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Objectives: Acute confusional state (ACS) is a common cause of admission to the emergency department (ED). It can be related to numerous etiologies. Electroencephalography (EEG) can show specific abnormalities in cases of non-convulsive status epilepticus (NCSE), or metabolic or toxic encephalopathy. However, up to 80% of patients with a final diagnosis of NCSE have an ACS initially attributed to another cause. The exact place of EEG in the diagnostic work-up remains unclear., Methods: Data of consecutive patients admitted to the ED for an ACS in a two-year period and who were referred for an EEG were collected. The initial working diagnosis was based on medical history, clinical, biological and imaging investigations allowing classification into four diagnostic categories. Comparison to the final diagnosis was performed after EEG recordings (and sometimes additional tests) were performed, which allowed the reclassification of some patients from one category to another., Results: Seventy-five patients (mean age: 71.1 years) were included with the following suspected diagnoses: seizures for 8 (11%), encephalopathy for 14 (19%), other cause for 34 (45%) and unknown for 19 (25%). EEG was recorded after a mean of 1.5 days after symptom onset, and resulted in the reclassification of patients as follows: seizure for 15 (20%), encephalopathy for 15 (20%), other cause for 29 (39%) and unknown cause for 16 (21%). Moreover, ongoing epileptic activity (NCSE or seizure) and interictal epileptiform activity were found in eight (11%) patients initially diagnosed in another category., Discussion: In our cohort, EEG was a key examination in the management strategy of ACS in 11% of patients admitted to the ED. It resulted in a diagnosis of epilepsy in these patients admitted with unusual confounding presentations., Competing Interests: Declaration of competing interest Pierre Lozeron received financial support from LFB to attend medical congresses. Sabine Prud'hon, Hélène Amiel, Nathalie Kubis and Adrien Zanin declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Recreational nitrous oxide (N 2 O) use has become more widespread worldwide, leading to an increase in myelopathies and peripheral neuropathies. The aim of this study was to describe clinical and socioeconomical characteristics of severe N 2 O-induced (NI) neurological disorders (NI-NDs), to determine its incidence in the Greater Paris area and to compare it with that of similar inflammatory neurological disorders., Methods: We performed a retrospective multicentric cohort study of all adult patients with severe NI-NDs in the neurology and general internal medicine departments of the Greater Paris area from 2018 to 2021. The incidence was compared with that of non-NI-myelitis and Guillain-Barré syndrome (GBS) using a sample of 91,000 hospitalized patients sourced from health insurance data., Results: Among 181 patients, 25% had myelopathy, 37% had peripheral neuropathy and 38% had mixed disease. Most were aged between 20 and 25 years, lived in socially disadvantaged urban areas, and exhibited high rates of unemployment (37%). The incidence of NI-NDs increased during 2020 and reached a peak mid-2021. The 2021 incidence in 20-25-year-olds was 6.15 [4.72; 8.24] per 100,000 persons for NI-myelopathy and 7.48 [5.59; 9.37] for NI-peripheral neuropathy. This was significantly higher than for non-NI-myelitis (0.35 [0.02; 2.00]) and GBS (2.47 [0.64; 4.30]). The incidence of NI-NDs was two to three times higher in the most socially disadvantaged areas., Conclusion: The recent increase in recreational N 2 O use has led to a rise in the incidence of severe NI-NDs, particularly in young adults with low socioeconomic status for whom NI-NDs strongly outweigh similar neurological disorders., (© 2024. The Author(s).)

Introduction: Prognostication of outcome in severe stroke patients necessitating invasive mechanical ventilation poses significant challenges. The objective of this study was to assess the prognostic significance and prevalence of early electroencephalogram (EEG) abnormalities in adult stroke patients receiving mechanical ventilation., Methods: This study is a pre-planned ancillary investigation within the prospective multicenter SPICE cohort study (2017-2019), conducted in 33 intensive care units (ICUs) in the Paris area, France. We included adult stroke patients requiring invasive mechanical ventilation, who underwent at least one intermittent EEG examination during their ICU stay. The primary endpoint was the functional neurological outcome at one year, determined using the modified Rankin scale (mRS), and dichotomized as unfavorable (mRS 4-6, indicating severe disability or death) or favorable (mRS 0-3). Multivariable regression analyses were employed to identify EEG abnormalities associated with functional outcomes., Results: Of the 364 patients enrolled in the SPICE study, 153 patients (49 ischemic strokes, 52 intracranial hemorrhages, and 52 subarachnoid hemorrhages) underwent at least one EEG at a median time of 4 (interquartile range 2-7) days post-stroke. Rates of diffuse slowing (70% vs. 63%, p = 0.37), focal slowing (38% vs. 32%, p = 0.15), periodic discharges (2.3% vs. 3.7%, p = 0.9), and electrographic seizures (4.5% vs. 3.7%, p = 0.4) were comparable between patients with unfavorable and favorable outcomes. Following adjustment for potential confounders, an unreactive EEG background to auditory and pain stimulations (OR 6.02, 95% CI 2.27-15.99) was independently associated with unfavorable outcomes. An unreactive EEG predicted unfavorable outcome with a specificity of 48% (95% CI 40-56), sensitivity of 79% (95% CI 72-85), and positive predictive value (PPV) of 74% (95% CI 67-81). Conversely, a benign EEG (defined as continuous and reactive background activity without seizure, periodic discharges, triphasic waves, or burst suppression) predicted favorable outcome with a specificity of 89% (95% CI 84-94), and a sensitivity of 37% (95% CI 30-45)., Conclusion: The absence of EEG reactivity independently predicts unfavorable outcomes at one year in severe stroke patients requiring mechanical ventilation in the ICU, although its prognostic value remains limited. Conversely, a benign EEG pattern was associated with a favorable outcome., (© 2024. The Author(s).)

