Prognostic factors of tumefactive demyelinating lesions and differential features for multiple sclerosis in etiology.

BACKGROUND: Many different pathologies may underlie tumefactive demyelinating lesions. Identifying clinical and radiologic distinguishing features before pathologic examination is essential for diagnosis and treatment. In this study, we aimed to determine the clinical and radiologic features affecting the etiology and disease course of patients with tumefactive lesions (TDL). MATERIALS AND METHODS: We included 35 clinicoradiologically or histologically diagnosed TDL patients in our center over 11 years. Patient records were retrospectively evaluated and recorded. Clinical features, cerebral neuroimaging, and histologic biopsy preparations, if any, were assessed by three independent neurologists, two neuroradiologists, and two pathologists at admission and follow-up, respectively. RESULTS: The mean age of patients with TDL was 40.02±14.40 years. Symptom onset was 15 (1-365) days. The most common complaints at initial presentation were hemiparesis or hemiplegia, sensory complaints, and cognitive impairment (aphasia or apraxia). The lesions were most commonly localized in the frontal lobe (42.9 %). Mass effect was 17.1 %, edema 60 %, diffusion restriction 62.1 %, and contrast enhancement 71.9 % (mostly ring-shaped (68.8 %)) on MR images. Acute onset and OCB type-2 positivity were associated with MS diagnosis. On the other hand, CSF protein levels above 45 mg/dL were found to be related to non-MS etiologies. Only the predominance of aphasia or apraxia at onset was a risk factor for early high disability (EDSS>4; 3rd month). Subacute-chronic onset, being older than 40 years, or having brainstem symptoms at onset were independent risk factors for late high disability (2nd year). CONCLUSION: Acute onset or OCB type 2 positivity is a clue for early diagnosis of MS, while elevated CSF protein is a clue for demyelinating diseases other than MS. Presentation with cognitive dysfunction at onset is an independent risk factor for early disability, while age above 40 years, subacute-chronic presentation and brainstem findings at presentation are independent risk factors for late disability.

Osmotic demyelination as a complication of hyponatremia correction: a systematic review.

BACKGROUND: Rapid correction of hyponatremia, especially when severe and chronic, can result in osmotic demyelination. The latest guideline for diagnosis and treatment of hyponatremia (2014) recommends a correction limit of 10 mEq/L/day. Our aim was to summarize published cases of osmotic demyelination to assess the adequacy of this recommendation. METHOD: Systematic review of case reports of osmotic demyelination. We included cases confirmed by imaging or pathology exam, in people over 18 years of age, published between 1997 and 2019, in English or Portuguese. RESULTS: We evaluated 96 cases of osmotic demyelination, 58.3% female, with a mean age of 48.2 ± 12.9 years. Median admission serum sodium was 105 mEq/L and > 90% of patients had severe hyponatremia (<120 mEq/L). Reports of gastrointestinal tract disorders (38.5%), alcoholism (31.3%) and use of diuretics (27%) were common. Correction of hyponatremia was performed mainly with isotonic (46.9%) or hypertonic (33.7%) saline solution. Correction of associated hypokalemia occurred in 18.8%. In 66.6% of cases there was correction of natremia above 10 mEq/L on the first day of hospitalization; the rate was not reported in 22.9% and in only 10.4% was it less than 10 mEq/L/day. CONCLUSION: The development of osmotic demyelination was predominant in women under 50 years of age, with severe hyponatremia and rapid correction. In 10.4% of cases, there was demyelination even with correction <10 mEq/L/day. These data reinforce the need for conservative targets for high-risk patients, such as 4-6 mEq/L/day, not exceeding the limit of 8 mEq/L/day.

Association between vaccination and the risk of central demyelination: results from a case-referent study.

