BACKGROUND:Status epilepticus (SE) is associated with substantial mortality and morbidity that increase with seizure duration. Prompt diagnosis is essential, but access to electroencephalography (EEG) is often limited outside regular working hours. We examined whether EEG delay due to prolonged waiting times for EEG is associated with worse outcomes. METHODS:This retrospective cohort study comprised adults (≥18 years; n=163) with first-time, non-anoxic, EEG-verified non-convulsive SE treated at Odense University Hospital, Denmark (2008-2017). EEG delay was defined as the time from last antiseizure treatment or clinical suspicion of SE to EEG confirmation. Outcomes were new neurological deficit at discharge and 2-year all-cause mortality. External validation used two retrospective German cohorts (n=906) differing in weekend EEG availability. RESULTS:Median EEG delay was 11.7 hours (IQR 3.5-22.6) and correlated with SE duration (r=0.2, p<0.01). Longer delay was associated with new neurological deficits at discharge (p<0.001 across delay groups; ρ=0.152, p=0.03) and higher long-term mortality (log-rank p=0.007), driven mainly by delays>22.6 hours. Multivariable analyses for 1 year mortality adjusting for factors including aetiology and age supported an independent association between delay and higher mortality. Delays were longer for Friday/Saturday admissions when next-day EEG was unavailable, with lower survival. In validation, lack of weekend EEG access showed etiology-dependent weekend-weekday mortality differences (eg, +18.8% in remote symptomatic SE; p=0.01) not seen in centres with weekend EEG availability. CONCLUSION:In this cohort, prolonged waiting times for EEG for the diagnosis of SE were associated with worse neurological outcomes at discharge and higher mortality. Improving timely EEG access, including weekends, may be a modifiable system-level target to improve SE outcomes.

Objective: CMAP scan-based motor unit number estimation (MUNE) methods offer non-invasive, physiologically meaningful measures of motor unit integrity. This study evaluated and compared the test-retest measurement properties of three algorithms: STEPIX, CDIX, and StairFit, with comparison to previously published MScanFit values. Methods: MUNE was estimated from the abductor pollicis brevis (APB), abductor digiti minimi (ADM), and tibialis anterior (TA) muscles in 148 healthy adults recruited across 15 international sites. Relative reliability was assessed using intraclass correlation coefficient (ICC) and concordance correlation coefficient (CCC). Agreement was evaluated using Bland-Altman analysis and estimation statistics. Absolute measurement error was quantified using the standard error of measurement (SEM), SEM%, and smallest detectable changes (SDC). Sensitivity analyses were performed after excluding site- or participant-level data that exceeded quality control thresholds. Results: Across all muscles and algorithms, relative reliability was poor-to-moderate (ICC: 0.29-0.76), with SEM% values of 12-29%. CDIX demonstrated the lowest reliability and highest measurement error, while StairFit and STEPIX performed comparably. CMAP peak amplitude showed moderate-to-good relative reliability (ICC: 0.73-0.82) with SEM% values of 12-16%. Sensitivity analyses improved CMAP peak reliability, but produced only modest changes in MUNE measurement properties. Percent-change analyses indicated that visit-to-visit CMAP peak variability contributed to MUNE variability, but the strength of this association differed across algorithms. Conclusion: CMAP scan MUNE methods showed limited test-retest measurement properties in healthy individuals. Variability reflected contributions from both CMAP acquisition and algorithm-based estimation. Significance: No algorithm consistently achieved the combined reliability, precision, and SDC values needed for tracking individual-level change under the conditions studied. Future studies should evaluate whether measurement properties improve in clinical populations with motor unit loss.