Several disabling symptoms potentially related to dysautonomia have been reported in "long-COVID" patients. Unfortunately, these symptoms are often nonspecific, and autonomic nervous system explorations are rarely performed in these patients. This study aimed to evaluate prospectively a cohort of long-COVID patients presenting severe disabling and non-relapsing symptoms of potential dysautonomia and to identify sensitive tests. Autonomic function was assessed by clinical examination, the Schirmer test; sudomotor evaluation, orthostatic blood pressure (BP) variation, 24-h ambulatory BP monitoring for sympathetic evaluation, and heart rate variation during orthostatism, deep breathing and Valsalva maneuvers for parasympathetic evaluation. Test results were considered abnormal if they reached the lower thresholds defined in publications and in our department. We also compared mean values for autonomic function tests between patients and age-matched controls. Sixteen patients (median age 37 years [31-43 years], 15 women) were included in this study and referred 14.5 months (median) [12.0-16.5 months] after initial infection. Nine had at least one positive SARS-CoV-2 RT-PCR or serology result. Symptoms after SARS-CoV-2 infection were severe, fluctuating and disabling with effort intolerance. Six patients (37.5%) had one or several abnormal test results, affecting the parasympathetic cardiac function in five of them (31%). Mean Valsalva score was significantly lower in patients than in controls. In this cohort of severely disabled long-COVID patients, 37.5% of them had at least one abnormal test result showing a possible contribution of dysautonomia to these nonspecific symptoms. Interestingly, mean values of the Valsalva test were significantly lower in patients than in control subjects, suggesting that normal values thresholds might not be appropriate in this population., (© 2023. The Author(s).)

Objectives: Permanent visual impairment is a major complication of giant cell arteritis (GCA). We investigated the added value of color Doppler imaging (CDI) of the central retinal artery (CRA) in patients with suspected GCA for early risk evaluation before temporal artery biopsy (TAB) results become available., Methods: We conducted a non-interventional observational study of 30 consecutive patients hospitalized for suspected GCA, including a comprehensive analysis of clinical, laboratory, imaging, CDI and pathology data. GCA was diagnosed or excluded (GCA+, GCA-, respectively) according to American College of Rheumatology (ACR) criteria and TAB findings. Three patients not meeting ACR criteria were excluded secondarily. The GCA- group contained ten patients, and the GCA+ group contained 17 patients, including eight with unilateral, transient or permanent clinical visual impairment (CVI)., Results: Mean blood flow velocity (mBFV) in the CRA was impaired in the affected eyes of GCA + CVI+ patients (1.9 ± 0.9 cm.s -1 , p < 0.001) relative to controls (4.1 ± 1.0 cm.s -1 ), GCA- patients (3.6 ± 0.7 cm.s -1 ) and GCA + CVI- patients (3.8 ± 0.8 cm.s -1 ). The mBFVs of the CRA was similar for affected and fellow eyes (right or left). CRA mBFV measurements effectively differentiated between patients with and without CVI (ROC-curve analysis, AUC = 0.925 [95%CI: 0.700 to 0.996], p < 0.0001, 88% sensitivity, 89% specificity, and cutoff of ≤2.7 cm.s -1 for affected eyes; 75% sensitivity, 100% specificity and cutoff of ≤2.2 cm.s -1 for fellow eyes)., Conclusion: CDI facilities the early detection of visual ischemia risk in GCA+ patients, justifying urgent high-dose corticosteroid administration to save at least the fellow eye before pathology results become available., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Despite multimodal assessment (clinical examination, biology, brain MRI, electroencephalography, somatosensory evoked potentials, mismatch negativity at auditory evoked potentials), coma prognostic evaluation remains challenging., Methods: We present here a method to predict the return to consciousness and good neurological outcome based on classification of auditory evoked potentials obtained during an oddball paradigm. Data from event-related potentials (ERPs) were recorded noninvasively using four surface electroencephalography (EEG) electrodes in a cohort of 29 post-cardiac arrest comatose patients (between day 3 and day 6 following admission). We extracted retrospectively several EEG features (standard deviation and similarity for standard auditory stimulations and number of extrema and oscillations for deviant auditory stimulations) from the time responses in a window of few hundreds of milliseconds. The responses to the standard and the deviant auditory stimulations were thus considered independently. By combining these features, based on machine learning, we built a two-dimensional map to evaluate possible group clustering., Results: Analysis in two-dimensions of the present data revealed two separated clusters of patients with good versus bad neurological outcome. When favoring the highest specificity of our mathematical algorithms (0.91), we found a sensitivity of 0.83 and an accuracy of 0.90, maintained when calculation was performed using data from only one central electrode. Using Gaussian, K-neighborhood and SVM classifiers, we could predict the neurological outcome of post-anoxic comatose patients, the validity of the method being tested by a cross-validation procedure. Moreover, the same results were obtained with one single electrode (Cz)., Conclusion: statistics of standard and deviant responses considered separately provide complementary and confirmatory predictions of the outcome of anoxic comatose patients, better assessed when combining these features on a two-dimensional statistical map. The benefit of this method compared to classical EEG and ERP predictors should be tested in a large prospective cohort. If validated, this method could provide an alternative tool to intensivists, to better evaluate neurological outcome and improve patient management, without neurophysiologist assistance., Competing Interests: AF, AR, NK, and DH have a patent application for the prediction of coma outcome (French patent FR1852473, titled “Outil prédictif de la sortie du coma des patients après un arrêt cardio-respiratoire”). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Floyrac, Doumergue, Legriel, Deye, Megarbane, Richard, Meppiel, Masmoudi, Lozeron, Vicaut, Kubis and Holcman.)

