Defining benchmark outcomes for mesial temporal lobe epilepsy surgery: A global multicenter analysis of 1119 cases.

OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.

Long-term clinical course and treatment outcomes of individuals with Nodding Syndrome.

Nodding Syndrome is a poorly understood epilepsy disorder in sub-Saharan Africa. The cause(s) of the disease, risk factors and long-term outcomes are unknown or controversial. The objectives of this study were to describe the long-term clinical course and treatment outcomes of individuals suffering from Nodding Syndrome. In addition, we aimed to provide a comprehensive characterization of the epileptological and social features of patients with Nodding Syndrome. From 11/2014 to 4/2015, we conducted a hospital-based, cross-sectional and observational study in Mahenge, Tanzania. Seventy-eight individuals (female:male ratio: 40:38, age at examination: 21.1 ± 6.39 (SD) years) have been enrolled, of whom 38 (49%) had also been examined in 2005 and in 2009. The 10-year clinical course analysis of this revisited subgroup revealed a calculated case fatality of 0.8-2.3%. Progressive physical or cognitive deterioration has not been observed in any of the 78 individuals and more than half of the people studied (38/69; 55%) managed to live and work independently. 14/78 individuals (18%) were seizure-free, (no head nodding, no other seizure types), 13 of whom were taking antiseizure medication. Phenytoin was more effective against head nodding seizures (14/19 (74%)) than monotherapy with other available antiseizure medication (phenobarbitone 12/25 (48%) and carbamazepine 7/22 (32%), p = 0.02, chi-square test). Our ten-year clinical outcome data show that Nodding Syndrome is not a fatal disease, however, the response to treatment is worse than in epilepsy patients in general. Phenytoin may be more effective than carbamazepine and phenobarbitone, but further studies are needed to confirm this observation.

Breath-Hold-Triggered BOLD fMRI in Drug-Resistant Nonlesional Focal Epilepsy-A Pilot Study.

PURPOSE: Individuals with drug-resistant epilepsy may benefit from epilepsy surgery. In nonlesional cases, where no epileptogenic lesion can be detected on structural magnetic resonance imaging, multimodal neuroimaging studies are required. Breath-hold-triggered BOLD fMRI (bh-fMRI) was developed to measure cerebrovascular reactivity in stroke or angiopathy and highlights regional network dysfunction by visualizing focal impaired flow increase after vasodilatory stimulus. This regional dysfunction may correlate with the epileptogenic zone. In this prospective single-center single-blind pilot study, we aimed to establish the feasibility and safety of bh-fMRI in individuals with drug-resistant non-lesional focal epilepsy undergoing presurgical evaluation. METHODS: In this prospective study, 10 consecutive individuals undergoing presurgical evaluation for drug-resistant focal epilepsy were recruited after case review at a multidisciplinary patient management conference. Electroclinical findings and results of other neuroimaging were used to establish the epileptogenic zone hypothesis. To calculate significant differences in cerebrovascular reactivity in comparison to the normal population, bh-fMRIs of 16 healthy volunteers were analyzed. The relative flow change of each volume of interest (VOI) of the atlas was then calculated compared to the flow change of the whole brain resulting in an atlas of normal cerebral reactivity. Consequently, the mean flow change of every VOI of each patient was tested against the healthy volunteers group. Areas with significant impairment of cerebrovascular reactivity had decreased flow change and were compared to the epileptogenic zone localization hypothesis in a single-blind design. RESULTS: Acquisition of bh-fMRI was feasible in 9/10 cases, with one patient excluded due to noncompliance with breathing maneuvers. No adverse events were observed, and breath-hold for intermittent hypercapnia was well tolerated. On blinded review, we observed full or partial concordance of the local network dysfunction seen on bh-fMRI with the electroclinical hypothesis in 6/9 cases, including cases with extratemporal lobe epilepsy and those with nonlocalizing 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). CONCLUSION: This represents the first report of bh-fMRI in individuals with epilepsy undergoing presurgical evaluation. We found bh-fMRI to be feasible and safe, with a promising agreement to electroclinical findings. Thus, bh-fMRI may represent a potential modality in the presurgical evaluation of epilepsy. Further studies are needed to establish clinical utility.