BACKGROUND: Few studies documented the potential association between vaccination and the risk of central demyelination (CD). Specifically, anti-hepatitis B and anti-human papillomavirus (HPV) vaccines have been the subject of distrust with regard to their implication to trigger CD. METHODS: From a systematic national registry, patients with first signs of CD (cases) were identified and documented for their exposure to vaccination up to 24 months before the first signs occurred. This exposure was compared to that of a representative sample of general practice patients without a history of CD, randomly selected from a national registry (referents). CD cases were 2:1 matched on age, sex, index date (ID), and region of residence. Vaccines against influenza, HPV, hepatitis B and diphtheria-tetanus-pertussis-poliomyelitis-haemophilus (DTPPHae) were considered. Associations between vaccination and CD were assessed using multivariate conditional logistic regressions, controlled for confounding factors. FINDINGS: 564 CD cases were matched to 1,128 randomly selected referents (age range: 2-79 years old). Overall, 123 (22%) CD cases and 320 (28%) referents had received at least one vaccine within 24 months before ID. Adjusted odds ratios (ORs) for any vaccination were 0.69, 95% confidence interval (CI) [0.54-0.88] with respect to any CD first signs, 0.68 [0.51-0.90] for myelitis and 0.70 [0.42-1.17] for optic neuritis. Adjusted ORs for any CD first signs were 1.02 [0.71-1.47] for influenza vaccine (administered in 9.6% of cases and 10.4% of referents) and 0.72 [0.53-0.99] for DTPPHae vaccine (administered in 10.8% of cases and 14.5% of referents). Vaccines against hepatitis B and HPV were only administered in 1.1% and 1.2% of cases and in 2.9% and 3.2% of referents respectively, which statistically explained the point estimates < 1 (ORs of 0.39 [0.16-0.94] and of 0.32 [0.13-0.80]). INTERPRETATION: No increased risk of CD incidence was observed amongst vaccinated patients. Lower rates of vaccination against hepatitis B and HPV observed in patients with CD compared to referents may be due to the reluctance of physicians to vaccinate patients considered at risk of CD.

Higher consumption of ultra-processed foods and increased likelihood of central nervous system demyelination in a case-control study of Australian adults.

BACKGROUND: Consumption of ultra-processed foods (UPFs) has been linked to risk of chronic diseases, with scant evidence in relation to multiple sclerosis (MS). METHODS: We tested associations between UPF consumption and likelihood of a first clinical diagnosis of central nervous system demyelination (FCD) (267 cases, 508 controls), a common precursor to MS. We used data from the 2003-2006 Ausimmune Study and logistic regression with full propensity score matching for age, sex, region of residence, education, smoking history, body mass index, physical activity, history of infectious mononucleosis, dietary misreporting, and total energy intake. RESULTS: Higher UPF consumption was statistically significantly associated with an increased likelihood of FCD (adjusted odds ratio = 1.08; 95% confidence interval = 1.0,1.15; p = 0.039), representing an 8% increase in likelihood of FCD per one energy-adjusted serving/day of UPFs. CONCLUSION: Higher intakes of UPF were associated with increased likelihood of FCD in this Australian cohort. Nutrition education and awareness of healthy eating patterns may benefit those at high risk of FCD.

[Osmotic demyelination syndrome and overly rapid correction of hyponatremia]. / Syndrome de démyélinisation osmotique : quelle vitesse de correction de la natrémie ?

Hyponatremia is a frequent condition in hospitalized patients and is associated with significant morbidity and mortality. An association between rapid correction of hyponatremia and the occurrence of osmotic demyelination syndrome has been reported. Osmotic demyelination syndrome may present with severe neurologic symptoms, including in rare cases locked-in. Therefore, rapid correction of hyponatremia is recommended only in the presence of severe symptoms. In those cases, hypertonic saline (NaCl 3% 2 ml/Kg over 20 minutes) is recommended with close plasma sodium monitoring. After symptoms improvement, increases in sodium concentration should not exceed 8 mmol/l/24h. In cases without severe neurologic symptoms, the use of 3% NaCl solution should be avoided, and management should target the underlying causes of hyponatremia.

L'hyponatrémie est fréquente à l'hôpital avec une morbimortalité significative. Une association entre la vitesse de correction d'une hyponatrémie et la survenue d'un syndrome de démyélinisation osmotique (SDO) a été mise en évidence dans des études observationnelles. Dès lors, une correction rapide d'une hyponatrémie doit être réservée aux patients avec des symptômes sévères d'hyponatrémie. Dans ces situations, l'utilisation de NaCl 3 % (2 ml/kg) en bolus est recommandée avec des contrôles rapprochés de la natrémie. Après l'amélioration des symptômes, une vitesse de correction inférieure à 8 mmol/24 heures est indiquée. En l'absence de symptômes sévères, il est préférable d'éviter l'utilisation du NaCl 3 % et de traiter selon le mécanisme sous-jacent.

Evidences of the radiofrequency exposure on the antioxidant status, potentially contributing to the inflammatory response and demyelination in rat brain.