Enhancing the collateral blood supply during the acute phase of cerebral ischemia may limit both the extension of the core infarct, by rescuing the penumbra area, and the degree of disability. Many imaging techniques have been applied to rodents in preclinical studies, to evaluate the magnitude of collateral blood flow and the time course of responses during the early phase of ischemic stroke. The collateral supply follows several different routes at the base of the brain (the circle of Willis) and its surface (leptomeningeal or pial arteries), corresponding to the proximal and distal collateral pathways, respectively. In this review, we describe and illustrate the cerebral collateral systems and their modifications following pre-Willis or post-Willis occlusion in rodents. We also review the potential pharmaceutical agents for stimulating the collateral blood supply tested to date. The time taken to establish a collateral blood flow supply through the leptomeningeal anastomoses differs between young and adult animals and between different species and genetic backgrounds. Caution is required when transposing preclinical findings to humans, and clinical trials must be performed to check the added value of pharmacological agents for stimulating the collateral blood supply at appropriate time points. However, collateral recruitment appears to be a rapid, beneficial, endogenous mechanism that can be stimulated shortly after artery occlusion. It should be considered a treatment target for use in addition to recanalization strategies., (© 2021. The Author(s).)

Objectives: Recreational nitrous oxide (N 2 O) abuse is increasingly popular among youth. We report a systematic clinical, electrophysiological and biological follow-up of patients with neuropathy caused by N 2 O., Methods: We retrospectively report seven patients with neuropathy attributed to N 2 O abuse and their comprehensive follow-up. Demographic, toxicological, clinical, biological and electrophysiological data were collected at first and second examination. Functional data were collected at the last evaluation., Results: Seven patients aged 18-30, consuming more than 140 gas-filled balloons (one balloon is filled with approximately 8 g of N 2 O) per week for over a month, developed a severe, predominantly motor, length-dependent, progressive neuropathy over 3 to 6 weeks. Two-thirds presented associated signs of myelopathy. Distal lower limbs motor deficit and ataxia led to moderate disability. Spinal cord imaging was frequently normal. Nerve conduction studies disclosed an almost exclusively motor axonal neuropathy affecting the lower limbs with active denervation. Homocysteine plasma level was systematically elevated, whereas cobalamin plasma levels were normal in almost all patients. At short-term follow-up after intoxication discontinuation, ataxia and motor deficit only partially resolved despite vitamin B12 supplementation, while active denervation and homocysteinemia decreased. At last follow-up (median 9.2 months, IQR 7.5-10.75), mean ONLS was 2.0 (IQR 2.0-2.0)., Discussion: Young patients, with induced N 2 O motor neuropathy remain disabled after 5 to 14.5 months of gas withdrawal, despite vitamin B12 supplementation. A longer follow-up is needed to fully appraise the severity of these toxic neuropathies., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Intermittent photic stimulation (IPS) is an activation procedure performed during electroencephalography (EEG) to detect photosensitive patients. This procedure is recommended in routine EEGs but the benefit of IPS in the general population is not clearly ascertained., Methods: We retrospectively analyzed 7683 EEGs of patients referred for a routine EEG to the Clinical Physiology Department of Lariboisière hospital, mainly from the emergency ward and the department of neurology, not specifically involved in epilepsy. All EEGs were performed with a standardized protocol. Photic driving response, photomyoclonic response and photoparoxysmal response (PPR) were specifically collected. A correlation analysis was performed between the response induced by IPS, demographical and clinical data, and current treatment or recreational drug use., Results: Median age was 56.4 years (41.7-71.2); 3,042 (39.6%) of patients were female; 1,208 patients (15.7%) had a past medical history of epilepsy. Photic driving response occurred in 67 EEGs (0.9%), and PPR in 6 EEGs (0.1%), all with a known history of epilepsy. Thus 0.5% (6/1,208) of epilepsy patients had a PPR. Photomyoclonic responses were not observed. Juvenile myoclonic epilepsy was the only factor associated with the presence of PPR (RR=75.26 [11.82-479.21]). PPR was not associated with clinical symptoms or seizures. There was no correlation with the type of treatment or recreational drug use., Conclusions: Our results confirm that responses to IPS are rare in adult patients and especially PPR. Moreover, all patients with a PPR had a known previous history of epilepsy. These results question the benefit of IPS in adult patients with no history of epilepsy., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background and Purpose: Post-stroke cognitive impairment (PSCI) has become a major public health issue, as a leading cause of dementia. The inflammation that develops soon after cerebral artery occlusion and may persist for weeks or months after stroke is a key component of PSCI. Our aim was to take advantage of the immunomodulatory properties of peripheral blood mononuclear cells (PB-MNC) stimulated with ephrin-B2/fc (PB-MNC + ) for preventing PSCI., Methods: Cortical infarct was induced by thermocoagulation of the middle cerebral artery in male diabetic mice (streptozotocin IP). PB-MNC were isolated from diabetic human donors, washed with recombinant ephrin-B2/Fc and injected into the mice intravenously on the following day. Infarct volume, sensorimotor deficit, cell death and immune cell densities were assessed on day 3. Six weeks later, cognitive assessment was performed using the Barnes maze., Results: PB-MNC + transplanted in post-stroke diabetic mice reduced the neurological deficit, infarct volume and apoptosis at D3, without modification of microglial cells, astrocytes and T-lymphocytes densities in the brain. Barnes maze assessment of memory showed that the learning, retention and reversal phases were not significantly modified by cell therapy., Conclusions: Intravenous PB-MNC + administration the day after stroke induction in diabetic mice improved sensorimotor deficit and reduced infarct volume at the short term, but was unable to prevent long-term memory loss. To what extent diabetes impacts on cell therapy efficacy will have to be specifically investigated in the future. Including vascular risk factors systematically in preclinical studies of cell therapy will provide a comprehensive understanding of the mechanisms potentially limiting cell efficacy and also to identify good and bad responders, particularly in the long term., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In the presence of tumor angiogenesis, blood flow must increase, leading to an elevation of blood flow velocities (BFVels) and wall shear stress (WSS) in upstream native arteries. An adaptive arterial remodeling is stimulated, whose purpose lies in the enlargement of the arterial inner diameter, aiming for normalization of BFVels and WSS. Remodeling engages delayed processes that are efficient only several weeks/months after initiation, independent from those governing expansion of the neovascular network. Therefore, during tumor expansion, there is a time interval during which elevation of BFVels and WSS could reflect disease progression. Conversely, during the period of stability, BFVels and WSS drop back to normal values due to the achievement of remodeling processes. Ovarian peritoneal carcinomatosis (OPC), pseudomyxoma peritonei (PMP), and superficial arteriovenous malformations (AVMs) are diseases characterized by the development of abnormal vascular networks developed on native ones. In OPC and PMP, preoperative blood flow in the superior mesenteric artery (SMA) correlated with the per-operative peritoneal carcinomatosis index (OPC: n = 21, R = 0.79, p < 0.0001, PMP: n = 66, R = 0.63, p < 0.0001). Moreover, 1 year after surgery, WSS in the SMA helped in distinguishing patients with PMP from those without disease progression [ROC-curve analysis, AUC = 0.978 (0.902-0.999), p < 0.0001, sensitivity: 100.0%, specificity: 93.5%, cutoff: 12.1 dynes/cm 2 ]. Similarly, WSS in the ipsilateral afferent arteries close to the lesion distinguished stable from progressive AVM [ROC-curve analysis, AUC: 0.988, (0.919-1.000), p < 0.0001, sensitivity: 93.5%, specificity: 95.7%; cutoff: 26.5 dynes/cm 2 ]. Blood flow volume is indicative of the tumor burden in OPC and PMP, and WSS represents an early sensitive and specific vascular marker of disease progression in PMP and AVM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Barral, El-Sanharawi, Dohan, Sebuhyan, Guedon, Delarue, Boutigny, Mohamedi, Magnan, Kemel, Ketfi, Kubis, Bisdorff-Bresson, Pocard and Bonnin.)

