Characterisation of a novel [18F]FDG brain PET database and combination with a second database for optimising detection of focal abnormalities, using focal cortical dysplasia as an example.

BACKGROUND: Brain [18F]FDG PET is used clinically mainly in the presurgical evaluation for epilepsy surgery and in the differential diagnosis of neurodegenerative disorders. While scans are usually interpreted visually on an individual basis, comparison against normative cohorts allows statistical assessment of abnormalities and potentially higher sensitivity for detecting abnormalities. Little work has been done on out-of-sample databases (acquired differently to the patient data). Combination of different databases would potentially allow better power and discrimination. We fully characterised an unpublished healthy control brain [18F]FDG PET database (Marseille, n = 60, ages 21-78 years) and compared it to another publicly available database (MRXFDG, n = 37, ages 23-65 years). We measured and then harmonised spatial resolution and global values. A collection of patient scans (n = 34, 13-48 years) with histologically confirmed focal cortical dysplasias (FCDs) obtained on three generations of scanners was used to estimate abnormality detection rates using standard software (statistical parametric mapping, SPM12). RESULTS: Regional SUVs showed similar patterns, but global values and resolutions were different as expected. Detection rates for the FCDs were 50% for comparison with the Marseille database and 53% for MRXFDG. Simply combining both databases worsened the detection rate to 41%. After harmonisation of spatial resolution, using a full factorial design matrix to accommodate global differences, and leaving out controls older than 60 years, we achieved detection rates of up to 71% for both databases combined. Detection rates were similar across the three scanner types used for patients, and high for patients whose MRI had been normal (n = 10/11). CONCLUSIONS: As expected, global and regional data characteristics are database specific. However, our work shows the value of increasing database size and suggests ways in which database differences can be overcome. This may inform analysis via traditional statistics or machine learning, and clinical implementation.

Neuromodulation Techniques in Children with Super-Refractory Status Epilepticus.

Status epilepticus (SE) is a life-threatening condition and medical emergency which can have lifelong consequences, including neuronal death and alteration of neuronal networks, resulting in long-term neurologic and cognitive deficits in children. When standard pharmacological treatment for SE is not successful in controlling seizures, the condition evolves to refractory SE (rSE) and finally to super-refractory SE (srSE) if it exceeds 24 h despite using anaesthetics. In this systematic review, we present literature data on the potential uses of clinical neuromodulation techniques for the management of srSE in children, including electroconvulsive therapy, vagus nerve stimulation, and deep brain stimulation. The evaluation of these techniques is limited by the small number of published paediatric cases (n = 25, one with two techniques) in peer-reviewed articles (n = 18). Although neuromodulation strategies have not been tested through randomised, prospective controlled clinical trials, this review presents the existing data and the potential benefits of neuromodulation therapy, suggesting that these techniques, when available, could be considered at earlier stages within the course of srSE intending to prevent long-term neurologic complications. Clinical trials aiming to establish whether early intervention can prevent long-term sequelae are necessary in order to establish the potential clinical value of neuromodulation techniques for the treatment of srSE in children.

Neuromodulation in new-onset refractory status epilepticus.

Background: New-onset refractory status epilepticus (NORSE) and its subset of febrile infection-related epilepsy syndrome (FIRES) are devastating clinical presentations with high rates of mortality and morbidity. The recently published consensus on the treatment of these conditions includes anesthetics, antiseizure drugs, antivirals, antibiotics, and immune therapies. Despite the internationally accepted treatment, the outcome remains poor for a significant percentage of patients. Methods: We conducted a systematic review of the use of neuromodulation techniques in the treatment of the acute phase of NORSE/FIRES using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Our search strategy brought up 74 articles of which 15 met our inclusion criteria. A total of 20 patients were treated with neuromodulation. Thirteen cases represented FIRES and in 17 cases the NORSE remained cryptogenic. Ten had electroconvulsive therapy (ECT), seven had vagal nerve stimulation (VNS), and four had deep brain stimulation (DBS); one patient had initially VNS and later DBS. Eight patients were female and nine were children. In 17 out of 20 patients, the status epilepticus was resolved after neuromodulation, while three patients died. Conclusion: NORSE can have a catastrophic course and the first treatment goal should be the fastest possible termination of status epilepticus. The data presented are limited by the small number of published cases and the variability of neuromodulation protocols used. However, they show some potential clinical benefits of early neuromodulation therapy, suggesting that these techniques could be considered within the course of FIRES/NORSE.