Background:Chronic microglial activation is a key characteristic of Alzheimer's disease (AD). In mouse models of AD, microglial activation is considered associated with microglial cell population expansion. Objective:To elucidate species- and gene-dosage-dependent differences and similarities in microglial cell population expansion in response to amyloid-β (Aβ) plaque pathology. Methods:The total number of Iba1+ microglia in the neocortex of hemizygous APPswe/PS1ΔE9 (APP/PS1) mice and hemi- and homozygous TgF344-AD rats, carrying the same human mutations, was estimated by use of stereological techniques. Furthermore, microglial cluster formation was assessed. Proliferation was assessed in the mouse model. Results:A significant two-fold increase in microglia was observed in the neocortex of hemizygous APP/PS1 mice at 18 months and of homozygous TgF344-AD rats at 17 months. In comparison, the number of microglia in hemizygous TgF344-AD rats, remained constant from 4 to 17 months. Microglial clusters formed prior to the increase in microglial numbers in both species. The clusters were typically small, surrounding the smaller-sized Aβ plaques, occasionally also containing recently proliferated microglia. The Aβ plaque loads were comparable in hemizygous TgF344-AD rats and APP/PS1 mice, and two-three-fold higher in homozygous TgF344-AD rats. The microglial population remained constant across ages in wild types in both species. Conclusions:Transgenic mouse and rat AD models show significant differences in microglial population expansion, with a more restrained expansion in the rat. However, in both species and regardless of gene-dosage, population expansion is preceded by microglial clustering around Aβ plaques, indicating that cluster-formation is a key event in AD neuropathology.

BACKGROUND AND AIMS:Skin biopsies are the primary diagnostic test for small fiber neuropathy, but recently corneal confocal microscopy (CCM) has been developed as an alternative. We compared the correlations of each of these morphometric assessments with peripheral nerve function evaluated through comprehensive quantitative sensory testing (QST) in a mixed etiology polyneuropathy cohort. METHODS:CCM and skin biopsies were performed in a prospective cohort of unselected patients undergoing polyneuropathy diagnostic work-up. We used predefined criteria to identify patients with small or mixed fiber neuropathy. The correlations between corneal nerve fiber density (CNFD), fiber length (CNFL), branch density (CNBD), and tortuosity (CNFT) and the intraepidermal nerve fiber density (IENFD) at the distal leg and the results of QST at the foot were determined. RESULTS:Two-hundred and forty-four patients were included in the analysis. CNFD was negligibly correlated with warm detection threshold (WDT) (r = -0.15; p = 0.023), while there was no statistically significant correlation with other QST measures. There were no statistically significant correlations between neither CNFL nor CNBD and any of the QST measures. CNFT correlated negligibly with WDT (r = 0.17; p = 0.008) and vibration detection threshold (VDT) (r = -0.13; p = 0.044). IENFD correlated moderately with WDT (r = -0.33; p < 0.0001) and mechanical pain threshold (r = -0.37; p < 0.0001) and weakly with cold detection threshold (r = 0.21; p = 0.0008), mechanical detection threshold (r = -0.21; p = 0.0008) and VDT (r = 0.23; p = 0.0004). INTERPRETATION:IENFD correlated better with small and large fiber function at the foot than CCM measures in patients with mixed etiology polyneuropathy. Longitudinal studies are needed to assess the clinical utility for neuropathy progression.

BACKGROUND AND AIMS:Loss of motor units in chronic inflammatory demyelinating polyneuropathy is difficult to assess by conventional nerve conduction due to collateral innervation. We aimed to assess the association between a motor unit number estimate (MUNE) derived from the compound muscle action potential (CMAP) scan using MScanFit and hand function and the clinical response to intravenous immunoglobulin (IVIG). METHODS:Forty-nine CIDP patients and 52 control subjects were included. CMAP scan recordings were obtained from the right abductor pollicis brevis muscle. The primary outcome was the correlation between MUNE and the duration of the nine-hole-peg test (9-HPT) at baseline and the change in the duration of the 9-HPT following treatment with IVIG. Secondary outcomes were grip strength, 10-m-walk test, six-spot-step test, medical research council sum score, inflammatory neuropathy cause and treatment sensory sum score, overall neuropathy limitations scale, and the Rasch-built overall disability scale (R-ODS). RESULTS:MScanFit analysis suggested both loss of motor units (reduced MUNE (p = 0.022) and N50 (p < 0.0001)) and collateral reinnervation (increased median amplitude (p < 0.0001) and size of the largest unit (p < 0.0001)) in CIDP patients compared to controls. In CIDP patients, there was a statistically significant correlation between MUNE and the duration of the 9-HPT (Spearman's r = -0.342; p = 0.016). Further, patients with a low MUNE had the largest reduction in the duration of the 9-HPT following IVIG treatment (r = -0.577; p = 0.043). MUNE also correlated significantly with R-ODS (r = -0.722; p = 0.007). INTERPRETATION:MScanFit MUNE could be a useful method for assessing motor axonal loss in CIDP, which correlates with the clinical function and treatment response.

