RESUMO
Neurosarcoidosis, a rare granulomatous disease, causes inflammation and damage to the central nervous system (CNS). A major diagnostic challenge in neurosarcoidosis is the absence of well-defined biomarkers. The need for biopsy to make the diagnosis can lead to delays and misdiagnosis if histopathology is inaccessible or indeterminate, highlighting the need for more accessible diagnostic indicators. The current gold standard for a "definite" neurosarcoidosis diagnosis requires biopsy of CNS tissue revealing non-caseating granulomas. However, such biopsies are inherently invasive and carry associated procedural risks. Notably, angiotensin-converting enzyme (ACE), commonly associated with systemic sarcoidosis, is recognized as a poor biomarker for neurosarcoidosis due to its lack of accuracy in the context of CNS involvement. Furthermore, imaging in neurosarcoidosis, while widely utilized and important for narrowing the diagnosis, lacks specificity. Decades of research have yielded molecular and immunologic biomarkers-soluble interleukin-2 receptor (IL-2R), serum amyloid A1, the CD4/CD8 ratio, neopterin, interferon-gamma (IFN-γ), and chemokine ligand 2 (CCL2)-that hold potential for improving diagnostic accuracy. However, these biomarkers are not yet established in clinical care as they may be difficult to obtain and are derived from small studies. They also suffer from a lack of specificity against other inflammatory and infectious central nervous system diseases. New biomarkers are needed for use alongside those previously discovered to improve diagnosis of this rare disease. This review synthesizes existing literature on neurosarcoidosis biomarkers, aiming to establish a foundation for further research in this evolving field. It also consolidates information on biomarkers of systemic sarcoidosis such as IL-8 and soluble CD40L that have not yet been studied in neurosarcoidosis but hold potential as markers of CNS disease.
Assuntos
Biomarcadores , Doenças do Sistema Nervoso Central , Sarcoidose , Sarcoidose/líquido cefalorraquidiano , Sarcoidose/diagnóstico , Sarcoidose/sangue , Humanos , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/sangue , Biópsia , Peptidil Dipeptidase A/líquido cefalorraquidiano , Peptidil Dipeptidase A/sangue , Receptores de Interleucina-2/sangueRESUMO
METHODS: Cerebrospinal fluid (CSF) and plasma levels of 38 biomarkers from 20 neurosarcoidosis (NS) patients were compared to healthy controls (HC). RESULTS: In CSF, 25 biomarkers were significantly elevated compared to HC: IFNγ, TNFα, TNFß, IL-2, IL-6, IL-10, IL-12B, IL-15, IL-16, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26, CXCL8, CXCL10, TNFR2, VEGF-A, PIGF, SAA, VCAM1, and ICAM1. In plasma, 12 biomarkers were significantly elevated compared to HC: IFNγ, TNFα, CCL2, CCL3, CCL4, CCL17, CXCL10, VEGFR1, PIGF, SAA, VCAM1, and ICAM1. CONCLUSION: NS patients have profoundly elevated cytokines, chemokines, vascular angiogenesis, and vascular injury biomarkers in CSF and plasma.
Assuntos
Doenças do Sistema Nervoso Central , Quimiocinas , Citocinas , Sarcoidose , Biomarcadores , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Humanos , Sarcoidose/sangue , Sarcoidose/líquido cefalorraquidianoRESUMO
BACKGROUND: Neuron-specific enolase (NSE) is released into serum when nerve cells are damaged, and the levels thereof are used to determine neurological prognosis in patients who have suffered cardiac arrest or stroke. Delayed neuropsychiatric sequelae (DNS), a major complication of carbon monoxide poisoning (COP), can be caused by inflammatory response which is a mechanism of neuronal injury in cardiac arrest and stroke. NSE is known as a predictor of neurological prognosis in ischemic brain injury after cardiac arrest, and it is also reported as a predictor of DNS in acute COP. When serum NSE is measured serially in cardiac arrest patients, the best time to predict neurological prognosis is known at 48-72 h, but there are no studies analyzing serial serum NSE in acute COP. Thus, we explored whether serum NSE levels measured three times at 24 h intervals after COP predicted the development of DNS. METHODS: This prospective observational study was conducted on patients treated for COP from May 2018 to April 2020 in a tertiary care hospital in Korea. Neuron-specific enolase levels were assessed 24, 48, and 72 h after presentation at hospital. We used logistic regression to explore the association between NSE levels and DNS development. RESULTS: The NSE level was highest at 48 h, and the difference between the DNS group and the non-DNS group was greatest on the same time point. On multivariable logistic regression analysis, the NSE level at 48 h of >20.98 ng/mL (odds ratio [OR], 3.570; 95% confidence interval [CI], 1.412-9.026; P = .007) and the initial Glasgow Coma Scale (GCS) score of <9 (OR, 4.559; 95% CI, 1.658-0.12.540; P = .003) was statistically significant for DNS development. CONCLUSION: Early identification of those who will experience DNS in acute COP patients is clinically important for deciding treatment. In this study, we revealed that NSE level of >20.98 ng/mL at 48 h time point can be used as an independent predictor of DNS (OR, 3.570; 95% CI, 1.412-9.026; P = .007; AUC, 0.648).