Present study exhibited the oxidative potential of microwave radiation (MWR) leading to the neurodegeneration in rats. Wistar rats were exposed at 2100 MHz frequency for 4 h/day, 5 days/week/3 months. Animals were exposed at an estimated specific absorption rate (0.453 W/kg) and power density (8.237 µW/m2). After exposure irradiated group was compared with control group. Results indicated that microwave exposure significantly increased the levels of serological triglycerides and cholesterol. Oxidative stress is observed through alteration of glutathione homeostasis followed by activated inflammatory response further confirmed by pro and anti-inflammatory cytokines in the exposed group. Histopathological assessments and electron microscopic observation confirmed a significant change in the myelination pattern and cellular organelles in the brain of exposed animals. Taking everything into account it can be concluded that chronic exposure of 2100-MHz frequency caused oxidative stress, which leads to neural damage and demyelination and may affect neural communication.

Refractory Hypernatremia and Osmotic Demyelination Syndrome After Liver Transplantation: A Case Report.

Osmotic demyelination syndrome is an uncommon neurologic condition, characterized by noninflammatory demyelination involving the pons and other areas of the central nervous system. As chronic hyponatremia is frequently associated with cirrhosis, patients undergoing liver transplantation are at an increased risk for developing this condition. We report the case of a patient who developed refractory hypernatremia and osmotic demyelination syndrome after liver transplantation. The patient was a 40-year-old man, who underwent liver transplantation for the treatment of cryptogenic cirrhosis, and had a preoperative sodium level of 128 mmol/L. Although there were no intraoperative complications, the patient showed signs of mental confusion and drowsiness in the second postoperative day, and we noticed an increase to 136 mmol/L in his serum sodium. Treatment with 5% dextrose and desmopressin was initiated, but his serum sodium continued to increase steadily, while his neurologic condition gradually worsened. Serum sodium rose to 157 mmol/L, and a magnetic resonance imaging of the brain showed extensive lesions consistent with osmotic demyelination syndrome. The clinical condition of the patient continued to deteriorate until his death 17 days after the transplant. Although the occurrence of this syndrome after liver transplantation is well described, the steady increase in serum sodium despite early treatment, as described in this case, is highly unusual, and highlights the great attention that must be taken with monitoring and control of serum sodium in patients who undergo liver transplant in the context of chronic hyponatremia. This manuscript is compliant with the Helsinki Congress and the Istanbul Declaration.

Ceramide kinase knockout ameliorates multiple sclerosis-like behaviors and demyelination in cuprizone-treated mice.

Changes in sphingolipid metabolism regulate and/or alter many cellular functions in the brain. Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). CerK and C1P were reported to regulate many cellular responses, but their roles in immune-related diseases in vivo have not been well elucidated. Thus, we investigated the effects of CerK knockout on the onset/progression of multiple sclerosis (MS), which is a chronic neurodegenerative disease accompanied by the loss of myelin sheaths in the brain. MS-model mice were prepared using a diet containing the copper chelator cuprizone (CPZ). Treatment of 8-week-old mice with 0.2% CPZ for 8 weeks resulted in motor dysfunction based on the Rota-rod test, and caused the loss of myelin-related proteins (MRPs) in the brain and demyelination in the corpus callosum without affecting synaptophysin levels. CerK knockout, which did not affect developmental changes in MRPs, ameliorated the motor dysfunction, loss of MRPs, and demyelination in the brain in CPZ-treated mice. Loss of tail tonus, another marker of motor dysfunction, was detected at 1 week without demyelination after CPZ treatment in a CerK knockout-independent manner. CPZ-induced loss of tail tonus progressed, specifically in female mice, to 6-8 weeks, and the loss was ameliorated by CerK knockout. Activities of ceramide metabolic enzymes including CerK in the lysates of the brain were not affected by CPZ treatment. Inhibition of CerK as a candidate for MS treatment was discussed.

A standard hemodialysis prescription to prevent osmotic demyelination in hyponatremic patients requiring dialysis.

INTRODUCTION: We aimed to investigate the effect of a standard hemodialysis prescription in hyponatremic patients requiring hemodialysis on the development of osmotic demyelination syndrome. METHODS: Ninety-nine patients who were treated with hemodialysis for the first time and had a pre-dialysis sodium value of ≤125 meq/L included in the study. Standard hemodialysis treatment was applied to all patients. Biochemical data before, immediately after and 24 h after hemodialysis were recorded retrospectively. All patients followed up for 2 weeks and magnetic resonance imaging was performed in patients with neurological symptoms. RESULTS: Eight patients had a sodium increase of more than 12 meq/L at 24-h after hemodialysis. Although hyponatremia was corrected rapidly with hemodialysis, none of the 99 azotemic patients developed osmotic demyelination syndrome. CONCLUSION: We did not observe osmotic demyelination syndrome in hyponatremic patients with azotemia treated with standard protocol hemodialysis. However, caution should still be exercised in high-risk patients for osmotic demyelination.