Epilepsy and nodding syndrome in association with an Onchocerca volvulus infection drive distinct immune profile patterns.

Previous studies have described the association of onchocerciasis (caused by Onchocerca volvulus) with epilepsy, including nodding syndrome, although a clear etiological link is still missing. Cases are found in different African countries (Tanzania, South Sudan, Uganda, Democratic Republic of the Congo, Central African Republic and Cameroon). In our study we investigated immunological parameters (cytokine, chemokine, immunoglobulin levels) in individuals from the Mahenge area, Tanzania, presenting with either epilepsy or nodding syndrome with or without O. volvulus infection and compared them to O. volvulus negative individuals from the same endemic area lacking neurological disorders. Additionally, cell differentiation was performed using blood smears and systemic levels of neurodegeneration markers, leiomodin-1 and N-acetyltyramine-O, ß-glucuronide (NATOG) were determined. Our findings revealed that cytokines, most chemokines and neurodegeneration markers were comparable between both groups presenting with epilepsy or nodding syndrome. However, we observed elevated eosinophil percentages within the O. volvulus positive epilepsy/nodding syndrome patients accompanied with increased eosinophilic cationic protein (ECP) and antigen-specific IgG levels in comparison to those without an O. volvulus infection. Furthermore, highest levels of NATOG were found in O. volvulus positive nodding syndrome patients. These findings highlight that the detection of distinct biomarkers might be useful for a differential diagnosis of epilepsy and nodding syndrome in O. volvulus endemic areas. Trial-registration: NCT03653975.

Focal Cortex Stimulation With a Novel Implantable Device and Antiseizure Outcomes in 2 Prospective Multicenter Single-Arm Trials.

Importance: For the large population of people with drug-refractory epilepsy, alternative treatment approaches are needed. Clinical trial outcomes of a novel stimulation device, which is newly available in Europe for the treatment of patients with a predominant seizure focus, are reported for the first time. Objective: To perform a pooled analysis of the results of 2 prospective, multicenter, single-arm trials, A Pilot Study to Assess the Feasibility of Neurostimulation With the EASEE System to Treat Medically Refractory Focal Epilepsy (EASEE II) and A Pilot Study to Assess the Feasibility of Patient-Controlled Neurostimulation With the EASEE System to Treat Medically Refractory Focal Epilepsy (PIMIDES I), assessing the safety and efficacy of epicranial focal cortex stimulation (FCS) with a novel implantable device (EASEE [Precisis]) as adjunctive treatment for adult patients with drug-refractory focal epilepsy. Design, Setting, and Participants: This study was a pooled analysis of 2 nonrandomized uncontrolled trials, EASEE II and PIMIDES I, which began on January 15, 2019, and January 14, 2020, respectively, and ended on July 28, 2021. EASEE II and PIMIDES I were the first in-human, prospective, single-arm trials with an 8-month evaluation period. Patients were recruited at 7 European epilepsy centers. Consecutive participants with drug-refractory focal epilepsy were enrolled. Study data were analyzed from September 29, 2021, to February 2, 2022. Interventions: After a 1-month prospective baseline period, patients were implanted with the neurostimulation device. After a 1-month postimplantation recovery period, unblinded FCS was activated using both high-frequency and direct current (DC)-like components performed via electrode arrays placed epicranially above the individual epileptic focus region. Main Outcomes and Measures: Efficacy was prospectively assessed by the responder rate in the sixth month of stimulation compared with baseline; safety and additional end points were assessed after device implantation and during the stimulation period. Results: Of the 34 adult patients enrolled at 6 German and 1 Belgian investigational site, 33 (mean [SD] age, 34.6 [13.5] years; 18 male patients [54.5%]) received the neurostimulation device implant. A total of 32 patients underwent combined high-frequency direct current-like stimulation at least until the 8-month postimplant follow-up visit. After 6 months of stimulation, 17 of 32 patients (53.1%) were responders to treatment with at least a 50% reduction in seizure frequency compared with baseline, corresponding to a significant median seizure reduction by 52% (95% CI, 0.37%-0.76%; P < .001). No device- or procedure-related serious adverse events were reported (0; 95% CI, 0%-10.58%). There were no significant alterations in cognition, mood, or overall quality of life. Conclusions and Relevance: Results of this pooled analysis of 2 nonrandomized uncontrolled trials suggest that FCS with a novel neurostimulation device was associated with an effective reduction in seizure frequency in patients with drug-refractory focal epilepsy and may offer a promising treatment option for patients with a predominant epileptic focus. Trial Registration: German Clinical Trials Register: DRKS00015918 and DRKS00017833, respectively, and jointly under PROSPERO: CRD42021266440.

Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies.

BACKGROUND: De novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described to cause developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. METHODS: 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with homology modelling. FINDINGS: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures; two variants were also associated with mild to moderate ID. All missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The R359C variant altered PI(4,5)P2-interaction. INTERPRETATION: Our study identified deleterious KCNQ5 variants in GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5-expressing neurons. Further studies on network level are necessary to understand which circuits are affected and how this induces generalized seizures. FUNDING: DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation 'no epilep' (Germany).

Ictal Electroencephalographic Characteristics of Nodding Syndrome: A Comparative Case-Series from South Sudan, Tanzania, and Uganda.

Nodding syndrome (NS) is a poorly understood form of childhood-onset epilepsy that is characterized by the pathognomonic ictal phenomenon of repetitive vertical head drops. To evaluate the underlying ictal neurophysiology, ictal EEG features were evaluated in nine participants with confirmed NS from South Sudan, Tanzania, and Uganda and ictal presence of high frequency gamma oscillations on scalp EEG were assessed. Ictal EEG during the head nodding episode predominantly showed generalized slow waves or sharp-and-slow wave complexes followed by electrodecrement. Augmentation of gamma activity (30-70 Hz) was seen during the head nodding episode in all the participants. We confirm that head nodding episodes in persons with NS from the three geographically distinct regions in sub-Saharan Africa share the common features of slow waves with electrodecrement and superimposed gamma activity. ANN NEUROL 2022;92:75-80.

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Enhancing Safety in Epilepsy Surgery (EASINESS): Study Protocol for a Retrospective, Multicenter, Open Registry.

Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy. Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded. Outcomes: The collected data will be used for establishing standardized reference values ("benchmarks") for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications. Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials. Clinical trial registration: This study is indexed at clinicaltrials.gov (NT 04952298).

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature.

Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for KV1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated. Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of KV1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia. Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of KV1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels. Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional KV1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.

Genetics of Paroxysmal Dyskinesia: Novel Variants Corroborate the Role of KCNA1 in Paroxysmal Dyskinesia and Highlight the Diverse Phenotypic Spectrum of KCNA1- and SLC2A1-Related Disorders.

Paroxysmal dyskinesias (PxD) are rare movement disorders with characteristic episodes of involuntary mixed hyperkinetic movements. Scientific efforts and technical advances in molecular genetics have led to the discovery of a variety of genes associated with PxD; however, clinical and genetic information of rarely affected genes or infrequent variants is often limited. In our case series, we present two individuals with PxD including one with classical paroxysmal kinesigenic dyskinesia, who carry new likely pathogenic de novo variants in KCNA1 (p.Gly396Val and p.Gly396Arg). The gene has only recently been discovered to be causative for familial paroxysmal kinesigenic dyskinesia. We also provide genetic evidence for pathogenicity of two newly identified disease-causing variants in SLC2A1 (p.Met96Thr and p.Leu231Pro) leading to paroxysmal exercise-induced dyskinesia. Since clinical information of carriers of variants in known disease-causing genes is often scarce, we encourage to share clinical data of individuals with rare or novel (likely) pathogenic variants to improve disease understanding.

Frame-based and robot-assisted insular stereo-electroencephalography via an anterior or posterior oblique approach.