Assuntos
Intoxicação por Monóxido de Carbono/sangue , Doenças do Sistema Nervoso Central/induzido quimicamente , Fosfopiruvato Hidratase/sangue , Adulto , Intoxicação por Monóxido de Carbono/patologia , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismoRESUMO
Objective: To assess the quality of SpO2 and PCO2 recordings via transcutaneous monitoring in children with neurological conditions.Methods: Overnight transcutaneous SpO2 and PCO2 were analyzed. The presence of drift and drift correction was noted, and the rate of disrupted recordings scored (0: absence, 1; presence). The quality of recordings was also scored (0, 1, 2 for poor, medium, and high).Results: A total of 228 recordings from 64 children aged 9.7 ± 6 years were analyzed of which 42 used positive pressure respiratory support. The mean quality of the recordings was scored as 1.27 (0-2). PCO2 drift, drift correction, and disrupted recordings were present in 25%, 58%, and 26% of recordings, respectively. Satisfactory clinical decisions were taken in 91% of cases.Conclusion: The quality of transcutaneous sensor recordings was acceptable and clinical findings were deemed as satisfactory in the large majority of cases. Correction of PCO2 drift was challenging.
Assuntos
Monitorização Transcutânea dos Gases Sanguíneos/normas , Dióxido de Carbono/sangue , Oxigênio/sangue , Síndromes da Apneia do Sono/sangue , Adolescente , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Doenças Neuromusculares/sangue , Doenças Neuromusculares/fisiopatologia , Pressão Parcial , Respiração com Pressão Positiva , Garantia da Qualidade dos Cuidados de Saúde , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/fisiopatologia , Síndromes da Apneia do Sono/terapiaRESUMO
Neuronal injury is a universal event that occurs in disease processes that affect both the central and peripheral nervous systems. A blood biomarker linked to neuronal injury would provide a critical measure to understand and treat neurologic diseases. Neurofilament light chain (NfL), a cytoskeletal protein expressed only in neurons, has emerged as such a biomarker. With the ability to quantify neuronal damage in blood, NfL is being applied to a wide range of neurologic conditions to investigate and monitor disease including assessment of treatment efficacy. Blood NfL is not specific for one disease and its release can also be induced by physiological processes. Longitudinal studies in multiple sclerosis, traumatic brain injury, and stroke show accumulation of NfL over days followed by elevated levels over months. Therefore, it may be hard to determine with a single measurement when the peak of NfL is reached and when the levels are normalized. Nonetheless, measurement of blood NfL provides a new blood biomarker for neurologic diseases overcoming the invasiveness of CSF sampling that restricted NfL clinical application. In this review, we examine the use of blood NfL as a biologic test for neurologic disease.
Assuntos
Biomarcadores/sangue , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/diagnóstico , Proteínas de Neurofilamentos/sangue , HumanosRESUMO
Neurosarcoidosis (NS) is an often severe, destructive manifestation with a likely under-reported prevalence of 5 to 15% of sarcoidosis cases, and in its active phase demands timely treatment intervention. Clinical signs and symptoms of NS are variable and wide-ranging, depending on anatomical involvement. Cranial nerve dysfunction, cerebrospinal parenchymal disease, aseptic meningitis, and leptomeningeal disease are the most commonly recognized manifestations. However, non-organ-specific potentially neurologically driven symptoms, such as fatigue, cognitive dysfunction, and small fiber neuropathy, appear frequently.Heterogeneous clinical presentations and absence of any single conclusive test or biomarker render NS, and sarcoidosis itself, a challenging definitive diagnosis. Clinical suspicion of NS warrants a thorough systemic and neurologic evaluation hopefully resulting in supportive extraneural physical exam and/or tissue findings. Treatment targets the severity of the manifestation, with careful discernment of whether NS reflects active potentially reversible inflammatory granulomatous disease versus inactive postinflammatory damage whereby functional impairment is unlikely to be pharmacologically responsive. Non-organ-specific symptoms are poorly understood, challenging in deciphering reversibility and often identified too late to respond to conventional immunosuppressive/pharmacological treatment. Physical therapy, coping strategies, and stress reduction may benefit patients with all disease activity levels of NS.This publication provides an approach to screening, diagnosis, disease activity discernment, and pharmacological as well as nonpharmacological treatment interventions to reduce disability and protect health-related quality of life in NS.