BACKGROUND:The management of refractory status epilepticus (SE) remains an area of low evidence with varying management strategies. Treatment in the ICU is often postponed due to potential complications from sedation, and it is unknown if its efficacy is superior to additional treatment attempts with IV anti-seizure medications (ASMs). The Fast Acute Sedation at Intensive Care vs. High-Dose IV Anti-Seizure Medication for Treatment of Non-Convulsive Status Epilepticus (FAST) trial aims to compare the efficacy of rapid sedation in the ICU vs. add-on high-dose IV ASM alone for the treatment of refractory SE. METHODS/RESULTS:This prospective, randomized, multicenter trial will enroll adult patients with non-convulsive status epilepticus (NCSE) who either meet current EEG criteria or have unambiguous NCSE with minor motor phenomena ("subtle SE") but without ongoing tonic-clonic seizures that are refractory to benzodiazepines and treatment with at least one second-line ASM. Patients will be randomized to receive either rapid deep sedation for 20 hours with propofol and eventually low-dose midazolam or additional high-dose IV anticonvulsant therapy (levetiracetam, valproate, fosphenytoin, lacosamide, or topiramate) in the intermediate care unit. The primary endpoint is treatment failure, either defined as NCSE on EEG 24 hours after randomization or persistent NCSE after 3 hours despite therapy on continuous EEG or clinically. Secondary endpoints include assessment of new-onset neurologic deficits and modified Rankin Scale at discharge, economic analyses, length of hospital stay, in-hospital infections, and survival. Evaluations will be performed at baseline, discharge, and 3, 6, 12, and 24 months. The target sample size is 116 patients; we expect to have to randomize about 140 patients to reach the required number of patients. CONCLUSIONS:The FAST trial is the first randomized clinical trial to investigate refractory NCSE. Regardless of the outcome, the results of this trial protocol will provide new class 1 evidence for the treatment of NCSE and establish the standard of care for this patient population in the future. TRIAL REGISTRATION:EU CT: 2024-515507-18-00/clinicaltrials.gov: NCT05263674.

There are few prospective studies on neuropathic pain in diabetic polyneuropathy (P-DPN). We aimed to examine the development of P-DPN over time as well as factors associated with both the development of and relief from pain. In this 5-year follow-up study, we included 102 patients with at least probable DPN at baseline, according to the Toronto consensus criteria, recruited from a nationwide Danish cohort of 5514 patients with newly diagnosed type 2 diabetes between 2016 and 2018. All participants underwent detailed phenotyping of both DPN and pain, consisting of a bedside sensory examination, quantitative sensory testing (QST), skin biopsies, and nerve conduction studies at baseline and follow-up. The estimated prevalence (95% CI) of at least probable P-DPN increased from 11.5% (8.2; 14.9) at baseline to 14.8% (9.2; 20.4) at follow-up, with a median (interquartile range) diabetes duration of 11.0 (9.2, 12.2) years. Among 64 patients with baseline nonpainful DPN, 38.2% developed pain at follow-up, while 28.9% of 38 patients with baseline P-DPN did not have pain at follow-up. A higher proportion of patients with baseline dysesthesia developed pain (42.9%), compared with patients without dysesthesia (27.9%, Χ2-test for trend: P < 0.0001). Development of pain was associated with female sex, lower baseline sensitivity to warm stimuli on QST, and lower baseline sural sensory nerve action potential amplitudes. Relief from pain was associated with lower baseline body mass index and cholesterol, as well as higher sensitivity to cold, mechanical, and vibratory stimuli on QST at baseline. This detailed study identified risk factors for neuropathic pain development and cessation.