OBJECTIVE: There is an increasing interest in stereo-electroencephalography (SEEG) for invasive evaluation of insular epilepsy. The implantation of insular SEEG electrodes, however, is still challenging due to the anatomical location and complex functional segmentation in both an anteroposterior and ventrodorsal (i.e., superoinferior) direction. While the orthogonal approach (OA) is the shortest trajectory to the insula, it might insufficiently cover these networks. In contrast, the anterior approach (AOA) or posterior oblique approach (POA) has the potential for full insular coverage, with fewer electrodes bearing a risk of being more inaccurate due to the longer trajectory. Here, the authors evaluated the implantation accuracy and the detection of epilepsy-related SEEG activity with AOA and POA insular trajectories. METHODS: This retrospective study evaluated the accuracy of 220 SEEG electrodes in 27 patients. Twelve patients underwent a stereotactic frame-based procedure (frame group), and 15 patients underwent a frameless robot-assisted surgery (robot group). In total, 55 insular electrodes were implanted using the AOA or POA considering the insular anteroposterior and ventrodorsal functional organization. The entry point error (EPE) and target point error (TPE) were related to the implantation technique (frame vs robot), the length of the trajectory, and the location of the target (insular vs noninsular). Finally, the spatial distribution of epilepsy-related SEEG activity within the insula is described. RESULTS: There were no significant differences in EPE (mean 0.9 ± 0.6 for the nonsinsular electrodes and 1.1 ± 0.7 mm for the insular electrodes) and TPE (1.5 ± 0.8 and 1.6 ± 0.9 mm, respectively), although the length of trajectories differed significantly (34.1 ± 10.9 and 70.1 ± 9.0 mm, repsectively). There was a significantly larger EPE in the frame group than in the robot group (1.5 ± 0.6 vs 0.7 ± 0.5 mm). However, there was no group difference in the TPE (1.5 ± 0.8 vs 1.6 ± 0.8 mm). Epilepsy-related SEEG activity was detected in 42% (23/55) of the insular electrodes. Spatial distribution of this activity showed a clustering in both anteroposterior and ventrodorsal directions. In purely insular onset cases, subsequent insular lesionectomy resulted in a good seizure outcome. CONCLUSIONS: The implantation of insular electrodes via the AOA or POA is safe and efficient for SEEG implantation covering both anteroposterior and ventrodorsal functional organization with few electrodes. In this series, there was no decrease in accuracy due to the longer trajectory of insular SEEG electrodes in comparison with noninsular SEEG electrodes. The results of frame-based and robot-assisted implantations were comparable.

Nerve Ultrasound as Helpful Tool in Polyneuropathies.

BACKGROUND: Polyneuropathies (PNP) are a broad field of diseases affecting millions of people. While the symptoms presented are mostly similar, underlying causes are abundant. Thus, early identification of treatable causes is often difficult. Besides clinical data and basic laboratory findings, nerve conduction studies are crucial for etiological classification, yet limited. Besides Magnetic Resonance Imaging (MRI), high-resolution nerve ultrasound (HRUS) has become a noninvasive, fast, economic and available tool to help distinguish different types of nerve alterations in neuropathies. METHODS: We aim to describe typical ultrasound findings in PNP and patterns of morphological changes in hereditary, immune-mediated, diabetic, metabolic and neurodegenerative PNP. Literature research was performed in PubMed using the terms 'nerve ultrasound', neuromuscular ultrasound, high-resolution nerve ultrasound, peripheral nerves, nerve enlargement, demyelinating, hereditary, polyneuropathies, hypertrophy'. RESULTS: Plenty of studies over the past 20 years investigated the value of nerve ultrasound in different neuropathies. Next to nerve enlargement, patterns of nerve enlargement, echointensity, vascularization and elastography have been evaluated for diagnostic terms. Furthermore, different scores have been developed to distinguish different etiologies of PNP. CONCLUSIONS: Where morphological alterations of the nerves reflect underlying pathologies, early nerve ultrasound might enable a timely start of available treatment and also facilitate follow up of therapy success.