Assuntos
Biomarcadores/análise , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/terapia , Sarcoidose/diagnóstico , Sarcoidose/terapia , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Diagnóstico Precoce , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Modalidades de Fisioterapia , Qualidade de Vida , Sarcoidose/sangue , Sarcoidose/líquido cefalorraquidianoRESUMO
OBJECTIVE: To systematically analyze soluble interleukin-2 receptor (sIL-2R) in CSF as a diagnostic and disease activity biomarker in patients with sarcoidosis involving the CNS (neurosarcoidosis). METHODS: sIL-2R was determined by chemiluminescent immunoassays in CSF/serum samples from patients with neurosarcoidosis (n = 23), MS (n = 19), neurotuberculosis (n = 8), viral (n = 18) and bacterial (n = 9) meningitis, cerebral lymphoma (n = 15), Guillain-Barré syndrome (n = 8), and 115 patients with noninflammatory neurologic diseases (NINDs) as controls. The sIL-2R index was calculated by dividing the CSF/serum sIL-2R quotient (QsIL-2R) through the CSF/serum albumin quotient (QAlb). sIL-2R quotient diagrams were established by plotting QsIL-2R against QAlb. sIL-2R levels were correlated with clinical, MRI, and CSF disease activity markers of neurosarcoidosis. RESULTS: Patients with neurosarcoidosis had higher CSF sIL-2R, QsIL-2R, and sIL-2R index values than patients with NINDs (p < 0.0001 for all pairwise group comparisons). sIL-2R quotient diagrams demonstrated an intrathecal sIL-2R synthesis in >50% of neurosarcoidosis samples. Similar findings were observed in viral/bacterial meningitis, CNS lymphoma, and, most pronounced, in neurotuberculosis, but not in patients with MS. CSF sIL-2R parameters were associated with clinical disease activity, leptomeningeal gadolinium enhancement, and the CSF white cell count in patients with neurosarcoidosis. CONCLUSIONS: CSF sIL-2R parameters are elevated in patients with neurosarcoidosis, but this finding is not specific for neurosarcoidosis. Nevertheless, CSF sIL-2R parameters may help distinguishing neurosarcoidosis from MS and are associated with clinical, radiologic, and CSF disease activity markers of neurosarcoidosis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF sIL-2R parameters distinguish neurosarcoidosis from NINDs and MS.
Assuntos
Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/diagnóstico , Receptores de Interleucina-2/metabolismo , Sarcoidose/líquido cefalorraquidiano , Sarcoidose/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/sangue , Receptores de Interleucina-2/sangue , Estudos Retrospectivos , Sarcoidose/sangue , Adulto JovemRESUMO
BACKGROUND: Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures. OBJECTIVE: Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma. METHODS: Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aß40, and Aß42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery. RESULTS: Tau increased during surgery (1752%, pâ=â0.0001) and NFL rose seven days post-surgery (1090%, pâ<â0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aß40 and Aß42. CONCLUSION: Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia.
Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Doenças do Sistema Nervoso Central/etiologia , Proteínas de Neurofilamentos/sangue , Proteínas tau/sangue , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/sangue , Anestesia Geral/efeitos adversos , Biomarcadores/sangue , Doenças do Sistema Nervoso Central/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Circulação Extracorpórea/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Otorrinolaringopatias/cirurgia , Fragmentos de Peptídeos/sangueRESUMO
OBJECTIVE: Although granulomatosis with polyangiitis (GPA; Wegener's granulomatosis) is classically characterized by systemic disease involving the kidneys and airway, approximately 10% of patients who have it present with isolated central nervous system disease. When involving the skull base, GPA frequently mimics more common pathology, resulting in diagnostic challenges and delay. The primary objective of this study is to characterize the cranial base manifestations of GPA, highlighting aspects most relevant to the skull base surgeon. STUDY DESIGN: Retrospective review. SETTING: Tertiary academic referral center. SUBJECTS AND METHODS: Retrospective analysis of all patients with skull base GPA treated at a tertiary referral center from January 1, 1996, to May 1, 2018. RESULTS: Twenty-nine patients met inclusion criteria. Twenty-one (72%) initially presented with skull base symptomatology as their cardinal manifestation of GPA. Twenty-four (82%) presented with cranial neuropathy at some point in their disease course. The trigeminal nerve was most commonly involved (12 of 24, 50%), followed by the facial (11 of 24, 46%) and optic (8 of 24, 33%) nerves. Eighteen patients reported hearing loss attributed to the GPA disease process, presenting as conductive, sensorineural, or mixed. The most common locations for GPA-derived inflammatory skull base disease on imaging included the cavernous sinus (12 of 29, 41%) and the orbit (7 of 29, 24%). CONCLUSION: Establishing the diagnosis of skull base GPA remains challenging. Cranial neuropathy is diverse in presentation and often mimics more common conditions. Imaging findings are also unpredictable and frequently nonspecific. Careful review of patient history, clinical presentation, serology and biopsy results, and imaging can reveal important clues toward the diagnosis.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Doenças dos Nervos Cranianos/diagnóstico , Granulomatose com Poliangiite/diagnóstico , Base do Crânio , Adulto , Idoso , Anticorpos Anticitoplasma de Neutrófilos/sangue , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/etiologia , Doenças dos Nervos Cranianos/sangue , Doenças dos Nervos Cranianos/etiologia , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/complicações , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND AND PURPOSE: Elevation of the chemokine CXCL13 in CSF frequently occurs during active and acute CNS inflammatory processes and presumably is associated with B cell-related immune activation. Elevation levels, however, vary a lot and "leaking" of CXCL13 from blood across dysfunctional brain barriers is a possible source. The aim was to clarify the relation between CXCL13 concentrations in CSF, CXCL13 concentrations in serum and blood-CSF barrier (BCSFB) function for a correct interpretation of the intrathecal origin of CXCL13. METHODS: We retrospectively analyzed CXCL13 of banked CSF/serum samples (n = 69) selected from patient records and categorized the CSF CXCL13 elevations as CXCL13 negative (< 30 pg/ml), low (30-100 pg/ml), medium (101-250 pg/ml), or high (> 250 pg/ml). CXCL13 concentrations in CSF and serum and the corresponding CSF/serum CXCL13 quotients (Qcxcl13) were compared to CSF/serum albumin quotients (QAlb) as a measure for BCSFB function. The CXCL13 negative category included two subgroups with normal and dysfunctional BCSFB. RESULTS: Serum CXCL13 concentrations were similar across categories with median levels around 100 pg/ml but differed between individuals (29 to > 505 pg/ml). Despite clear evidence in serum, CXCL13 was detectable only at trace amounts (medians 3.5 and 7.5 pg/ml) in CSF of the two CXCL13 negative subgroups irrespective of a normal or pathological QAlb. Moreover, we found no association between CSF and serum CXCL13 levels or between QAlb and CSF CXCL13 levels in any of the CSF CXCL13-delineated categories. CXCL13 apparently does not "leak" from blood into CSF. This implies an intrathecal origin also for low CSF CXCL13 levels and a caveat for analyzing the Qcxcl13, because higher serum than CSF concentrations arithmetically depress the Qcxcl13 resulting in misleadingly low CSF/serum quotients. CONCLUSION: We demonstrated that CXCL13 does not cross from blood into CSF, not even during severe BCSFB dysfunction. CSF CXCL13 elevations therefore most likely always are CNS-derived, which highlights their relevance as indicator of inflammatory CNS processes. We recommend data should not be corrected for BCSFB permeability (QAlb) and not to calculate CSF/serum quotients for CXCL13 as these may introduce error.
Assuntos
Doenças do Sistema Nervoso Central , Quimiocina CXCL13/sangue , Quimiocina CXCL13/líquido cefalorraquidiano , Inflamação , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/imunologia , Humanos , Inflamação/sangue , Inflamação/líquido cefalorraquidiano , Inflamação/imunologia , Estudos RetrospectivosRESUMO
The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and ß subtypes of nuclear TH receptors (TRα and TRß) showed that TRα and TRß are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRß selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRß agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRß agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3'-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRß mutations, and interesting results have recently been reported in patients with the Allan-Herndon-Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by ß-amyloid or by convulsive agents, but no clinical data are available so far.
