The alterations of cerebrospinal fluid TNF-alpha and TGF-beta2 levels in early relapsing-remitting multiple sclerosis.

AIM OF THE STUDY: This study aimed to analyze serum and cerebrospinal fluid (CSF) concentrations of proinflammatory and anti-inflammatory cytokines produced by T regulatory (Treg) cells in early RRMS according to the 2017 McDonald criteria. CLINICAL RATIONALE FOR THE STUDY: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with the cytokine network playing an important role. However, there is a continual lack of data regarding the immunopathogenesis of early RRMS, especially according to the 2017 McDonald criteria. MATERIALS AND METHODS: The study groups included early RRMS patients during relapse (n = 18), remission (n = 14), and the control group. The MS diagnosis was established according to the 2017 McDonald criteria. Patients were studied up to 1 year after diagnosis was made. A quantitative test kit based on ELISA was used for cytokine measurement in the serum and CSF. Comparative and correlation analyses between the levels of TNF-α, TGF-ß2, IgG index, and relapse duration were performed. RESULTS: Significantly higher CSF concentrations of TNF-α in both RRMS-relapse and RRMS-remission groups were found compared to the controls (p < 0.01). The CSF levels of TGF-ß2 in the RRMS-relapse group were significantly lower in comparison to the control group (p = 0.01). CONCLUSIONS AND CLINICAL IMPLICATIONS: An inappropriate inflammatory response seems to occur in early RRMS and includes the production of TNF-α and a decrease in TGF-ß2 release suggesting a significant Treg cells role. Further studies on the topic may contribute to developing new disease-modifying drugs and biochemical markers of the disorder.

The Comparison of Predictive Value Among Chemerin, IL-18 and Hormonal Parameters in Assessing the Risk of Metabolic Syndrome in Men.

Chemerin (CHEM) is a new proinflammatory adipokine involved in the immune, metabolic and reproductive processes. Low-grade state inflammation (LGSI) is a key element in the pathogenesis of metabolic syndrome (MS). Low SHBG is a good marker of male hypogonadism in MS. This study evaluated the prognostic value of selected adipokine, LGSI, and androgenic parameters in predicting the risk of MS among men. One hundred thirty-two random men aged 40 to 70 years old were enrolled. Measurements of anthropometric indices, blood pressure, and laboratory tests were carried out. A total of 62 men (47%) were diagnosed with MS. Chemerin concentrations were higher in men diagnosed with MS compared to healthy: 89.48 (78.12-112.10) vs. 77.9 (65.12-98.64) ng/mL; p = .002. Men diagnosed with MS presented with lower levels of total testosterone: 5.75 (4.00-6.57) vs. 6.40 (5.50-8.40) ng/mL; p = .0014 and SHBG: 46.58 (35.13-66.28) vs. 71.97 (56.1-92.7) nM/L; p < 0.000001. Elevated LGSI indices were demonstrated in men with MS as opposed to healthy [IL-18: 530.64 (409.12-640.56) vs. 418.85 (348.14-496.44) pg/mL; p = .000033 and hs-CRP: 2.15 (0.97-4.26) vs. 1.01 (0.41-2.68) ng/mL; p = .0057)]. In multivariate regression analysis, the highest negative predictive value in assessing the risk of MS was SHBG serum concentration, while the highest positive predictive values were: IL-18, hypertriglyceridemia, and waist circumference. Decreased SHBG levels, combined with elevated IL-18 concentrations in men showing hypertriglyceridemic waist phenotype, significantly increase the risk of MS.

SARS-CoV-2 Infection: Symptoms of the Nervous System and Implications for Therapy in Neurological Disorders.

In this paper, the neurological aspects of COVID-19 are presented, which may be of significance for physicians. Knowledge about the neurological symptoms of COVID-19 infection should help physicians in diagnoses and in taking appropriate precautions, as some manifestations can appear before typical pulmonary symptoms. Various mechanisms of SARS-CoV-2 neuroinvasion are discussed and symptoms are described, which can be subdivided into manifestations of the central nervous system (CNS) (headache, dizziness, stroke, impaired consciousness, encephalitis, meningitis, seizures) and peripheral nervous system (PNS) (characteristic hyposmia and hypogeusia, Guillain Barré syndrome, myalgia). Additionally, the implications of COVID-19 infection for treatment of patients with common neurological diseases and their management is presented. It can be concluded that neurological symptoms are part of a clinical spectrum of COVID-19 infection, involving the CNS and PNS. COVID-19 may influence decisions regarding the treatment of neurological disorders, especially those with an immune background.