Background Chronic microglial activation is a key characteristic of Alzheimer's disease (AD). In mouse models of AD, microglial activation is considered associated with microglial cell population expansion. Objective To elucidate species- and gene-dosage-dependent differences and similarities in microglial cell population expansion in response to amyloid-β (Aβ) plaque pathology. Methods The total number of Iba1 + microglia in the neocortex of hemizygous APP swe /PS1 ΔE9 ( APP/PS1) mice and hemi- and homozygous TgF344-AD rats, carrying the same human mutations, was estimated by use of stereological techniques. Furthermore, microglial cluster formation was assessed. Proliferation was assessed in the mouse model. Results A significant two-fold increase in microglia was observed in the neocortex of hemizygous APP/PS1 mice at 18 months and of homozygous TgF344-AD rats at 17 months. In comparison, the number of microglia in hemizygous TgF344-AD rats, remained constant from 4 to 17 months. Microglial clusters formed prior to the increase in microglial numbers in both species. The clusters were typically small, surrounding the smaller-sized Aβ plaques, occasionally also containing recently proliferated microglia. The Aβ plaque loads were comparable in hemizygous TgF344-AD rats and APP/PS1 mice, and two-three-fold higher in homozygous TgF344-AD rats. The microglial population remained constant across ages in wild types in both species. Conclusions Transgenic mouse and rat AD models show significant differences in microglial population expansion, with a more restrained expansion in the rat. However, in both species and regardless of gene-dosage, population expansion is preceded by microglial clustering around Aβ plaques, indicating that cluster-formation is a key event in AD neuropathology.

BACKGROUND:Fibromyalgia (FM) is a complex chronic pain disorder characterized by widespread musculoskeletal pain and symptoms suggesting autonomic dysfunction. Small fiber neuropathy (SFN) has been described in a subgroup of patients. We aimed to explore the value of structured symptom assessment to identify patients with SFN or autonomic neuropathy. METHODS:Forty-six female FM patients were assessed in a cross-sectional study including clinical examinations, validated questionnaires (modified neuropathic pain symptom inventory (m-NPSI), PainDETECT and the composite autonomic symptom score (COMPASS 31)) and diagnostic tests (intraepidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and quantitative sudomotor axon reflex test (QSART)). m-NPSI > 58, PainDETECT > 18, and COMPASS 31 > 16 were defined as suggestive of neuropathic pain and dysautonomia, respectively. SFN was defined as negative findings (hypoalgesia and reduced thermal sensation) and an abnormal diagnostic test (IENFD, thermal detection thresholds or QSART). Cardiovascular autonomic neuropathy (CAN) was defined as two abnormal cardiovascular reflex tests. Symptom scores were compared with patient controls and patients with an established diagnosis of neuropathy. RESULTS:Among FM patients, one had SFN, while two had definite CAN. Thirty-two, 20, and 43 of the FM patients had NPSI, PainDETECT, and COMPASS 31 scores suggesting neuropathy/dysautonomia. NPSI was higher in FM than in neuropathy patients. Increased mechanical pain sensitivity (15/46) and paradoxical heat sensation (23/46) were frequent QST findings in the FM group. CONCLUSION:SFN or autonomic neuropathy was infrequent in FM patients and not related to symptom scores, which were higher than those for patients with neuropathy.

OBJECTIVE:Idiopathic generalized epilepsy (IGE) in adults comprise juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic-clonic seizures alone (EGTCS), which are defined by their seizure types but also cover a broad endophenotype of symptoms. Controversy exists on whether adult IGE is a group of distinct diseases or a clinical spectrum of one disease. Here, we used a deeply phenotyped cohort to test the hypothesis that IGE comprises three distinct clinical entities. METHODS:Patients (>18 years old) with IGE were recruited between 2016 and 2020 at Odense University Hospital and the Danish Epilepsy Center. Complete data were available for basic demographics, imaging, social status, and treatment response. Subjects were offered neuropsychological screening (including symptoms of psychiatric disease). Electroencephalograms (EEGs) were reanalyzed, and missing data were imputed. After selecting the features and normalizing the data, the dataset and an identical randomized dataset were subjected to k-means cluster analysis. RESULTS:The dataset comprised 502 patients and 22 distinct nonoverlapping clinical features. Elbow and gap analyses revealed an optimal number of clusters of 1; the features with the highest eigenvalues were age at diagnosis and self-reported executive dysfunction. Applying k-means clustering yielded three low-quality clusters as assessed by silhouette score (mean = .400 ± .01). The corresponding mean silhouette score for the randomized control dataset was .390 (±.002). Age at diagnosis was associated with the epileptic discharges on EEG and treatment response. Self-reported executive dysfunction showed associations with psychiatric symptoms and impulsivity. JME, JAE, and EGTCS were loosely associated with the clusters (k = .088, p = .002) but showed a specific distribution within a matrix defined by age at diagnosis and self-reported executive dysfunction. SIGNIFICANCE:IGE in adults is best described as a continuum of symptoms, where age at diagnosis and executive dysfunction are two main factors explaining most of its clinical variability. The seizure-defined syndromes cover different patient groups within the clinical spectrum.