Assuntos
Hormônios Tireóideos/metabolismo , Acetatos/farmacologia , Anilidas/farmacologia , Animais , Doenças do Sistema Nervoso Central/sangue , Ensaios Clínicos como Assunto , Di-Iodotironinas/sangue , Desenho de Fármacos , Dislipidemias/sangue , Humanos , Hepatopatias/sangue , Masculino , Camundongos , Mutação , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fenóis/farmacologia , Piridazinas/farmacologia , Ratos , Transdução de Sinais , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/química , Tironinas/sangue , Tri-Iodotironina/análogos & derivados , Tri-Iodotironina/farmacologia , Uracila/análogos & derivados , Uracila/farmacologiaRESUMO
Distinguishing neurosarcoidosis (NS) from multiple sclerosis (MS) remains challenging and available parameters lack discriminatory power. Comprehensive flow cytometry data of blood and CSF leukocytes of patients with NS (n = 24), MS (n = 49) and idiopathic intracranial hypertension (IIH, n = 52) were analyzed by machine learning algorithms. NS featured a specific immune cell pattern with increased activated CD4+ T cells in CSF and increased plasma cells in blood. Combining blood and CSF parameters improved the differentiation. We thereby identify and independently validate a multi-dimensional model of blood and CSF supporting the difficult differential diagnosis between NS and MS.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Leucócitos , Esclerose Múltipla/diagnóstico , Sarcoidose/diagnóstico , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Separação Celular , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/imunologia , Diagnóstico Diferencial , Feminino , Citometria de Fluxo , Humanos , Contagem de Leucócitos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Modelos Imunológicos , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Estudos Retrospectivos , Sarcoidose/sangue , Sarcoidose/líquido cefalorraquidiano , Sarcoidose/imunologia , Adulto JovemRESUMO
The blood-brain barrier (BBB) dysfunction is an initial event of various neuroinflammatory diseases. However, the absence of reliable markers and mechanisms for BBB damage greatly limits the diagnosis and treatment of neuroinflammatory diseases. Soluble CD146 (sCD146) is mainly derived from vascular endothelial cells (ECs) and highly elevated in inflammatory settings. Based on a small cohort, our previous study showed that sCD146 is elevated in the cerebrospinal fluid (CSF) of multiple sclerosis (MS), which is accompanied with BBB damage. Nevertheless, whether sCD146 monitors and regulates the BBB dysfunction remains unknown. Methods: Coupled serum and CSF samples from patients with or without neuroinflammatory diseases were collected via multicenter collaborations. sCD146 was measured by sandwich ELISA using anti-CD146 antibodies AA1 and AA98, both of which were generated in our laboratory. The correlations between sCD146 and other clinical parameters or inflammatory factors were analyzed by Spearman's correlation coefficient analysis. The role of sCD146 on BBB function was examined in an in vitro BBB model. Results: Between July 20, 2011, and February 31, 2017, we collected coupled serum and CSF samples from 823 patients, of which 562 (68.3%) had neuroinflammatory diseases, 44 (5.3%) had remitting MS, and 217 (26.4%) had non-inflammatory neurological diseases (NIND). We found that sCD146 in CSF, but not in serum, is abnormally elevated in neuroinflammatory diseases (37.3 ± 13.3 ng/mL) compared with NIND (4.7 ± 2.9 ng/mL) and remitting MS (4.6 ± 3.5 ng/mL). Abnormally elevated CSF sCD146 is significantly correlated with the hyperpermeability-related clinical parameters of BBB and neuroinflammation-related factors. Moreover, CSF sCD146 shows higher sensitivity and specificity for evaluating BBB damage. Using an in vitro BBB model, we found that sCD146 impairs BBB function by promoting BBB permeability via an association with integrin αvß1. Blocking integrin αvß1 significantly attenuates sCD146-induced hyperpermeability of the BBB. Conclusion: Our study provides convincing evidence that CSF sCD146 is a sensitive marker of BBB damage and neuroinflammation. Furthermore, sCD146 is actively involved in BBB dysfunction.