Normative Observational Nerve Ultrasound Values in School-Age Children and Adolescents and Their Application to Hereditary Neuropathies.

Backgrounds: We have aimed to establish nerve ultrasound reference data in 8 to 17-year-old children and adolescents and to compare those data to younger children, adults, and age-matched children with polyneuropathies. Methods: High-resolution ultrasounds of the nerves were performed in 117 healthy children and adolescents at 20 predefined landmarks in the neck and the extremities of both sides. Mean values, side-to-side differences and intraneural ratios, as well as upper limits have been calculated. In a second step, a comparison between 25 children and adolescents of the same age range with proven hereditary and acquired neuropathies and lysosomal storage diseases has been carried out. Results: Nerve growth correlates significantly with age and reaches adult values at the age of around 15 years. The influence of body mass index and gender is negligible at most segments. By the use of age-specific upper limits, nerve enlargement could be seen in distinct types of neuropathies, particularly in demyelinating hereditary and inflammatory types, which is comparable to findings in adults, but also in rare lysosomal storage diseases. Conclusion: Nerve size correlates with age during childhood and reaches a climax in younger adults. Age-matched reference data are inevitable to differ between hypertrophic and non-hypertrophic nerve damage, e.g., in neuropathies.

Nerve ultrasound reference data in children from two to seven years.

OBJECTIVE: We examined selected peripheral and spinal nerves of children aged between two and seven years. METHOD: High resolution ultrasound was performed in 116 children (2-7 years of age) at 19 predefined landmarks of median, ulnar, tibial, fibular, sural and radial nerves, the vagus as well as cervical spinal nerve 5 and 6. Further, side-to-side measuring and grey-scale analysis was done at selected nerve sites. RESULTS: Nerves of children were on average smaller than those of adults. Nerve growth correlates significantly with age in all nerves, the mean values were similar in the age of two to four years and five to seven years. Body mass index (BMI) and gender showed moderate effect at some nerve sites, however not uniformly in all. A side-to-side difference of up to 30% in median, and up to 20% in tibial nerve can occur in healthy individuals. Grey-scale analysis for echointensity has been performed in median, ulnar and tibial nerves. CONCLUSION: Nerve size increases with age, BMI and gender have moderate effect. A side-to-side-difference of up to 30% can exist. SIGNIFICANCE: Reference values of nerve cross-sectional area, side-to-side-difference and echo intensity are necessary to detect nerve pathology in children as well as in adults.

Can Google Trends data improve forecasting of Lyme disease incidence?

BACKGROUND: Online activity-based epidemiological surveillance and forecasting is getting more and more attention. To date, Google search volumes have not been assessed for forecasting of tick-borne diseases. Thus, we performed an analysis of forecasting of the Lyme disease incidence based on the traditional data extended with Google Trends. METHODS: Data on the weekly incidence of Lyme disease in Germany from 16 June 2013 to 27 May 2018 were obtained from the database of the Robert Koch Institute. Data of Internet searches were obtained from Google Trends searching "Borreliose" in Germany for the "last 5 years" as a timespan category. Data were split into the training (from 16 June 2013 to 11 June 2017) and validation (from 12 June 2017, to 27 May 2018) data sets. A seasonal autoregressive moving average model, SARIMA (0,1,1) (0,1,1) [52] model was selected to describe the time series of the weekly Lyme incidence. After this, we added the Google Trends data as an external regressor and identified the SARIMA (0,1,1) (0,1,1) [52] model as optimal. We made predictions for the validation interval using these two models and compared predictions with the values of the validation data set. RESULTS: Forecasting for the validation timespan resulted in similar values for the models. Comparing the forecasted values with the reported ones resulted in an residual mean squared error (RMSE) of 0.3763; the mean absolute percentage error (MAPE) was 8.233 for the model without Google searches with an RMSE of 0.3732; and the MAPE was 8.17495 for the Google Trends values-expanded model. The difference between the predictive performances was insignificant (Diebold-Mariano Test, p-value = 0.4152). CONCLUSION: Google Trends data are a good correlate of the reported incidence of Lyme disease in Germany, but it failed to significantly improve the forecasting accuracy in models based on traditional data.