Heterogeneity of resting-state EEG features in juvenile myoclonic epilepsy and controls.

Abnormal EEG features are a hallmark of epilepsy, and abnormal frequency and network features are apparent in EEGs from people with idiopathic generalized epilepsy in both ictal and interictal states. Here, we characterize differences in the resting-state EEG of individuals with juvenile myoclonic epilepsy and assess factors influencing the heterogeneity of EEG features. We collected EEG data from 147 participants with juvenile myoclonic epilepsy through the Biology of Juvenile Myoclonic Epilepsy study. Ninety-five control EEGs were acquired from two independent studies [Chowdhury et al. (2014) and EU-AIMS Longitudinal European Autism Project]. We extracted frequency and functional network-based features from 10 to 20 s epochs of resting-state EEG, including relative power spectral density, peak alpha frequency, network topology measures and brain network ictogenicity: a computational measure of the propensity of networks to generate seizure dynamics. We tested for differences between epilepsy and control EEGs using univariate, multivariable and receiver operating curve analysis. In addition, we explored the heterogeneity of EEG features within and between cohorts by testing for associations with potentially influential factors such as age, sex, epoch length and time, as well as testing for associations with clinical phenotypes including anti-seizure medication, and seizure characteristics in the epilepsy cohort. P-values were corrected for multiple comparisons. Univariate analysis showed significant differences in power spectral density in delta (2-5 Hz) (P = 0.0007, hedges' g = 0.55) and low-alpha (6-9 Hz) (P = 2.9 × 10-8, g = 0.80) frequency bands, peak alpha frequency (P = 0.000007, g = 0.66), functional network mean degree (P = 0.0006, g = 0.48) and brain network ictogenicity (P = 0.00006, g = 0.56) between epilepsy and controls. Since age (P = 0.009) and epoch length (P = 1.7 × 10-8) differed between the two groups and were potential confounders, we controlled for these covariates in multivariable analysis where disparities in EEG features between epilepsy and controls remained. Receiver operating curve analysis showed low-alpha power spectral density was optimal at distinguishing epilepsy from controls, with an area under the curve of 0.72. Lower average normalized clustering coefficient and shorter average normalized path length were associated with poorer seizure control in epilepsy patients. To conclude, individuals with juvenile myoclonic epilepsy have increased power of neural oscillatory activity at low-alpha frequencies, and increased brain network ictogenicity compared with controls, supporting evidence from studies in other epilepsies with considerable external validity. In addition, the impact of confounders on different frequency-based and network-based EEG features observed in this study highlights the need for careful consideration and control of these factors in future EEG research in idiopathic generalized epilepsy particularly for their use as biomarkers.

Anabolic-androgenic steroids abuse-induced seizures: A case report in a young male bodybuilder.

None.

Serological, Molecular and Culture-Based Diagnosis of Lentiviral Infections in Small Ruminants.

Small ruminant lentiviruses (SRLVs) infections lead to chronic diseases and remarkable economic losses undermining health and welfare of animals and the sustainability of farms. Early and definite diagnosis of SRLVs infections is the cornerstone for any control and eradication efforts; however, a "gold standard" test and/or diagnostic protocols with extensive applicability have yet to be developed. The main challenges preventing the development of a universally accepted diagnostic tool with sufficient sensitivity, specificity, and accuracy to be integrated in SRLVs control programs are the genetic variability of SRLVs associated with mutations, recombination, and cross-species transmission and the peculiarities of small ruminants' humoral immune response regarding late seroconversion, as well as intermittent and epitope-specific antibody production. The objectives of this review paper were to summarize the available serological and molecular assays for the diagnosis of SRLVs, to highlight their diagnostic performance emphasizing on advantages and drawbacks of their application, and to discuss current and future perspectives, challenges, limitations and impacts regarding the development of reliable and efficient tools for the diagnosis of SRLVs infections.

Neuromodulation in Super-refractory Status Epilepticus.