Assuntos
Barreira Hematoencefálica/patologia , Antígeno CD146/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Células Endoteliais , Inflamação/líquido cefalorraquidiano , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Antígeno CD146/sangue , Linhagem Celular , Doenças do Sistema Nervoso Central/sangue , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The increased use of antidepressant treatment during pregnancy occurred without firm evidence on safety/efficacy. The present study investigated the correlation among S100B and paroxetine blood levels with the occurrence of short-term post-natal neurological abnormalities. METHODS: We conducted a cross-sectional study in 50 pregnant women using paroxetine because of depression and in 150 controls. Standard laboratory parameters and S100B were measured at seven monitoring time-points (maternal blood: T1, 16-20 wks; T2, 27-30 wks; T3, 35-40 wks; T4, at delivery; amniotic fluid, T5; venous and arterial cord blood, T6-T7). Paroxetine levels were measured at T1-T6. Neurological outcome was set at 7th day from birth. RESULTS: Higher S100B concentrations at T1-T7 were found in the paroxetine-treated group. S100B correlated with paroxetine blood levels. The paroxetine/S100B ratio cut-off of 1.31 at T2 achieved sensitivity 100%, specificity 96.5% and positive/negative predictive values 87.5-100, respectively, as a single marker to predict adverse neonatal neurological outcome. CONCLUSIONS: The present study offers additional support to the usefulness of longitudinal S100B and drug level monitoring in depressed pregnant women and in the early detection of cases at risk for short-term neurological abnormalities. Results open the way at further investigations correlating antidepressant drugs and neurobiomarkers in the maternal bloodstream.
Assuntos
Líquido Amniótico/química , Antidepressivos/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Relações Materno-Fetais/efeitos dos fármacos , Paroxetina/farmacologia , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Adulto , Biomarcadores/sangue , Doenças do Sistema Nervoso Central/sangue , Técnicas de Laboratório Clínico , Estudos Transversais , Relação Dose-Resposta a Droga , Feminino , Humanos , GravidezRESUMO
Circulating microRNAs (cimiRNAs) are a class of non-encoding RNAs found in bodily fluids such as blood, cerebrospinal fluid (CSF) and tears. CimiRNAs have been implicated as promising biomarkers for central nervous system (CNS) disorders because they are actively secreted as messengers and are profoundly involved in fine-tuning of developmental and differentiation processes. Furthermore, they are attractive biomarkers because they are extremely stable, tissue enriched and can be determined in a quantitative manner. This review aims to provide a comprehensive assessment on the current progress regarding the potential value of cimiRNAs as CNS biomarkers. Within this framework five CNS disorders are explored which share a common pathological hallmark namely cognitive impairment. The CNS disorders include Major depression disorder (MDD), Bipolar disorder (BD), Schizophrenia (SZ), Alzheimer's disease (AD) and Parkinson disease (PD). The similarities and differences between altered cimiRNAs in the different disorders are described. The miR-29 family, miR-34a-5p and miR-132-3p are discussed as common dysregulated cimiRNAs found in the CNS disorders. Furthermore, it is shown that the type of bodily fluid used for measuring cimiRNAs is important as inconsistencies in cimiRNAs expression directions are found when comparing CSF, blood cell-free and blood cell-bound samples.
Assuntos
Biomarcadores/sangue , MicroRNA Circulante/sangue , MicroRNAs/sangue , Doenças Neurodegenerativas/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/diagnóstico , Humanos , Doenças Neurodegenerativas/diagnósticoRESUMO
BACKGROUND: For centuries, humans have used medicinal plants in the management of both acute and chronic diseases. Currently, the practice of using medicinal plants to manage diseases is becoming increasingly-common; especially in medium to low-income economies where the cost of, or ease of access to orthodox medications are limitations to their effective and sustained use. Diabetes mellitus is a chronic disease whose prevalence continues to increase worldwide. An aspect of diabetes mellitus that causes significant morbidity is its neurological complications, which are known to be associated with an enormous economic burden and reduction in quality of life. OBJECTIVES: While research continues to demonstrate that a wide range of plants that are indigenous to Africa have significant antihyperglycaemic properties, scientific information on the neurobehavioural and/or neuromorphological effects of these plants appear to be lacking. Also, their possible benefits in the prevention or amelioration of the neurological complications of diabetes mellitus remain generally unexamined. METHODOLOGY: In this narrative review, we the examine available scientific literature dealing with the neurobehavioural and/or neuromorphological profiles of selected African plants with substantiated antihyperglycaemic properties; aiming to highlight their potential applications in the prevention and management of the neurological complications of diabetes mellitus. RESULTS: This review demonstrates that a number of the African plants with antidiabetic properties also exhibit central nervous system effects. CONCLUSION: While the neurobehavioural and neuromorphological effects of some of these plants had been investigated in animal models of DM; their possible roles in the prevention or amelioration of the neurological complications of DM are yet to be established.