Objective: Differentiating transient ischemic attack from stroke mimics may be difficult. Besides clinical evaluation and brain imaging, electroencephalography (EEG) may be a useful diagnostic tool., Methods: We conducted spectral analysis on 67 EEG of patients who had presented a transient neurological deficit (TND) within the previous seven days. Expert clinicians provided the final diagnosis: transient ischemic attack, migraine with aura, focal seizure or "other". We first calculated the relative power of the four EEG frequency bands (delta, theta, alpha and beta), in the whole hemisphere, then, according to the clinical symptoms, in the relevant electrodes of the symptomatic hemisphere. Finally, we calculated the relative power ratio between symptomatic and asymptomatic hemispheres., Results: Median age was 60.6 years (57% females). The etiological diagnosis was transient ischemic attack (27%), migraine with aura (11%), focal seizures (22%) and "other" (40%). We did not find significant differences in the theta and delta relative power analysis between groups. Over the symptomatic hemisphere only, we found a significant increase of the alpha relative power (p = 0.0026, p < 0.0001, p = 0.0014) in the migraine group compared to transient ischemic attack, migraine and focal seizures groups, and a significant decrease of the beta relative power (p = 0.0034, p = 0.0016, p = 0.0005) compared to the same groups., Conclusions: Migraine with aura presents a discriminative EEG relative power in comparison to transient neurological deficits of other origins. To further investigate the additive diagnosis value of EEG in other TND, future studies should be performed with an EEG obtained within the first 24 h after the onset of symptoms., Significance: Spectral EEG analysis discriminates migraine with aura groups from other groups, but not at the individual level., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: EEG-based prognostication studies in intensive care units often rely on a standard 21-electrode montage ( std EEG) requiring substantial human, technical, and financial resources. We here evaluate whether a simplified 4-frontal electrode montage ( 4-front EEG) can detect EEG patterns associated with poor outcomes in adult patients under veno-arterial extracorporeal membrane oxygenation (VA-ECMO)., Methods: We conducted a reanalysis of EEG data from a prospective cohort on 118 adult patients under VA-ECMO, in whom EEG was performed on admission to intensive care. EEG patterns of interest included background rhythm, discontinuity, reactivity, and the Synek's score. They were all reassessed by an intensivist on a 4-front EEG montage, whose analysis was then compared to an expert's interpretation made on std EEG recordings. The main outcome measure was the degree of correlation between 4-front EEG and std EEG montages to identify EEG patterns of interest. The performance of the Synek scores calculated on 4-front EEG and std EEG montage to predict outcomes (i.e., 28-day mortality and 90-day Rankin score [Formula: see text]) was investigated in a secondary exploratory analysis., Results: The detection of EEG patterns using 4-front EEG was statistically similar to that of std EEG for background rhythm (Spearman rank test, ρ = 0.66, p < 0.001), discontinuity (Cohen's kappa, [Formula: see text] = 0.955), reactivity ([Formula: see text] = 0.739) and the Synek's score (ρ = 0.794, p < 0.001). Using the Synek classification, we found similar performances between 4-front EEG and std EEG montages in predicting 28-day mortality (AUC 4-front EEG 0.71, AUC std EEG 0.68) and for 90-day poor neurologic outcome (AUC 4-front EEG 0.71, AUC std EEG 0.66). An exploratory analysis confirmed that the Synek scores determined by 4 or 21 electrodes were independently associated with 28-day mortality and poor 90-day functional outcome., Conclusion: In adult patients under VA-ECMO, a simplified 4-frontal electrode EEG montage interpreted by an intensivist, detected common EEG patterns associated with poor outcomes, with a performance similar to that of a standard EEG montage interpreted by expert neurophysiologists. This simplified montage could be implemented as part of a multimodal evaluation for bedside prognostication.