SUMMARY: Status epilepticus (SE) is a severe condition that needs immediate pharmacological treatment to tackle brain damage and related side effects. In approximately 20% of cases, the standard treatment for SE does not control seizures, and the condition evolves to refractory SE. If refractory status epilepticus lasts more than 24 hours despite the use of anesthetic treatment, the condition is redefined as super-refractory SE (srSE). sRSE is a destructive condition, potentially to cause severe brain damage. In this review, we discuss the clinical neuromodulation techniques for controlling srSE when conventional treatments have failed: electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation. Data show that neuromodulation therapies can abort srSE in >80% of patients. However, no randomized, prospective, and controlled trials have been completed, and data are provided only by retrospective small case series and case reports with obvious inclination to publication bias. There is a need for further investigation into the use of neuromodulation techniques as an early treatment of srSE and to address whether an earlier intervention can prevent long-term complications.

An evaluation of the effectiveness of perampanel in people with epilepsy who have previously undergone resective surgery and/or implantation of a vagal nerve stimulator.

About 30% of people with epilepsy (PWE) are drug-resistant. Those with focal seizures may be suitable for epilepsy surgery. Those not amenable to resective surgery can be considered for vagus nerve stimulation (VNS). However, after operative procedures, around 50% of patients continue to experience seizures. A multi-center retrospective study assessing perampanel effectiveness and tolerability for PWE who have undergone surgical resection and/or VNS implantation was performed. The primary outcome was ≥50% reduction in seizure frequency while secondary outcomes included side effects (SEs), dose-related effectiveness, and toxicity. The median perampanel dose was 6 mg. Only one PWE became seizure free. A ≥50% decrease in seizure frequency was observed in 52.8% of the post-resection group and 16.9% of the VNS group (p < 0.001), while SEs were seen in 44.8% and 41.1%, respectively. Perampanel doses greater than 8 mg led to better response in both groups, especially in the post-VNS cohort. SEs were not dose-related and the safety profile was similar to previous observational studies. Perampanel can be beneficial in these two super-refractory epilepsy groups, particularly in PWE with seizures after surgical resection. Doses of more than 8 mg appear to be well tolerated and may be more effective than lower doses in PWE after surgical interventions.

Trial Of Neurostimulation In Conversion Symptoms (TONICS): a feasibility randomised controlled trial of transcranial magnetic stimulation for functional limb weakness.

OBJECTIVES: Transcranial magnetic stimulation (TMS) has been used therapeutically for functional (conversion) motor symptoms but there is limited evidence for its efficacy and the optimal protocol. We examined the feasibility of a novel randomised controlled trial (RCT) protocol of TMS to treat functional limb weakness. DESIGN: A double-blind (patient, outcome assessor) two parallel-arm, controlled RCT. SETTING: Specialist neurology and neuropsychiatry services at a large National Health Service Foundation Trust in London, UK. PARTICIPANTS: Patients with a diagnosis of functional limb weakness (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition). Exclusion criteria included comorbid neurological or major psychiatric disorder, contraindications to TMS or previous TMS treatment. INTERVENTIONS: Patients were randomised to receive either active (single-pulse TMS to primary motor cortex (M1) above resting motor threshold) or inactive treatment (single-pulse TMS to M1 below resting motor threshold). Both groups received two TMS sessions, 4 weeks apart. OUTCOME MEASURES: We assessed recruitment, randomisation and retention rates. The primary outcome was patient-rated symptom change (Clinical Global Impression-Improvement scale, CGI-I). Secondary outcomes included clinician-rated symptom change, psychosocial functioning and disability. Outcomes were assessed at baseline, both TMS visits and at 3-month follow-up. RESULTS: Twenty-two patients were recruited and 21 (96%) were successfully randomised (active=10; inactive=11). Nineteen (91%) patients were included at follow-up (active=9; inactive=10). Completion rates for most outcomes were good (80%-100%). Most patients were satisfied/very satisfied with the trial in both groups, although ratings were higher in the inactive arm (active=60%, inactive=92%). Adverse events were not more common for the active treatment. Treatment effect sizes for patient-rated CGI-I scores were small-moderate (Cliff's delta=-0.1-0.3, CIs-0.79 to 0.28), reflecting a more positive outcome for the active treatment (67% and 44% of active arm-rated symptoms as 'much improved' at session 2 and follow-up, respectively, vs 20% inactive group). Effect sizes for secondary outcomes were variable. CONCLUSIONS: Our protocol is feasible. The findings suggest that supramotor threshold TMS of M1 is safe, acceptable and potentially beneficial as a treatment for functional limb weakness. A larger RCT is warranted. TRIAL REGISTRATION NUMBER: ISRCTN51225587.

Does sympathetic nervous system modulate tumor progression? A narrative review of the literature.

