ABSTRACT
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.
Subject(s)
Electroencephalography , Intensive Care Units , Respiration, Artificial , Stroke , Humans , Male , Female , Prospective Studies , Respiration, Artificial/methods , Respiration, Artificial/statistics & numerical data , Aged , Electroencephalography/methods , Electroencephalography/statistics & numerical data , Middle Aged , Prognosis , Stroke/physiopathology , Stroke/complications , Intensive Care Units/statistics & numerical data , Intensive Care Units/organization & administration , Cohort Studies , Aged, 80 and overABSTRACT
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 S1P1 (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P1 modulation in stroke. OBJECTIVE: To address roles and mechanisms of engagement of endothelial cell S1P1 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 S1P1 in the mouse brain. With an S1P1 signaling reporter, we reveal that abluminal polarization shields S1P1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P1 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 S1P1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P1 provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P1 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 S1P1-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 S1P1 agonists.
Subject(s)
Blood-Brain Barrier/metabolism , Cerebral Arteries/metabolism , Endothelial Cells/metabolism , Infarction, Middle Cerebral Artery/metabolism , Ischemic Attack, Transient/metabolism , Ischemic Stroke/metabolism , Lysophospholipids/metabolism , Sphingosine-1-Phosphate Receptors/metabolism , Sphingosine/analogs & derivatives , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/pathology , Blood-Brain Barrier/physiopathology , Cerebral Arteries/drug effects , Cerebral Arteries/pathology , Cerebral Arteries/physiopathology , Cerebrovascular Circulation , Disease Models, Animal , Endothelial Cells/pathology , Female , Infarction, Middle Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/physiopathology , Infarction, Middle Cerebral Artery/prevention & control , Ischemic Attack, Transient/pathology , Ischemic Attack, Transient/physiopathology , Ischemic Attack, Transient/prevention & control , Ischemic Stroke/pathology , Ischemic Stroke/physiopathology , Ischemic Stroke/prevention & control , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Microcirculation , Neuroprotective Agents/pharmacology , Signal Transduction , Sphingosine/metabolism , Sphingosine-1-Phosphate Receptors/agonists , Sphingosine-1-Phosphate Receptors/genetics , Vascular PatencyABSTRACT
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.
Subject(s)
Cell Cycle Proteins/genetics , Cochlear Diseases/genetics , Microcephaly/genetics , Nerve Tissue Proteins/genetics , Child , Child, Preschool , Cochlea/diagnostic imaging , Cochlea/metabolism , Cochlea/pathology , Cochlear Diseases/diagnostic imaging , Cochlear Diseases/pathology , Fanconi Anemia/genetics , Fanconi Anemia/pathology , Female , Humans , Hypothalamus/diagnostic imaging , Hypothalamus/pathology , Infant , Magnetic Resonance Imaging , Male , Microcephaly/diagnostic imaging , Microcephaly/pathology , Mutation , Neurogenesis/genetics , Pedigree , Retina/diagnostic imaging , Retina/pathologyABSTRACT
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 (15.8â±â3.3dynes/cm² vs. 9.6â±â2.0dynes/cm², mean±SD, pâ<â0.0001) with a cut-off of 11.5dynes/cm² (sensitivity: 92â%, specificity: 92â%, AUC: 0.955, [95â%CI: 0.789-0.998], pâ=â0.0001). WSS in the ipsilateral facial artery was also higher in progressive compared to stable sAVMs (50.7â±â14.5dynes/cm² vs. 25.2â±â7.1dynes/cm², pâ<â0.0001) with a cut-off of 34.0dynes/cm² (sensitivity: 100â%, specificity: 92â%, AUC: 0.974, [95â%CI: 0.819-1.000], pâ=â0.0001). 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.
Subject(s)
Arteriovenous Malformations , Blood Flow Velocity , Face , Arteries , Arteriovenous Malformations/diagnostic imaging , Disease Progression , Face/blood supply , Humans , Stress, MechanicalABSTRACT
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®) (1â¯mg/kg daily, sc) until 3 or 7â¯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 Aß40 and Aß42 were assessed until six weeks post stroke. In diabetic mice with pMCAo, proinflammatory mediators (IL-1ß, 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 (Pâ¯<â¯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-1ß), and neurogenesis was significantly increased at D7. Moreover, GA abrogates the accumulation of insoluble Aß40. 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.