Background: Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments. As patients survive longer, post-stroke cognitive impairment (PSCI) has become a major health public issue. Diabetes has been identified as an independent predictive factor for PSCI. Here, we characterized a clinically relevant mouse model of PSCI, induced by permanent cerebral artery occlusion in diabetic mice, and investigated whether a reliable biomarker of PSCI may emerge from the kynurenine pathway which has been linked to inflammatory processes., Methods: Cortical infarct was induced by permanent middle cerebral artery occlusion in male diabetic mice (streptozotocin IP). Six weeks later, cognitive assessment was performed using the Barnes maze, hippocampi long-term potentiation using microelectrodes array recordings, and neuronal death, white matter rarefaction and microglia/macrophages density assessed in both hemispheres using imunohistochemistry. Brain and serum metabolites of the kynurenin pathway were measured using HPLC and mass fragmentography. At last, these same metabolites were measured in the patient's serum, at the acute phase of stroke, to determine if they could predict PSCI 3 months later., Results: We found long-term spatial memory was impaired in diabetic mice 6 weeks after stroke induction. Synaptic plasticity was completely suppressed in both hippocampi along with increased neuronal death, white matter rarefaction in both striatum, and increased microglial/macrophage density in the ipsilateral hemisphere. Brain and serum quinolinic acid concentrations and quinolinic acid over kynurenic acid ratios were significantly increased compared to control, diabetic and non-diabetic ischemic mice, where PSCI was absent. These putative serum biomarkers were strongly correlated with degradation of long-term memory, neuronal death, microglia/macrophage infiltration and white matter rarefaction. Moreover, we identified these same serum biomarkers as potential predictors of PSCI in a pilot study of stroke patients., Conclusions: we have established and characterized a new model of PSCI, functionally and structurally, and we have shown that the QUIN/KYNA ratio could be used as a surrogate biomarker of PSCI, which may now be tested in large prospective studies of stroke patients.

Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P 1 (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P 1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P 1 modulation in stroke., Objective: To address roles and mechanisms of engagement of endothelial cell S1P 1 in the naive and ischemic brain and its potential as a target for cerebrovascular therapy., Methods and Results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P 1 in the mouse brain. With an S1P 1 signaling reporter, we reveal that abluminal polarization shields S1P 1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P 1 signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P 1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P 1 provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P 1 supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P 1 -selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion., Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P 1 agonists.

Background: Orthostatic tremor (OT) is characterized by tremor in orthostatism. Primary OT is characterized by a high-frequency tremor at surface EMG recording and assumed to be idiopathic, whereas slow-frequency OT is classically associated with neurological pathologies. We report here a retrospective monocentric cohort study of primary (fast OT) and pseudo-OT (slow OT) patients to describe associated neurological and non-neurological co-morbidities., Methods: Between November 2014 and October 2019, 27 patients with OT were selected from the EMG database of the Department of Clinical Physiology in Lariboisière' s hospital. Patients were classified in primary OT if tremor frequency was ≥ 13 Hz and in pseudo-OT if tremor frequency was < 13 Hz., Results: Leg tremor on standing represented 10.2% of all tremor recordings. Ten patients were included in the primary and 17 in the pseudo-OT group. Females were predominant (62.9%) (p = 0.04). Mean age at diagnosis was 64.8 ± 1.1 years. At the first visit, a movement disorder was associated with 30% of primary OT, among them one CADASIL patient, whereas extrapyramidal or cerebellar disorders were reported in 100% of pseudo-OT, among them three Wilson's disease patients. These pathologies all preceded primary OT and occurred concomitantly with pseudo-OT. Frequency remained unchanged during evolution, except pseudo-OT in two patients that completely resolved following the introduction of antiParkinsonian drugs. Treatment of primary OT was partially effective in 28% and in 50% of pseudo-OT patients., Conclusion: In this monocentric study, movement disorders were present in 30% of primary OT patients. This result questions the term "idiopathic" or "primary" OT, but the small number of patients does not allow answering this issue.