Neuropathic pain is common and difficult to treat. The sodium channel blocker lacosamide is efficacious in animal models of pain, but its effect on neuropathic pain in humans is inconclusive. In a multicentre, randomized, double-blinded placebo-controlled phenotype stratified trial, we examined if lacosamide produced better pain relief in patients with the irritable nociceptor phenotype compared to those without. The primary outcome was the change in daily average pain from baseline to last week of 12 weeks of treatment. Secondary and tertiary outcomes included pain relief, patient global impression of change and presence of 30% and 50% pain reduction. The study was prematurely closed with 93 patients included and 63 randomized to lacosamide or placebo in a 2:1 ratio, of which 49 fulfilled the per protocol criteria and was used for the primary objective. We did not find a better effect of lacosamide in patients with the irritable nociceptor phenotype, the 95% CI for the primary objective was 0.41 (−1.2 to 2.0). For all patients randomized, lacosamide had no effect on the primary outcome, but significantly more patients were responders to lacosamide than during placebo, with an NNT of 4.0 (95% CI 2.3–16.1) and 5.0 (95% CI 2.8–24.5) for 30% and 50% pain reduction respectively. We did not identify any predictors for response. Lacosamide was generally well tolerated. We could not confirm that lacosamide was more efficacious in patients with the irritable nociceptor type, but the study was prematurely closed, so we cannot exclude a small difference. Treatment of neuropathic pain is often a trial and error process. Little is known about which patient benefit from which kind of medication. The sodium channel blocker lacosamide shows variable effect on neuropathic pain. Pain sensory phenotype, as defined by quantitative sensory testing, did not predict response to treatment with lacosamide.

BACKGROUND AND OBJECTIVES:There is a need for knowledge regarding the natural course of diabetic polyneuropathy (DPN), a complication in type 2 diabetes (T2D). The aim of this study was to examine the development of DPN over time. METHODS:Patients with newly diagnosed T2D, recruited from a national cohort, and controls without diabetes of similar age and sex, underwent sensory phenotyping in 2016-2018. The Toronto consensus criteria were used to classify patients into possible, probable, and confirmed DPN. For this 5-year, observational, follow-up, cohort study, all participants were invited to a reexamination combining bedside sensory examination, quantitative sensory testing (QST), nerve conduction studies (NCSs), and skin biopsies measuring intraepidermal nerve fiber density (IENFD) in order to compare phenotypic and diagnostic changes over time. RESULTS:Of the baseline 389 patients and 97 controls, 184 patients (median [interquartile range] diabetes duration 5.9 [4.1-7.4] years, mean hemoglobin A1c [HbA1c] 51 ± 11 mmol/mol at baseline) and 43 controls completed follow-up (46.9%). Confirmed DPN was present in 35.8% and 50.3%, probable DPN in 27.2% and 14.6%, possible DPN in 17.2% and 16.6%, and no DPN in 15.2% and 17.9% at baseline and follow-up, respectively. The estimated prevalence (95% CI) of confirmed DPN was 33.5% (24.9-42.1) compared with 22.7% (17.5-28.0) at baseline. During the follow-up period, 43.9% of patients with probable DPN developed confirmed DPN. Progression of neuropathy occurred in 16.5% and 24.7% and regression in 5.9% and 18.6% of patients based on NCS and IENFD, respectively. Progression based on NCS and/or IENFD was associated with higher baseline waist circumference and triglycerides, and regression with lower baseline HbA1c. Patients with at least probable DPN at baseline but neither patients without DPN nor controls developed increased spread of hyposensitivity, more hyposensitivity on QST and lower NCS z-scores at follow-up, and worsening of nerve parameters at follow-up correlated with higher baseline triglycerides. DISCUSSION:In patients with well-regulated T2D, the proportion of patients with confirmed DPN increased over 5 years driven by progression from probable DPN. A large proportion of patients progressed, and a smaller proportion regressed on nerve parameters. Higher triglycerides correlated with this progression and may constitute a risk factor.