Evaluation of transient-evoked otoacoustic emissions in a healthy 1 to 10 year pediatric cohort in Sub-Saharan Africa.

OBJECTIVE: Transient-evoked otoacoustic emissions (TEOAEs) monitor cochlear function. High pass rates have been reported for industrialized countries. Pass rates in low and middle income countries such as Sub-Saharan Africa are rare, essentially lower and available for children up to 4 years of age and frequently based on hospital recruitments. This study aims at providing additional TEOAE pass rates of a healthy Sub-Saharan cohort aged 1-10 years with data from Gabon, Ghana and Kenya. Potentially confounding factors (recruitment site, age) are taken into consideration. METHODS: Healthy children were recruited in hospitals, schools and kindergartens. Inclusion criteria were age 1-10 years and normal otoscopic findings. Exclusion criteria were any sickness or physical ailment potentially impairing the hearing capacity. Five measurements per ear were performed with Capella Cochlear Emission Analyzer (MADSEN, Germany). An overall wave reproducibility of above 60% served as pass-criterion. Pass rates were compared between recruitment sites and age groups (1-5 and 6-10 years). RESULTS: Overall pass rate was 87.5% (n = 264; 231 passes vs. 33 fails). Of these 84.0% of hospital recruited children passed (n = 156; 131 passes vs. 25 fails), compared to 92.6% of community recruitments (n = 108; 100 passes vs. 8 fails), which was significantly different p = 0.039). If analyzed by age groups, this difference was only observed in children younger than 6 years (p = 0.007). CONCLUSION: Hospitals as recruitment sites for healthy controls seem to affect TEOAE pass rates. We advise for a cautious approach when recruiting healthy TEOAE control collectives under the age of 6 in a hospital setting. In children older than 6 years conventional pure-tone audiometry remains the standard method for hearing screening.

Severe malaria in children leads to a significant impairment of transitory otoacoustic emissions--a prospective multicenter cohort study.

BACKGROUND: Severe malaria may influence inner ear function, although this possibility has not been examined prospectively. In a retrospective analysis, hearing impairment was found in 9 of 23 patients with cerebral malaria. An objective method to quickly evaluate the function of the inner ear are the otoacoustic emissions. Negative transient otoacoustic emissions are associated with a threshold shift of 20 dB and above. METHODS: This prospective multicenter study analyses otoacoustic emissions in patients with severe malaria up to the age of 10 years. In three study sites (Ghana, Gabon, Kenya) 144 patients with severe malaria and 108 control children were included. All malaria patients were treated with parental artesunate. RESULTS: In the control group, 92.6 % (n = 108, 95 % confidence interval 86.19-6.2 %) passed otoacoustic emission screening. In malaria patients, 58.5 % (n = 94, malaria vs controls p < 0.001, 95 % confidence interval 48.4-67.9 %) passed otoacoustic emission screening at the baseline measurement. The value increased to 65.2 % (n = 66, p < 0.001, 95 % confidence interval 53.1-75.5 %) at follow up 14-28 days after diagnosis of malaria. The study population was divided into severe non-cerebral malaria and severe malaria with neurological symptoms (cerebral malaria). Whereas otoacoustic emissions in severe malaria improved to a passing percentage of 72.9 % (n = 48, 95 % confidence interval 59-83.4 %) at follow-up, the patients with cerebral malaria showed a drop in the passing percentage to 33 % (n = 18) 3-7 days after diagnosis. This shows a significant impairment in the cerebral malaria group (p = 0.012 at days 3-7, 95 % confidence interval 16.3-56.3 %; p = 0.031 at day 14-28, 95 % confidence interval 24.5-66.3 %). CONCLUSION: The presented data show that 40 % of children have involvement of the inner ear early in severe malaria. In children, audiological screening after severe malaria infection is not currently recommended, but is worth investigating in larger studies.