Purpose:  To assess the prognostic value of the wall shear stress (WSS) measured in the feeding native arteries upstream from facial superficial arteriovenous malformations (sAVMs). Reliable prognostic criteria are needed to distinguish progressive from stable sAVMs and thus support the indication for an aggressive or a conservative management to avoid severe facial disfigurement., Materials and Methods:  We prospectively included 25 patients with untreated facial sAVMs, 15 patients with surgically resected sAVMs and 15 controls. All had undergone Doppler ultrasound examination (DUS) with measurements of inner diameters, blood flow velocities, computation of blood flow and WSS of the feeding arteries. Based on the absence or presence of progression in clinical and imaging examinations 6 months after, we discriminated untreated patients as stable or progressive., Results:  WSS in the ipsilateral external carotid artery was higher in progressive compared to stable sAVMs (15.8 ± 3.3dynes/cm² vs. 9.6 ± 2.0dynes/cm², mean±SD, p < 0.0001) with a cut-off of 11.5dynes/cm² (sensitivity: 92 %, specificity: 92 %, AUC: 0.955, [95 %CI: 0.789-0.998], p = 0.0001). WSS in the ipsilateral facial artery was also higher in progressive compared to stable sAVMs (50.7 ± 14.5dynes/cm² vs. 25.2 ± 7.1dynes/cm², p < 0.0001) with a cut-off of 34.0dynes/cm² (sensitivity: 100 %, specificity: 92 %, AUC: 0.974, [95 %CI: 0.819-1.000], p = 0.0001). The hemodynamic data of operated patients were not different from those of the control group., Conclusion:  WSS measured in the feeding arteries of an sAVM may be a simple reliable criterion to distinguish stable from progressive sAVMs. This value should be considered to guide the therapeutic strategy as well as the long-term follow-up of patients with facial sAVMs., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level., Methods: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions., Results: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases., Conclusion: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential., Trial Registration Number: NCT01565005., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Hypertrophy/signal hyperintensity and/or gadolinium enhancement of plexus structures on magnetic resonance imaging (MRI) are observed in two-thirds of cases of typical chronic inflammatory demyelinating polyneuropathy (CIDP). The objective of our study was to determine the additional benefit of plexus MRI in patients referred to tertiary centers with baseline clinical and electrophysiological characteristics suggestive of typical or atypical CIDP., Methods: A total of 28 consecutive patients with initial suspicion of CIDP were recruited in nine centers and followed for 2 years. Plexus MRI data from the initial assessment were reviewed centrally. Physicians blinded to the plexus MRI findings established the final diagnosis (CIDP or neuropathy of another cause). The proportion of patients with abnormal MRI was analyzed in each group., Results: Chronic inflammatory demyelinating polyneuropathy was confirmed in 14 patients (50%), as were sensorimotor CIDP (n = 6), chronic immune sensory polyradiculoneuropathy (n = 2), motor CIDP (n = 1) and multifocal acquired demyelinating sensory and motor neuropathy (n = 5). A total of 37 plexus MRIs were performed (17 brachial, 19 lumbosacral and 8 in both localizations). MRI was abnormal in 5/37 patients (14%), all of whom were subsequently diagnosed with CIDP [5/14(36%)], after an atypical baseline presentation. With plexus MRI results masked, non-invasive procedures confirmed the diagnosis of CIDP in all but one patient [1/14 (7%)]. Knowledge of the abnormal MRI findings in the latter could have prevented nerve biopsy being performed., Conclusion: Systematic plexus MRI in patients with initially suspected CIDP provides little additional benefit in confirming the diagnosis of CIDP., (© European Academy of Neurology 2019.)

Hypertension is the first modifiable vascular risk factor accounting for 10.4 million deaths worldwide; it is strongly and independently associated with the risk of stroke and is related to worse prognosis. In addition, hypertension seems to be a key player in the implementation of vascular cognitive impairment. Long-term hypertension, complicated or not by the occurrence of ischemic stroke, is often reviewed on its vascular side, and parenchymal consequences are put aside. Here, we sought to review the impact of isolated hypertension or hypertension associated to stroke on brain atrophy, neuron connectivity and neurogenesis, and phenotype modification of microglia and astrocytes. Finally, we discuss the impact of antihypertensive therapies on cell responses to hypertension and functional recovery. This attractive topic remains a focus of continued investigation and stresses the relevance of including this vascular risk factor in preclinical investigations of stroke outcome., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Benjamin Maïer and Nathalie Kubis.)

Stroke is currently the second leading cause of death in industrialized countries and the second cause of dementia after Alzheimer's disease. Diabetes is an independent risk factor for stroke that exacerbates the severity of lesions, disability and cognitive decline. There is increasing evidence that sustained brain inflammation may account for this long-term prejudicial outcome in diabetic patients in particular. We sought to demonstrate that experimental permanent middle cerebral artery occlusion (pMCAo) in the diabetic mouse aggravates stroke, induces cognitive decline, and is associated with exacerbated brain inflammation, and that these effects can be alleviated and/or prevented by the immunomodulator, glatiramer acetate (GA). Male diabetic C57Bl6 mice (streptozotocin IP) subjected to permanent middle cerebral artery occlusion (pMCAo), were treated by the immunomodulator, GA (Copaxone®) (1 mg/kg daily, sc) until 3 or 7 days post stroke. Infarct volume, brain pro- and anti-inflammatory mediators, microglial/macrophage density, and neurogenesis were monitored during the first week post stroke. Neurological sensorimotor deficit, spatial memory and brain deposits of Aβ40 and Aβ42 were assessed until six weeks post stroke. In diabetic mice with pMCAo, proinflammatory mediators (IL-1β, MCP1, TNFα and CD68) were significantly higher than in non-diabetic mice. In GA-treated mice, the infarct volume was reduced by 30% at D3 and by 40% at D7 post stroke (P < 0.05), sensorimotor recovery was accelerated as early as D3, and long-term memory loss was prevented. Moreover, proinflammatory mediators significantly decreased between D3 (COX2) and D7 (CD32, TNFα, IL-1β), and neurogenesis was significantly increased at D7. Moreover, GA abrogates the accumulation of insoluble Aβ40. This work is the first one to evidence that the immunomodulatory drug GA reduces infarct volume and proinflammatory mediators, enhances early neurogenesis, accelerates sensorimotor recovery, and prevents long-term memory loss in diabetic mice with pMCAo., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Under General Anesthesia (GA), age and Burst Suppression (BS) are associated with cognitive postoperative complications, yet how these parameters are related to per-operative EEG and hypnotic doses is unclear. In this prospective study, we address this question comparing age and BS occurrences with a new score (BP TIVA ) based on Propofol doses, EEG and alpha-band power spectral densities, evaluated for SEF 95  = 8-13 Hz., Methods: 59 patients (55 [34-67] yr, 67% female) undergoing neuroradiology or orthopedic surgery were included. Total IntraVenous Anesthesia was used for Propofol and analgesics infusion. Cerebral activity was monitored from a frontal electrodes montage EEG., Results: BP TIVA was inversely correlated with age (Pearson r = -0.78, p < 0.001), and was significantly lower (p < 0.001) when BS occurred during the GA first minutes (induction). Additionally, the age-free BP TIVA score was better associated with BS at induction than age (AUC = 0.94 versus 0.82, p < 0.05)., Conclusion: We designed BP TIVA score based on hypnotics and EEG. It was correlated with age yet was better associated to BS occurring during GA induction, the latter being a cerebral fragility sign., Significance: This advocate for an approach based on evaluating the cerebral physiological age («brain age») to predict postoperative cognitive evolution., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