Importance:Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction/withdrawal of anesthesia. Current clinical knowledge of the disease and optimal treatment approach is sparse. Objective:To systematically assess clinical characteristics, causes, outcomes, prognostic factors, and treatment approaches for patients with SRSE. Design, Setting, and Participants:In this systematic review and meta-analysis, all studies reporting adult patients (18 years or older) diagnosed with nonanoxic SRSE were considered for inclusion, irrespective of study design. The databases used were MEDLINE, Cochrane Library, EMBASE, and ClinicalTrials.org (database inception through May 5, 2022). Data extraction and synthesis:The study complied with the PRISMA guidelines for reporting, data extraction, and data synthesis. Different tools were used to assess risk of bias. All available data were extracted and missing data were neither imputed nor completed by contacting the study authors. Main outcome and measures:Successful treatment of SRSE, in-hospital mortality, and disability at discharge (estimated modified Rankin Scale). Results:The study team identified a total of 95 articles and 30 conference abstracts reporting 1200 patients with nonanoxic SRSE (266 individual patients were available for meta-analysis). They had a mean SRSE duration of 36.3 days, mean age of 40.8 years, and equal sex distribution. Patients with SRSE had a distinct pattern of etiologies where acute cerebral events and unknown etiologies accounted for 41.6% and 22.3% of all etiologies, respectively. Reports of SRSE caused by, eg, alcohol, drugs, or tumors were rare. At discharge, only 26.8% had none to slight disability (none, 16 [8.4%]; nonsignificant and slight disability, 35 [18.4%]). In-hospital mortality was 24.1%. Mortality stabilized after long-term treatment (more than 28 days) but with increased rates of seizure cessation and moderate to severe disability. Established prognostic factors, such as age and etiology, were not associated with in-hospital mortality. Reported treatment with ketamine, phenobarbital, other barbiturates, vagus nerve stimulator, and ketogenic diet were not associated with outcome. Conclusion and Relevance:Patients with SRSE are distinct due to their pattern of care (eg, long-term treatment to younger patients without negative prognostic factors and unknown/nonmalignant etiologies) and their natural course of SE. Very long-term treatment was associated with lower mortality and high odds of cessation of SRSE but increased risk of moderate to severe disability.

Background and AimsCardiovascular autonomic neuropathy (CAN) in patients with diabetes is associated with poor prognosis. We aimed to assess signs of CAN and autonomic symptoms and to investigate the impact of sensorimotor neuropathy on CAN by examining type 2 diabetes patients with (DPN [distal sensorimotor polyneuropathy]) and without distal sensorimotor polyneuropathy (noDPN) and healthy controls (HC). Secondarily, we aimed to describe the characteristics of patients with CAN. MethodsA population of 374 subjects from a previously described cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) were included. Subjects were examined with the Vagus & TRADE; device for the diagnosis of CAN, where two or more abnormal cardiovascular autonomic reflex tests indicate definite CAN. Autonomic symptoms were assessed with Composite Autonomic Symptom Score 31 (COMPASS 31) questionnaire. DPN was defined according to the Toronto consensus panel definition. ResultsDefinite CAN was present in 22% with DPN, 7% without DPN and 3% of HC, and 91% of patients with definite CAN had DPN. Patients with DPN and definite CAN reported higher COMPASS 31 scores compared to patients with noDPN (20.0 vs. 8.3, p < 0.001) and no CAN (22.1 vs. 12.3, p = 0.01). CAN was associated with HbA1c and age in a multivariate logistic regression analysis but was not associated with IEFND or triglycerides. InterpretationOne in five patients with DPN have CAN and specific CAN characteristics may help identify patients at risk for developing this severe diabetic complication. Autonomic symptoms were strongly associated with having both DPN and CAN, but too unspecific for diagnosing CAN.