Subject(s)
Adjuvants, Immunologic/administration & dosage , Brain Infarction/immunology , Diabetes Complications , Glatiramer Acetate/administration & dosage , Memory Disorders/immunology , Neuroprotective Agents/administration & dosage , Stroke/complications , Animals , Brain/drug effects , Brain/immunology , Brain Infarction/complications , Brain Infarction/prevention & control , Diabetes Complications/immunology , Encephalitis/etiology , Encephalitis/immunology , Inflammation Mediators/immunology , Male , Memory Disorders/etiology , Memory Disorders/prevention & control , Mice, Inbred C57BL , Microglia/drug effects , Neurogenesis/drug effects , Stroke/immunologyABSTRACT
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.
Subject(s)
Brain/blood supply , Brain/metabolism , Hypertension/metabolism , Recovery of Function/physiology , Stroke/metabolism , Animals , Astrocytes/metabolism , Brain/pathology , Humans , Hypertension/pathology , Ischemic Attack, Transient/metabolism , Ischemic Attack, Transient/pathology , Microglia/metabolism , Parenchymal Tissue/blood supply , Parenchymal Tissue/metabolism , Parenchymal Tissue/pathology , Stroke/pathologyABSTRACT
The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-ß (Aß) 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 Aß in the hind limb; thus, circulating Aß 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-ß1 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.
Subject(s)
Alzheimer Disease/physiopathology , Hindlimb/physiopathology , Ischemia/physiopathology , Peripheral Vascular Diseases/physiopathology , Alzheimer Disease/blood , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Arterioles/metabolism , Arterioles/physiopathology , Capillaries/metabolism , Capillaries/physiopathology , Disease Models, Animal , Endothelin-1/blood , Femoral Artery/metabolism , Femoral Artery/physiopathology , Hindlimb/blood supply , Humans , Ischemia/genetics , Mice , Mice, Transgenic , Microcirculation/genetics , Nitric Oxide/blood , Peripheral Vascular Diseases/blood , Peripheral Vascular Diseases/genetics , Placenta Growth Factor/blood , Transforming Growth Factor beta1/bloodABSTRACT
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.
Subject(s)
Consciousness Disorders/classification , Electroencephalography/methods , Prognosis , Brain/physiology , Brain/physiopathology , HumansABSTRACT
Hand dystonia is a common complication of Wilson's disease (WD), responsible for handwriting difficulties and disability. Alteration of sensorimotor integration and overactivity of the somatosensory cortex have been demonstrated in dystonia. This study investigated the immediate after effect of an inhibitory repetitive transcranial magnetic stimulation (rTMS) applied over the somatosensory cortex on the writing function in WD patients with hand dystonia. We performed a pilot prospective randomized double-blind sham-controlled crossover rTMS study. A 20-min 1-Hz rTMS session, stereotaxically guided, was applied over the left somatosensory cortex in 13 WD patients with right dystonic writer's cramp. After 3 days, each patient was crossed-over to the alternative treatment. Patients were clinically evaluated before and immediately after each rTMS session with the Unified Wilson's Disease rating scale (UWDRS), the Writers' Cramp Rating Scale (WCRS), a specifically designed scale for handwriting difficulties in Wilson's disease patients (FAR, flow, accuracy, and rhythmicity evaluation), and a visual analog scale (VAS) for handwriting discomfort. No significant change in UWDRS, WCRS, VAS, or FAR scores was observed in patients treated with somatosensory inhibitory rTMS compared to the sham protocol. The FAR negatively correlated with UWDRS (r = -0.6; P = 0.02), but not with the WCRS score, disease duration, MRI diffusion lesions, or with atrophy scores. In our experimental conditions, a single inhibitory rTMS session applied over somatosensory cortex did not improve dystonic writer cramp in WD patients.