Assuntos
Doenças do Sistema Nervoso Central/terapia , Complicações do Diabetes/terapia , Diabetes Mellitus/terapia , Hipoglicemiantes/uso terapêutico , Fitoterapia , Plantas Medicinais , África , Animais , Glicemia/análise , Sistema Nervoso Central/efeitos dos fármacos , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/prevenção & controle , Complicações do Diabetes/sangue , Complicações do Diabetes/complicações , Complicações do Diabetes/prevenção & controle , Modelos Animais de Doenças , HumanosRESUMO
INTRODUCTION: Among antibiotics, Central Nervous System (CNS) adverse drug reactions (ADRs) are often under-suspected and overlooked. Cephalosporins are an important cause of drug-induced CNS ADRs but the characteristics of such ADR have not been fully explored. We aimed to characterize the profile of cephalosporins serious CNS ADRs. METHOD: We performed an analysis of serious reports recorded in the French Pharmacovigilance database from 1987 to 2017. RESULTS: A total of 511 serious ADRs reports was analyzed. Patients had a mean age of 67.1â¯years and were mainly men (52.5%), with a mean creatinine clearance of 32.9â¯ml/min. The most involved molecules were cefepime (33.1%), ceftriaxone (29.7%), ceftazidime (19.6%), cefotaxime (9%) and cefazoline (2.9%), mostly administered intravenously (87.3%). A CNS history was observed in 25% of the reports (nâ¯=â¯128). Patients exhibited encephalopathy (30.3%), confusional state (19.4%), convulsion (15.1%), myoclonia (9.4%), status epilepticus (9.2%), coma (6.3%) and hallucination (4.3%). The mean time of onset was 7.7â¯days and the mean duration was 6â¯days. Cephalosporin plasma levels were recorded for 153 patients (29.9%) and 107 were above the standards including 62 (57.9%) related to renal impairment. Electroencephalograms were performed in 38.2% (nâ¯=â¯195) of the patients and 81% (nâ¯=â¯158) were abnormal. CONCLUSION: This study characterizes an off-target CNS ADRs of several cephalosporins. Ceftriaxone represented a large part of our reports after cefepime and it would be relevant to warn healthcare professionals. Investigations (EEG, though plasma levels and renal function) can be precious tools for clinicians to make a prompt diagnosis and improve patients' outcomes.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Antibacterianos/efeitos adversos , Doenças do Sistema Nervoso Central/epidemiologia , Cefalosporinas/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Farmacovigilância , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Idoso , Antibacterianos/sangue , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/induzido quimicamente , Cefalosporinas/sangue , Bases de Dados Factuais/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Relatório de PesquisaRESUMO
BACKGROUND: Hypomagnesaemia is present in 40-50% of children with autosomal dominant renal cysts and diabetes syndrome (RCAD). On the contrary, the prevalence of hypomagnesaemia in children with autosomal dominant polycystic kidney disease (ADPKD) has never been examined. We aimed to investigate whether hypomagnesaemia is present in children with polycystic kidney diseases. METHODS: Children with cystic kidney diseases were investigated in a cross-sectional study. Serum concentrations of magnesium (S-Mg) and fractional excretion of magnesium (FE-Mg) were tested. Fifty-four children with ADPKD ( n = 26), autosomal recessive polycystic kidney disease (ARPKD) ( n = 16) and RCAD ( n = 12) with median age of 11.2 (0.6-18.6) years were investigated. RESULTS: Hypomagnesaemia (S-Mg < 0.7 mmol/L) was detected in none of the children with ADPKD/ARPKD and in eight children (67%) with RCAD. Median S-Mg in children with ADPKD/ARPKD was significantly higher than in children with RCAD (0.89 vs. 0.65 mmol/L, P < 0.01). The FE-Mg was increased in 23% of patients with ADPKD/ARPKD (all had chronic kidney disease stages 2-4) and in 63% of patients with RCAD, where it significantly correlated with estimated glomerular filtration rate (r = -0.87, P < 0.01). CONCLUSIONS: Hypomagnesaemia is absent in children with ADPKD or ARPKD and could serve as a marker for differential diagnostics between ADPKD, ARPKD and RCAD in children with cystic kidney diseases of unknown origin where molecular genetic testing is lacking. However, while hypomagnesaemia, in the absence of diuretics, appears to rule out ADPKD and ARPKD, normomagnesaemia does not rule out RCAD at least in those aged <3 years.