ImportanceSuper-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction/withdrawal of anesthesia. Current clinical knowledge of the disease and optimal treatment approach is sparse.ObjectiveTo systematically assess clinical characteristics, causes, outcomes, prognostic factors, and treatment approaches for patients with SRSE.Design, Setting, and ParticipantsIn this systematic review and meta-analysis, all studies reporting adult patients (18 years or older) diagnosed with nonanoxic SRSE were considered for inclusion, irrespective of study design. The databases used were MEDLINE, Cochrane Library, EMBASE, and ClinicalTrials.org (database inception through May 5, 2022).Data extraction and synthesisThe study complied with the PRISMA guidelines for reporting, data extraction, and data synthesis. Different tools were used to assess risk of bias. All available data were extracted and missing data were neither imputed nor completed by contacting the study authors.Main outcome and measuresSuccessful treatment of SRSE, in-hospital mortality, and disability at discharge (estimated modified Rankin Scale).ResultsThe study team identified a total of 95 articles and 30 conference abstracts reporting 1200 patients with nonanoxic SRSE (266 individual patients were available for meta-analysis). They had a mean SRSE duration of 36.3 days, mean age of 40.8 years, and equal sex distribution. Patients with SRSE had a distinct pattern of etiologies where acute cerebral events and unknown etiologies accounted for 41.6% and 22.3% of all etiologies, respectively. Reports of SRSE caused by, eg, alcohol, drugs, or tumors were rare. At discharge, only 26.8% had none to slight disability (none, 16 [8.4%]; nonsignificant and slight disability, 35 [18.4%]). In-hospital mortality was 24.1%. Mortality stabilized after long-term treatment (more than 28 days) but with increased rates of seizure cessation and moderate to severe disability. Established prognostic factors, such as age and etiology, were not associated with in-hospital mortality. Reported treatment with ketamine, phenobarbital, other barbiturates, vagus nerve stimulator, and ketogenic diet were not associated with outcome.Conclusion and RelevancePatients with SRSE are distinct due to their pattern of care (eg, long-term treatment to younger patients without negative prognostic factors and unknown/nonmalignant etiologies) and their natural course of SE. Very long-term treatment was associated with lower mortality and high odds of cessation of SRSE but increased risk of moderate to severe disability.

Purpose This study aimed to assess the effect of different blood pressure levels on global cerebral metabolism in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Methods In a double-blinded trial, we randomly assigned 60 comatose patients following OHCA to low (63 mmHg) or high (77 mmHg) mean arterial blood pressure (MAP). The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Global cerebral metabolism utilizing jugular bulb microdialysis (JBM) and cerebral oxygenation (rSO 2 ) was monitored continuously for 96 h. The lactate-to-pyruvate (LP) ratio is a marker of cellular redox status and increases during deficient oxygen delivery (ischemia, hypoxia) and mitochondrial dysfunction. The primary outcome was to compare time-averaged means of cerebral energy metabolites between MAP groups during post-resuscitation care. Secondary outcomes included metabolic patterns of cerebral ischemia, rSO 2 , plasma neuron-specific enolase level at 48 h and neurological outcome at hospital discharge (cerebral performance category). Results We found a clear separation in MAP between the groups (15 mmHg, p < 0.001). Cerebral biochemical variables were not significantly different between MAP groups (LPR low MAP 19 (16–31) vs. high MAP 23 (16–33), p = 0.64). However, the LP ratio remained high (> 16) in both groups during the first 30 h. During the first 24 h, cerebral lactate > 2.5 mM, pyruvate levels > 110 µM, LP ratio > 30, and glycerol > 260 µM were highly predictive for poor neurological outcome and death with AUC 0.80. The median (IQR) rSO 2 during the first 48 h was 69.5% (62.0–75.0%) in the low MAP group and 69.0% (61.3–75.5%) in the high MAP group, p = 0.16. Conclusions Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns, probably illustrating that insufficient tissue oxygenation and recirculation during the initial hours after ROSC were essential factors determining neurological outcome.