As the second cause of death and cognitive decline in industrialized countries, stroke is a major burden for society. Vascular risks factors such as hypertension and diabetes are involved in most stroke patients, aggravate stroke severity, but are still poorly taken into account in preclinical studies. Microangiopathy and sustained inflammation are exacerbated, likely explaining the severity of stroke in those patients. We sought to demonstrate that intravenous administration of human adipose derived-mesenchymal stem cells (hADMSC) that have immunomodulatory properties, could accelerate sensorimotor recovery, prevent long-term spatial memory impairment and promote neurogenesis, in diabetic or hypertensive mice, subjected to permanent middle cerebral artery occlusion (pMCAo). Diabetic (streptozotocin IP) or hypertensive (L-NAME in drinking water) male C57Bl6 mice subjected to pMCAo, were treated by hADMSC (500,000 cells IV) 2 days after cerebral ischemia induction. Infarct volume, neurogenesis, microglial/macrophage density, T-lymphocytes density, astrocytes density, and vessel density were monitored 7 days after cells injection and at 6 weeks. Neurological sensorimotor deficit and spatial memory were assessed until 6 weeks post-stroke. Whatever the vascular risk factor, hADMSC showed no effect on functional sensorimotor recovery or cognitive decline prevention at short or long-term assessment, nor significantly modified neurogenesis, microglial/macrophage, T-lymphocytes, astrocytes, and vessel density. This work is part of a European program (H2020, RESSTORE). We discuss the discrepancy of our results with those obtained in rats and the optimal cell injection time frame, source and type of cells according to the species stroke model. A comprehensive understanding of the mechanisms preventing recovery should help for successful clinical translation, but first could allow identifying good and bad responders to cell therapy in stroke.

Stroke is a major public health issue with limited treatment. The pharmacologically or mechanically removing of the clot is accessible to less than 10% of the patients. Stem cell therapy is a promising alternative strategy since it increases the therapeutic time window but many issues remain unsolved. To avoid a new dramatic failure when translating experimental data on the bedside, this review aims to highlight the indispensable checkpoints to make a successful clinical trial based on the current preclinical literature. The large panel of progenitors/ stem cells at the researcher's disposal is to be used wisely, regarding the type of cells, the source of cells, the route of delivery, the time window, since it will directly affect the outcome. Mechanisms are still incompletely understood, although recent studies have focused on the inflammation modulation of most cells types.

Idiopathic peripheral facial palsy, also named Bell's palsy, is the most common cause of peripheral facial palsy in adults. Although it is considered as a benign condition, its social and psychological impact can be dramatic, especially in the case of incomplete recovery. The main pathophysiological hypothesis is the reactivation of HSV 1 virus in the geniculate ganglia, leading to nerve edema and its compression through the petrosal bone. Patients experience an acute (less than 24 hours) motor deficit involving ipsilateral muscles of the upper and lower face and reaching its peak within the first three days. Frequently, symptoms are preceded or accompanied by retro-auricular pain and/or ipsilateral face numbness. Diagnosis is usually clinical but one should look for negative signs to eliminate central facial palsy or peripheral facial palsy secondary to infectious, neoplastic or autoimmune diseases. About 75% of the patients will experience spontaneous full recovery, this rate can be improved with oral corticotherapy when introduced within the first 72 hours. To date, no benefit has been demonstrated by adding an antiviral treatment. Hemifacial spasms (involuntary muscles contractions of the hemiface) or syncinesia (involuntary muscles contractions elicited by voluntary ones, due to aberrant reinnervation) may complicate the disease's course. Electroneuromyography can be useful at different stages: it can first reveal the early conduction bloc, then estimate the axonal loss, then bring evidence of the reinnervation process and, lastly, help for the diagnosis of complications., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Background: Electroencephalography (EEG) is a well-established tool for assessing brain function that is available at the bedside in the intensive care unit (ICU). This review aims to discuss the relevance of electroencephalographic reactivity (EEG-R) in patients with impaired consciousness and to describe the neurophysiological mechanisms involved., Methods: We conducted a systematic search of the term "EEG reactivity and coma" using the PubMed database. The search encompassed articles published from inception to March 2018 and produced 202 articles, of which 42 were deemed relevant, assessing the importance of EEG-R in relationship to outcomes in patients with impaired consciousness, and were therefore included in this review., Results: Although definitions, characteristics and methods used to assess EEG-R are heterogeneous, several studies underline that a lack of EEG-R is associated with mortality and unfavorable outcome in patients with impaired consciousness. However, preserved EEG-R is linked to better odds of survival. Exploring EEG-R to nociceptive, auditory, and visual stimuli enables a noninvasive trimodal functional assessment of peripheral and central sensory ascending pathways that project to the brainstem, the thalamus and the cerebral cortex. A lack of EEG-R in patients with impaired consciousness may result from altered modulation of thalamocortical loop activity by afferent sensory input due to neural impairment. Assessing EEG-R is a valuable tool for the diagnosis and outcome prediction of severe brain dysfunction in critically ill patients., Conclusions: This review emphasizes that whatever the etiology, patients with impaired consciousness featuring a reactive electroencephalogram are more likely to have a favorable outcome, whereas those with a nonreactive electroencephalogram are prone to having an unfavorable outcome. EEG-R is therefore a valuable prognostic parameter and warrants a rigorous assessment. However, current assessment methods are heterogeneous, and no consensus exists. Standardization of stimulation and interpretation methods is needed.

