 6, and 12 months, respectively. Conclusions This pooled analysis using data from a variety of real-world settings suggests BRV is effective and well tolerated in routine clinical practice in a highly drug-resistant patient population

Impact of a pharmaceutical care programme on health-related quality of life among women with epilepsy: a randomised controlled trial (IPHIWWE study)

This paper was presented in part at the II Congreso Colombiano de Atención Farmacéutica, Medellín, Colombia, September 27, 2013.Background: Epilepsy is a complex chronic disorder which affects health-related quality of life (HRQOL), especially in women. Pharmaceutical care (PC) allows direct intervention between the pharmacist, the patient and the other healthcare team members to optimise treatments in order to reduce negative outcomes related to medication and contribute to improving HRQOL. The aim of the study was to establish the impact of the application of a pharmaceutical care programme on the HRQOL of women with epilepsy.Methods: This study is a pragmatic randomised controlled trial involving women with epilepsy (WWE) over 18 years of age. The intervention group (IG) received a pharmaceutical care programme consisting of medication review follow-up according to Dáder’s method, health education and therapeutic drug monitoring of anticonvulsants. The impact was assessed by changes in seizure frequency, in the self-administered questionnaires (the QOLIE-31, Liverpool AEP, CES-D, Haynes-Sackett test and Moriski-Green test) and between the first interview and the one at the end of six months of follow-up. A Student’s t-test was performed to compare the final QOLIE-31 score between groups and a paired Student’s t-test was used to determine the change in each group between the start and the end of follow-up.Results: One hundred eighty-two WWE entered the study and 144 (79.1%) completed it. The t-test for comparing the final QOLIE-31 scores between groups yielded a t = −2.166 and confidence interval (CI) (95%): −10.125; −0.4625, p-value =0.0319. The change (Δ) in the QOLIE-31 score for the IG was 12.45 points (p-value <0.001) and for the control group it was 2.61 (p-value =0.072). With 10.7 as the minimally important change we found a relative risk of 2.17 (CI: 1.37; 3.43) and a number needed to treat (NNT) of 3.5.Conclusions: The study demonstrated that the application of a pharmaceutical care programme significantly improves HRQOL in WWE. The NNT we found allows a recommendation to implement the PC programme for the additional benefit that would be obtained in patients’ HRQOL.This study was funded by a competitive investigator grant award from the Universidad Nacional de Colombia (Colombia) - Research Division of Bogotá (ref: 202010011419 Quipu Code)