Background and AimsIntravenous immunoglobulin (IVIg) has a rapid clinical effect which cannot be explained by remyelination during each treatment cycle in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to investigate axonal membrane properties during the IVIg treatment cycle and their potential correlation with clinically relevant functional measurements. MethodsMotor nerve excitability testing (NET) of the median nerve was performed before and 4 and 18 days after initiation of an IVIg treatment cycle in 13 treatment-naive (early) CIDP patients and 24 CIDP patients with long term (late) IVIg treatment, 12 CIDP patients treated with subcutaneous immunoglobulin (SCIg) and 55 healthy controls. Clinical function was measured extensively using the Six Spot Step test, 10-Meter Walk test, 9-Hole Peg test, grip strength, MRC sum score, Overall Neuropathy Limitations Score and Patient Global Impression of Change. ResultsSuperexcitability and S2 accommodation decreased significantly in the early treatment group from baseline to day 4 and returned to baseline levels at day 18, suggesting temporary depolarization of the axonal membrane. A similar trend was observed for the late IVIg group. Substantial clinical improvement was observed in both early and late IVIg groups during the entire treatment cycle. No statistically significant correlation was found between clinical and NET changes. No change was found in NET or clinical function in the SCIg group or controls. InterpretationNET suggested temporary depolarization of the axonal membrane during IVIg treatment in treatment naive CIDP patients. The relation to clinical improvement, however, remains speculative.

OBJECTIVE:To assess the repeatability and suitability for multicentre studies of MScanFit motor unit number estimation (MUNE), which involves modelling compound muscle action potential (CMAP) scans. METHODS:Fifteen groups in 9 countries recorded CMAP scans twice, 1-2 weeks apart in healthy subjects from abductor pollicis brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) muscles. The original MScanFit program (MScanFit-1) was compared with a revised version (MScanFit-2), designed to accommodate different muscles and recording conditions by setting the minimal motor unit size as a function of maximum CMAP. RESULTS:Complete sets of 6 recordings were obtained from 148 subjects. CMAP amplitudes differed significantly between centres for all muscles, and the same was true for MScanFit-1 MUNE. With MScanFit-2, MUNE differed less between centres but remained significantly different for APB. Coefficients of variation between repeats were 18.0% for ADM, 16.8% for APB, and 12.1% for TA. CONCLUSIONS:It is recommended for multicentre studies to use MScanFit-2 for analysis. TA provided the least variable MUNE values between subjects and the most repeatable within subjects. SIGNIFICANCE:MScanFit was primarily devised to model the discontinuities in CMAP scans in patients and is less suitable for healthy subjects with smooth scans.

Objective: Idiopathic generalized epilepsies (IGE) are genetic epilepsies with alterations of thalamo-frontocortical circuits that play a major role in seizure generation and propagation. Psychiatric diseases and drug resistance are strongly associated, but it remains unknown if they are symptoms of the same pathophysiological process. Hypothesizing that the same network alterations are associated with the fre-quency of epileptic discharges (ED) and psychiatric symptoms, we here tested the association of self -reported psychiatric symptoms and IGE severity estimated by electroencephalographic (EEG) biomarkers.Methods: Idiopathic generalized epilepsies patients were asked to fill out four validated psychiatric screening tools assessing symptoms of personality disorders (Standard Assessment of Personality -Abbreviated Scale), depression (Major Depression Inventory), impulsiveness (Barratt Impulsiveness Scale), and anxiety (brief Epilepsy Anxiety Survey Instrument). Blinded to results and clinical data on the patients, we analyzed the patients' EEGs, assessed, and quantified ED. The number and duration of ED divided by the duration of the EEG served as a proxy for the severity of IGE that was correlated with the results of the psychiatric screening.Results: Paired data from 64 patients were available for analysis. The duration of EDs per minute EEG was inversely associated with the time since the last seizure. The number of patients with generalized poly -spike trains (n = 2), generalized paroxysmal fast activity (n = 3), and prolonged epileptiform discharges (n = 10) were too low for statistically meaningful analyses. Self-reported symptoms of depression, per-sonality disorder, and impulsivity were not associated with EDs. In contrast, the duration of EDs per min-ute EEG was associated with self-reported symptoms of anxiety in univariate analyses, not significant, however, following adjustment for time since the last seizure in regression models.Significance: Self-reported symptoms of psychiatric diseases were not strongly associated with EDs as the best available quantifiable biomarker of IGE severity. As expected, the duration of EDs per minute and anxiety was inversely associated with time since the last seizure. Our data argue against a direct link be-tween the frequency of EDs - as an objective proxy of IGE severity - and psychiatric symptoms.& COPY; 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).