Farnesol Ameliorates Demyelinating Phenotype in a Cellular and Animal Model of Charcot-Marie-Tooth Disease Type 1A.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disease affecting the peripheral nervous system that is caused by either the demyelination of Schwann cells or degeneration of the peripheral axon. Currently, there are no treatment options to improve the degeneration of peripheral nerves in CMT patients. In this research, we assessed the potency of farnesol for improving the demyelinating phenotype using an animal model of CMT type 1A. In vitro treatment with farnesol facilitated myelin gene expression and ameliorated the myelination defect caused by PMP22 overexpression, the major causative gene in CMT. In vivo administration of farnesol enhanced the peripheral neuropathic phenotype, as shown by rotarod performance in a mouse model of CMT1A. Electrophysiologically, farnesol-administered CMT1A mice exhibited increased motor nerve conduction velocity and compound muscle action potential compared with control mice. The number and diameter of myelinated axons were also increased by farnesol treatment. The expression level of myelin protein zero (MPZ) was increased, while that of the demyelination marker, neural cell adhesion molecule (NCAM), was reduced by farnesol administration. These data imply that farnesol is efficacious in ameliorating the demyelinating phenotype of CMT, and further elucidation of the underlying mechanisms of farnesol's effect on myelination might provide a potent therapeutic strategy for the demyelinating type of CMT.

Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion.

Cerebrovascular pathologies are commonly associated with dementia. Because air pollution increases arterial disease in humans and rodent models, we hypothesized that air pollution would also contribute to brain vascular dysfunction. We examined the effects of exposing mice to nanoparticulate matter (nPM; aerodynamic diameter ≤200 nm) from urban traffic and interactions with cerebral hypoperfusion. C57BL/6 mice were exposed to filtered air or nPM with and without bilateral carotid artery stenosis (BCAS) and analyzed by multiparametric MRI and histochemistry. Exposure to nPM alone did not alter regional cerebral blood flow (CBF) or blood brain barrier (BBB) integrity. However, nPM worsened the white matter hypoperfusion (decreased CBF on DSC-MRI) and exacerbated the BBB permeability (extravascular IgG deposits) resulting from BCAS. White matter MRI diffusion metrics were abnormal in mice subjected to cerebral hypoperfusion and worsened by combined nPM+BCAS. Axonal density was reduced equally in the BCAS cohorts regardless of nPM status, whereas nPM exposure caused demyelination in the white matter with or without cerebral hypoperfusion. In summary, air pollution nPM exacerbates cerebrovascular pathology and demyelination in the setting of cerebral hypoperfusion, suggesting that air pollution exposure can augment underlying cerebrovascular contributions to cognitive loss and dementia in susceptible elderly populations.

Neurosteroid-based intervention using Ganaxolone and Emapunil for improving stress-induced myelination deficits and neurobehavioural disorders.

BACKGROUND: Prenatal stress is associated with long-term disturbances in white matter development and behaviour in children, such as attention deficit hyperactivity disorder (ADHD) and anxiety. Oligodendrocyte maturation and myelin formation is a tightly orchestrated process beginning during gestation, and therefore is very vulnerable to the effects of maternal prenatal stresses in mid-late pregnancy. The current study aimed to examine the effects of prenatal stress on components of the oligodendrocyte lineage to identify the key processes that are disrupted and to determine if postnatal therapies directed at ameliorating white matter deficits also improve behavioural outcomes. METHODS: Pregnant guinea pig dams were exposed to control-handling or prenatal stress with strobe light exposure for 2hrs/day on gestational age (GA) 50, 55, 60 and 65, and allowed to spontaneously deliver ~GA70. Pups were administered oral ganaxolone (5 mg/kg/day in 45% cyclodextrin) or the TSPO agonist, emapunil (XBD173; 0.3 mg/kg/day in 1% tragacanth gum) or vehicle, on postnatal days (PND) 1-7. Behavioural outcomes were assessed using open field and elevated plus maze testing on PND7 and PND27. Hippocampal samples were collected at PND30 to assess markers of oligodendrocyte development through assessment of total oligodendrocytes (OLIG2) and mature cells (myelin basic protein; MBP), and total neurons (NeuN) by immunostaining. Real-time PCR was conducted on hippocampal regions to assess markers of the oligodendrocyte lineage, markers of neurogenesis and components of the neurosteroidogenesis pathway. Plasma samples were collected for steroid quantification of cortisol, allopregnanolone, progesterone and testosterone by ELISA. RESULTS: Prenatal stress resulted in hyperactivity in male offspring, and anxiety-like behaviour in female offspring in the guinea pig at an age equivalent to late childhood. Postnatal ganaxolone and emapunil treatment after prenatal stress restored the behavioural phenotype to that of control in females only. The oligodendrocyte maturation lineage, translation of MBP mRNA-to-protein, and neurogenesis were disrupted in prenatally-stressed offspring, resulting in a decreased amount of mature myelin. Emapunil treatment restored mature myelin levels in both sexes, and reversed disruptions to the oligodendrocyte lineage in female offspring, an effect not seen with ganaxolone treatment. CONCLUSION: The marked and persisting behavioural and white matter perturbations observed in a clinically relevant guinea pig model of prenatal stress highlights the need for postnatal interventions that increase myelin repair and improve long-term outcomes. The effectiveness of emapunil treatment in restoring female offspring behaviour, and promoting maturation of myelin indicates that early therapeutic interventions can reverse the damaging effects of major stressful events in pregnancy. Further studies optimising target mechanisms and dosing are warranted.