The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-β (Aβ) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P < 0.001), collateral recruitment (- 24%, P < 0.001), capillary density (- 22%; P < 0.01) and arteriole density (- 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Aβ in the hind limb; thus, circulating Aβ is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-β1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD.

Clinical trials of cell therapy in stroke favor autologous cell transplantation. To date, feasibility studies have used bone marrow-derived mononuclear cells, but harvesting bone marrow cells is invasive thus complicating bedside treatment. We investigated the therapeutic potential of peripheral blood-derived mononuclear cells (PB-MNC) harvested from diabetic patients and stimulated by ephrin-B2 (PB-MNC+) (500,000 cells), injected intravenously 18-24 hours after induced cerebral ischemia in mice. Infarct volume, neurological deficit, neurogenesis, angiogenesis, and inflammation were investigated as were the potential mechanisms of PB-MNC+ cells in poststroke neurorepair. At D3, infarct volume was reduced by 60% and 49% compared to unstimulated PB-MNC and PBS-treated mice, respectively. Compared to PBS, injection of PB-MNC+ increased cell proliferation in the peri-infarct area and the subventricular zone, decreased microglia/macrophage cell density, and upregulated TGF- β expression. At D14, microvessel density was decreased and functional recovery was enhanced compared to PBS-treated mice, whereas plasma levels of BDNF, a major regulator of neuroplasticity, were increased in mice treated with PB-MNC+ compared to the other two groups. Cell transcriptional analysis showed that ephrin-B2 induced phenotype switching of PB-MNC by upregulating genes controlling cell proliferation, inflammation, and angiogenesis, as confirmed by adhesion and Matrigel assays. Conclusions . This feasibility study suggests that PB-MNC+ transplantation poststroke could be a promising approach but warrants further investigation. If confirmed, this rapid, noninvasive bedside cell therapy strategy could be applied to stroke patients at the acute phase.

Objective: To investigate the weight of visual and proprioceptive inputs, measured indirectly in standing position control, in patients with chronic acquired demyelinating polyneuropathy (CADP)., Design: Prospective case study., Subjects: Twenty-five patients with CADP and 25 healthy controls., Methods: Posture was recorded on a double force platform. Stimulations were optokinetic (60°/s) for visual input and vibration (50 Hz) for proprioceptive input. Visual stimulation involved 4 tests (upward, downward, rightward and leftward) and proprioceptive stimulation 2 tests (triceps surae and tibialis anterior). A composite score, previously published and slightly modified, was used for the recorded postural signals from the different stimulations., Results: Despite their sensitivity deficits, patients with CADP were more sensitive to proprioceptive stimuli than were healthy controls (mean composite score 13.9 ((standard deviation; SD) 4.8) vs 18.4 (SD 4.8), p = 0.002). As expected, they were also more sensitive to visual stimuli (mean composite score 10.5 (SD 8.7) vs 22.9 (SD 7.5), p <0.0001)., Conclusion: These results encourage balance rehabilitation of patients with CADP, aimed at promoting the use of proprioceptive information, thereby reducing too-early development of visual compensation while proprioception is still available.

Identification of stroke mimics and 'chameleons' among transient neurological deficits (TND) is critical. Diagnostic workup consists of a brain imaging study, for a vascular disease or a brain tumour and EEG, for epileptiform discharges. The precise role of EEG in this diagnostic workup has, however, never been clearly delineated. However, this could be crucial in cases of atypical or incomplete presentation with consequences on disease management and treatment. We analysed the EEG patterns on 95 consecutive patients referred for an EEG within 7 days of a TND with diagnostic uncertainty. Patients were classified at the discharge or the 3-month follow-up visit as: 'ischemic origin', 'migraine aura', 'focal seizure', and 'other'. All patients had a brain imaging study. EEG characteristics were correlated to the TND symptoms, imaging study, and final diagnosis. Sixty four (67%) were of acute onset. Median symptom duration was 45 min. Thirty two % were 'ischemic', 14% 'migraine aura', 19% 'focal seizure', and 36% 'other' cause. EEGs were recorded with a median delay of 1.6 day after symptoms onset. Forty EEGs (42%) were abnormal. Focal slow waves were the most common finding (43%), also in the ischemic group (43%), whether patients had a typical presentation or not. Epileptiform discharges were found in three patients, one with focal seizure and two with migraine aura. Non-specific EEG focal slowing is commonly found in TND, and may last several days. We found no difference in EEG presentation between stroke mimics and stroke chameleons, and between other diagnoses.