OBJECTIVE: The role of the sympathetic nervous system (SNS) in tumor development, progression and metastasis is studied for more than half a century and is attracting more attention during the last years. In this narrative review, we aim to a chronological and methodological presentation of the most interesting and pioneering studies on the subject. METHODS: The complexity of the autonomic nervous system's interaction with the immune system, its direct and indirect effects on tumors and their surrounding tissues, plus the diversity and heterogeneity in the design and methodology of the studies, provide hard-to-interpret data and, at times, controversial findings. Studies are categorized into four main groups regarding the distribution of sympathetic nerve fibers inside the tumor, the effect of sympathectomy on cancer progression, the role of neurotransmitters on tumor growth and the impact of sympathetic adrenergic signaling on the anti-tumor immune response. RESULTS: Studies from all four categories converge to a common point. There is strong evidence that SNS function plays a role in the development and progression of tumors and subsequently the modification of SNS function, locally or diffusely, can affect the course of tumor growth. CONCLUSION: The impact of SNS function on cancer behavior may be exerted in two ways, directly via the sympathetic nerve fibers or through widely distributed neurotransmitters. Modification of them, combined or not with treatments altering the immune function, could be the target for future therapeutic implications.

Perampanel for the treatment of epilepsy; Longitudinal actuarial analysis and dose responses based on monthly outcomes.

PURPOSE: To explore the retention rates and the efficacy and tolerability of perampanel (PER) by using monthly real life data for a period of 12 months. METHODS: Longitudinal outcomes of (PER) usage were assessed using actuarial statistics in an observational nonrandomised multicentre study of 181 people with epilepsy (PWE) refractory to first and second line drugs. Graded seizure outcomes, toxicity and the dose of PER were recorded for each month. RESULTS: PWE were followed for a mean of 15.1 months. The total cumulative probability for retention on PER at 12 months was 61.7% and for ≥50% improvement was 38.2%. Most improvements in seizure control occurred soon after initiation of PER, 17% by one month, 32% by six months and 38% by twelve months, and mostly at low doses 53% on 2 mg and 90% up to 6 mg. Improvements, when they occurred, were sustained. The most common side effects were neuropsychiatric, occurring in 28%. The emergence of side effects did not appear to be dose related. Although people with intellectual disability (ID) were more likely to remain on PER they did not show improved seizure control and also reported more side effects. Patients treated with VNS and PER had a worse outcome. CONCLUSION: Overall around a third of people showed a useful, response to PER therapy. The response to PER is noted usually early in the treatment and for the majority of the patients for doses up to 8 mg.

Increased hair cortisol and antecedent somatic complaints in children with a first epileptic seizure.

OBJECTIVE: Stress is the most frequent seizure-precipitating factor reported by patients with epilepsy, while stressful life events may increase seizure susceptibility in humans. In this study, we investigated the relations between both biological and behavioral measures of stress in children with a first epileptic seizure (hereafter called seizure). We hypothesized that hair cortisol, a biomarker of chronic stress reflecting approximately 3months of preceding exposure, might be increased in children with a first seizure. We also employed standardized questionnaires to examine presence of stress-related behavioral markers. METHODS: This was a cross-sectional clinical study investigating stress-related parameters in children with a first seizure (First Epileptic Seizure Group (FESG), n=22) in comparison to healthy children without seizures (Control Group, n=29). Within 24h after a first seizure, hair samples were collected from children for the determination of cortisol. In parallel, perceived stress and anxiety and depressive symptoms were examined with appropriate self- and parent-completed questionnaires, and history of stressful life events during the past year was recorded. Emotional and behavioral problems were also assessed by parent-reported validated and widely-used questionnaires. RESULTS: Higher hair cortisol measurements were observed in the FESG than control children (7.5 versus 5.0pg/mg respectively, p=0.001). The former were more likely to complain of somatic problems than the latter (59.8 vs. 55.4 according to DSM-oriented Scale, p=0.021); however, there were no differences in perceived stress and anxiety or depressive symptoms between the two groups. Using ROC analysis of hair cortisol measurements for predicting disease status, the maximum sensitivity and specificity were observed for a cut-off point of 5.25pg/mg. SIGNIFICANCE: Increased hair cortisol indicates chronic hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis prior to the first seizure. This might have contributed to the epileptogenesis process and may help explain the higher incidence of antecedent somatic complaints in the first seizure group.