Subject(s)
Dystonic Disorders/etiology , Evoked Potentials, Somatosensory/physiology , Hand/physiopathology , Hepatolenticular Degeneration/complications , Somatosensory Cortex/physiopathology , Transcranial Magnetic Stimulation , Adult , Aged , Cross-Over Studies , Double-Blind Method , Dystonic Disorders/diagnostic imaging , Electroencephalography , Female , Hepatolenticular Degeneration/diagnostic imaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Retrospective Studies , Somatosensory Cortex/diagnostic imaging , Visual Analog Scale , WritingABSTRACT
Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta-like 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4(+/-) mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4(+/-) mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Ischemia/physiopathology , Membrane Proteins/metabolism , Microvessels/embryology , Morphogenesis/physiology , Neovascularization, Physiologic/physiology , Receptors, Notch/metabolism , Signal Transduction/physiology , Adaptor Proteins, Signal Transducing , Analysis of Variance , Animals , Calcium-Binding Proteins , Immunohistochemistry , Ischemia/metabolism , Mice , Microvessels/physiology , Real-Time Polymerase Chain Reaction , Regional Blood Flow/physiology , X-Ray MicrotomographyABSTRACT
PURPOSE: We investigated whether forearm skin blood flow could be improved when a multilayer pulsatile inflatable suit was applied at a low pressure to the lower limbs and abdomen. We hypothesized that a non-invasive purely mechanical stimulation of the lower limbs could induce remote forearm blood flow modifications. METHODS: The pulsatile suit induced a sequential compartmentalized low compression (65 mmHg), which was synchronized with each diastole of the cardiac cycle with each phase evolving centripetally (lower limbs to abdomen). Modifications of the forearm skin blood flow were continuously recorded by laser Doppler flowmetry (LDF) at baseline and during the pulsatile suit application. Endothelium-dependent and endothelium-independent vasodilations of the forearm skin microcirculation were measured by LDF in response to a local transdermal iontophoretic application of acetylcholine (ACh-test) and to hyperthermia (hyperT- test). RESULTS: Twenty-four healthy volunteers, 12 men and 12 women (43±14 years) were included in the study. LDF responses increased 1) under pulsatile suit (97±106%, p.
Subject(s)
Forearm/blood supply , Intermittent Pneumatic Compression Devices , Lower Extremity/blood supply , Skin/blood supply , Adolescent , Adult , Aged , Blood Flow Velocity , Female , Humans , Male , Middle AgedABSTRACT
Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc.
Subject(s)
Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Femoral Artery/physiopathology , Recovery of Function/physiology , Sciatic Nerve/physiopathology , Vascular Diseases/physiopathology , Analysis of Variance , Angiography , Animals , Antibiotics, Antineoplastic/toxicity , Diabetes Mellitus, Experimental/chemically induced , Disease Models, Animal , Hindlimb/physiopathology , Laser-Doppler Flowmetry , Ligation/adverse effects , Mice , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Neural Conduction/physiology , Plant Lectins/metabolism , Sciatic Nerve/blood supply , Sciatic Nerve/pathology , Streptozocin/toxicity , Time Factors , Vascular Diseases/etiologyABSTRACT
OBJECTIVES: The objective is to determine if muscle MRI is useful for assessing neuropathy severity. METHODS: Clinical, MRI and electromyography (EMG) examinations were performed in 17 patients with focal lower limb neuropathies. MRI Short Tau Inversion Recovery (STIR) signal intensity, amyotrophy, and muscle fatty infiltration measured after T1-weighted image acquisition, EMG spontaneous activity (SA), and maximal voluntary contraction (MVC) were graded using semiquantitative scores and quantitative scores for STIR signal intensity and were correlated to the Medical Research Council (MRC) score for testing muscle strength. Within this population, subgroups were selected according to severity (mild versus severe), duration (subacute versus chronic), and topography (distal versus proximal) of the neuropathy. RESULTS: EMG SA and MVC MRI amyotrophy and quantitative scoring of muscle STIR intensity were correlated with the MRC score. Moreover, MRI amyotrophy was significantly increased in severe, chronic, and proximal neuropathies along with fatty infiltration in chronic lesions. CONCLUSIONS: Muscle MRI atrophy and quantitative evaluation of signal intensity were correlated to MRC score in our study. Semiquantitative evaluation of muscle STIR signal was sensitive enough for detection of topography of the nerve lesion but was not suitable to assess severity. Muscle MRI could support EMG in chronic and proximal neuropathy, which showed poor sensitivity in these patients.