Differential outcomes for frontal versus posterior demyelination in childhood cerebral adrenoleukodystrophy.

In the most common variant of childhood cerebral adrenoleukodystrophy (cALD), demyelinating brain lesions are distributed predominately in parieto-occipital white matter. Less frequently, lesions first develop in frontal white matter. This matched cohort study examined whether outcomes after standard treatment with hematopoietic cell transplantation (HCT) differ in patients with early stage frontal lesions as compared to parieto-occipital lesions. Retrospective chart review identified seven pediatric patients with frontal cALD lesions and MRI severity score < 10 who underwent a single HCT at our center between 1990 and 2019. Concurrent MRI, neurocognitive and psychiatric outcomes at last comprehensive follow-up (mean 1.2 years; range 0.5-2.1 years) were compared with a group of seven boys with the parieto-occipital variant matched on pre-HCT MRI severity score. Both groups showed similar rates of transplant complications and radiographic disease advancement. Neurocognitive outcomes were broadly similar, with more frequent working memory deficits among individuals with frontal lesions. Psychiatric problems (hyperactivity, aggression, and atypical behavior) were considerably more common and severe among patients with frontal lesions. Aligned with the critical role of the frontal lobes in emotional and behavioral regulation, functional disruption of self-regulation skills is widely observed among patients with frontal lesions. Comprehensive care for cALD should address needs for psychiatric care and management.

Tumefactive demyelination in pediatrics: An unusual late neurological complication of hematopoietic stem cell transplant.

Immune-mediated demyelination is a rare posttransplant complication. Here, we report an 8.5-year-old boy who developed left hemiparesis, 18 months post matched sibling donor hematopoietic stem cell transplant (HSCT) for relapsed acute myeloid leukemia and was diagnosed to have tumefactive demyelination. The diagnosis was established based on clinical and radiological features. The complete resolution of the lesions with steroids further established the immune-mediated pathophysiology.

Clinical risk factors and prognostic model for idiopathic inflammatory demyelinating diseases after haploidentical hematopoietic stem cell transplantation in patients with hematological malignancies.

Idiopathic inflammatory demyelinating diseases (IIDDs) of the central nervous system (CNS) are rare but serious neurological complications of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). However, the risk factors and a method to predict the prognosis of post-transplantation CNS IIDDs are not available. This retrospective study first reviewed data from 4532 patients who received haplo-HSCT during 2008-2019 in our center, and 184 patients (4.1%) with IIDDs after haplo-HSCT were identified. Grades II to IV acute graft-versus-host disease (aGVHD) (p < 0.001) and chronic GVHD (cGVHD) (p = 0.009) were identified as risk factors for developing IIDDs after haplo-HSCT. We then divided the 184 IIDD patients into a derivation cohort and validation cohort due to transplantation time to develop and validate a model for predicting the prognosis of IIDDs. In the multivariate analysis of the derivation cohort, four candidate predictors were entered into the final prognostic model: cytomegalovirus (CMV) infection, Epstein-Barr virus (EBV) infection, IgG synthesis (IgG-syn) and spinal cord lesions. The prognostic model had an area under the receiver operating characteristic curve of 0.864 (95% CI: 0.803-0.925) in the internal validation cohort and 0.871 (95% CI: 0.806-0.931) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. Decision curve analysis indicated that IIDD patients could benefit from the clinical application of the prognostic model. The identification of IIDD patients after allo-HSCT who have a poor prognosis might allow timely treatment and improve patient survival and outcomes.