Assuntos
Hipercalciúria/epidemiologia , Magnésio/sangue , Nefrocalcinose/epidemiologia , Rim Policístico Autossômico Dominante/epidemiologia , Erros Inatos do Transporte Tubular Renal/epidemiologia , Adolescente , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diagnóstico Diferencial , Feminino , Humanos , Hipercalciúria/sangue , Hipercalciúria/diagnóstico , Lactente , Recém-Nascido , Doenças Renais Císticas/sangue , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/epidemiologia , Masculino , Nefrocalcinose/sangue , Nefrocalcinose/diagnóstico , Rim Policístico Autossômico Dominante/sangue , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Recessivo/sangue , Rim Policístico Autossômico Recessivo/diagnóstico , Rim Policístico Autossômico Recessivo/epidemiologia , Prevalência , Erros Inatos do Transporte Tubular Renal/sangue , Erros Inatos do Transporte Tubular Renal/diagnósticoRESUMO
Immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) are detected in the serum of some patients with demyelinating diseases. These patients are known to show repeated clinical episodes of inflammatory demyelinating attacks in the central nervous system. Although the associated pathogenicity and mechanism of inflammatory demyelination remains inconclusive, it is known that patients with MOG-IgG antibodies have a different clinical spectrum from those with other demyelinating diseases, such as multiple sclerosis. Based on our database of 85 MOG-IgG positive (+) cases, the most frequently associated clinical episodes were isolated optic neuritis (67.5%), encephalitis (26.5%), and myelitis (19.3%). Optic neuritis in MOG-IgG (+) disease usually involves the long segment of optic nerves and sometimes happens bilaterally, but visual acuity usually recovers with proper treatment in the acute phase. Brain and brainstem lesions usually present vague and focal appearances with irregular margins, typically in subcortical or brainstem regions, but occasionally in the cortex or corpus callosum. Due to these characteristics, MOG-IgG (+) cases with brain or brainstem lesions are sometimes diagnosed with acute disseminated encephalomyelitis, meningitis, or symptomatic epilepsy. The myelitis in MOG-IgG (+) typically shows longitudinally extensive lesions as seen in neuromyelitis optica spectrum disorders. Acute treatment to reduce attack-related disability is recommended in MOG-IgG (+) disease, and long-term immunosuppression may be considered in patients with a high frequency of relapses and/or high risk of neurological disability.
Assuntos
Autoanticorpos/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico , Glicoproteína Mielina-Oligodendrócito/sangue , Autoanticorpos/imunologia , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/imunologia , Doenças Desmielinizantes/imunologia , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/sangue , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/imunologiaRESUMO
BACKGROUND: Bothersome symptoms from sarcoidosis can develop in the absence of identified granulomas. These parasarcoidosis complaints can include small fiber neuropathy, diaphoresis, dysautonomia, and fatigue. Similar issues are also encountered in some cancer patients, especially those with onconeural antibodies. METHODS: Serum was obtained for onconeural antibody testing from sarcoidosis patients with parasarcoidosis symptoms seen at the University of Cincinnati Sarcoidosis clinic during a six month period. Detection of antibodies was performed using an onconeural antibody panel. RESULTS: A total of 268 patients with sarcoidosis and one or more features suggesting parasarcoidosis symptoms were enrolled in the study. Of these, 60 (22.4%) had one or more positive onconeural antibodies. In a control group of 46 non sarcoidosis patients seen in the interstitial lung disease clinic, there were only three patients with a positive antibody (Chi square=6.143, p=0.0132). A subgroup of sarcoidosis and control patients completed the small fiber neuropathy screening list. Sarcoidosis patients had a significantly higher score than the control patients (sarcoidosis: 7 [0-49] (Median [range] versus non sarcoidosis: 3 [0-31], p=0.0074). However, no significant differences were measured in the SFNL scores for sarcoidosis patients with an onconeural antibody (9 [3-36]) versus without (7 [0-49]). CONCLUSION: In patients with parasarcoidosis symptoms, approximately 30% have evidence of onconeural antibody production. This may be a potential cause for parasarcoidosis symptoms in some patients.