Subject(s)
Muscle, Skeletal/innervation , Muscular Atrophy/diagnosis , Peripheral Nervous System Diseases/diagnosis , Adult , Aged , Diagnosis, Differential , Electromyography/methods , Feasibility Studies , Humans , Lower Extremity/innervation , Magnetic Resonance Imaging/methods , Middle Aged , Muscle Contraction/physiology , Radiculopathy/diagnosisSubject(s)
Brain Ischemia/therapy , Cerebrovascular Circulation/physiology , Collateral Circulation/physiology , Stroke/therapy , Adult , Animals , Brain Ischemia/diagnosis , Brain Ischemia/physiopathology , Female , Humans , Infant , Male , Risk Factors , Stroke/diagnosis , Stroke/physiopathology , Time FactorsABSTRACT
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.
Subject(s)
Confusion , Electroencephalography , Emergency Service, Hospital , Humans , Electroencephalography/methods , Male , Female , Aged , Confusion/diagnosis , Confusion/physiopathology , Middle Aged , Aged, 80 and over , Adult , Seizures/diagnosis , Seizures/physiopathology , Status Epilepticus/diagnosis , Status Epilepticus/physiopathology , Acute DiseaseABSTRACT
BACKGROUND: Recreational nitrous oxide (N2O) 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 N2O-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 N2O 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.
Subject(s)
Nitrous Oxide , Substance-Related Disorders , Humans , Nitrous Oxide/adverse effects , Male , Female , Adult , Retrospective Studies , Paris/epidemiology , Young Adult , Middle Aged , Incidence , Substance-Related Disorders/epidemiology , Nervous System Diseases/epidemiology , Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/epidemiology , Peripheral Nervous System Diseases/chemically induced , Spinal Cord Diseases/epidemiology , Spinal Cord Diseases/chemically induced , Aged , Adolescent , Recreational Drug Use/statistics & numerical dataABSTRACT
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.
ABSTRACT
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.
Subject(s)
Giant Cell Arteritis , Retinal Artery , Humans , Biopsy , Eye/pathology , Giant Cell Arteritis/complications , Giant Cell Arteritis/diagnosis , Giant Cell Arteritis/pathology , Hemodynamics , Retinal Artery/pathology , Retrospective Studies , Vision DisordersABSTRACT
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.
Subject(s)
COVID-19 , Primary Dysautonomias , Humans , Female , Adult , SARS-CoV-2 , Autonomic Nervous System , Primary Dysautonomias/diagnosis , Cardiovascular Physiological Phenomena , Heart Rate/physiologyABSTRACT
Pro-angiogenic cell-based therapies constitute an interesting and attractive approach to enhancing post-stroke neurogenesis and decreasing neurological deficit. However, most new stroke-induced neurons die during the first few weeks after ischemia, thus impairing total recovery. Although the neovascularization process involves different cell types and various growth factors, most cell therapy protocols are based on the biological effects of single-cell-type populations or on the administration of heterogeneous populations of progenitors, namely human cord blood-derived CD34(+) cells, with scarce vascular progenitor cells. Tight cooperation between endothelial cells and smooth muscle cells/pericytes is critical for the development of functional neovessels. We hypothesized that neuroblast survival in stroke brain depends on mature vascular network formation. In this study, we injected a combination of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs), isolated from human umbilical cord blood, into a murine model of permanent focal ischemia induced by middle cerebral artery occlusion. The co-administration of SMPCs and EPCs induced enhanced angiogenesis and vascular remodeling in the peri-infarct and infarct areas, where vessels exhibited a more mature phenotype. This activation of vessel growth resulted in the maintenance of neurogenesis and neuroblast migration to the peri-ischemic cortex. Our data suggest that a mature vascular network is essential for neuroblast survival after cerebral ischemia, and that co-administration of EPCs and SMPCs may constitute a novel therapeutic strategy for improving the treatment of stroke.