What do we currently know about the clinically isolated syndrome suggestive of multiple sclerosis? An update.

Multiple sclerosis (MS) is a chronic, demyelinating, not fully understood disease of the central nervous system. The first demyelinating clinical episode is called clinically isolated syndrome (CIS) suggestive of MS. Although the most common manifestations of CIS are long tracts dysfunction and unilateral optic neuritis, it can also include isolated brainstem syndromes, cerebellar involvement, and polysymptomatic clinical image. Recently, the frequency of CIS diagnosis has decreased due to the more sensitive and less specific 2017 McDonald criteria compared with the revisions from 2010. Not all patients with CIS develop MS. The risk of conversion can be estimated based on many predictive factors including epidemiological, ethnical, clinical, biochemical, radiological, immunogenetic, and other markers. The management of CIS is nowadays widely discussed among clinicians and neuroscientists. To date, interferons, glatiramer acetate, teriflunomide, cladribine, and some other agents have been evaluated in randomized, placebo-controlled, double-blind studies relying on large groups of patients with the first demyelinating event. All of these drugs were shown to have beneficial effects in patients with CIS and might be used routinely in the future. The goal of this article is to explore the most relevant topics regarding CIS as well as to provide the most recent information in the field. The review presents CIS definition, classification, clinical image, predictive factors, and management. What is more, this is one of very few reviews summarizing the topic in the light of the 2017 McDonald criteria.

Primary progressive multiple sclerosis and neurofibromatosis type 1.

BACKGROUND: Multiple sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous system. The clinical phenotype is probably modified by interactions from genetic and environmental factors. Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disease. NF1 gene mutations lead to clinical manifestation in the peripheral and central nervous system. Coexistence of MS and NF1 is a rare condition. OBJECTIVE: To report the case of the patient with primary progressive MS (PPMS) and NF1. METHODS: A retrospective analysis of a patient who has undergone whole exome sequencing confirmed by Sanger sequencing. RESULTS: We reported a novel de novo c.6817delC deletion and rs1801052 polymorphism in NF1 gene associated with NF1 symptoms, as well as numerous polymorphisms in SPG7, SPG15, SPG39 genes responsible for benign spastic paraplegia. CONCLUSION: Co-occurrence of PPMS and NF1 may be a consequence of genetic changes.

Multiple sclerosis - the remarkable story of a baffling disease.

Multiple sclerosis has always been an enigma to its sufferers, their families, medical investigators, and clinicians. For many centuries, there have been attempts to understand its causes and nature, and to discover treatment methods. In the Middle Ages, the disease was claimed to be sent directly from God. A significant development in exploring multiple sclerosis took place in the 19th century, when Jean-Martin Charcot and his colleagues distinguished the disease, precisely described its symptoms, attempted to explain its pathophysiology, and introduced the first methods of symptomatic treatment. The 20th century was a period of discovery and development of diagnostic techniques, such as cerebrospinal fluid analysis, evoked potentials, and magnetic resonance imaging as well as an era of introducing steroid therapy for acute treatment. Currently, the dynamic development of disease modifying therapy and neuroimaging can be observed. The paper aims to delve into the remarkable history of multiple sclerosis by focusing on the earliest case reports and discovery of the disease and exploring its nature, diagnostic methods, and treatment.

Glutamate-Related Antibodies and Peripheral Insulin-Like Growth Factor in Bipolar Disorder and Lithium Prophylaxis.

AIMS: The aim of this study was to evaluate serum levels of the antineuronal antibodies anti-N-methyl-D-aspartate receptor (NMDAR) and anti-glutamic acid decarboxylase (GAD), and insulin-like growth factor 1 (IGF-1), in patients with bipolar disorder (BD), during manic and depressive episodes and in remission compared to euthymic patients receiving long-term lithium therapy. METHODS: Serum levels of anti-NMDAR and anti-GAD 450/620 antibodies, as well as IGF-1, were measured using the ELISA method in 19 manic and 17 depressed patients both in an acute episode and in remission after the episode. All of the subjects were under pharmacological treatment. The control group included 18 euthymic BD patients receiving lithium for 9-44 years (mean 22 ± 11) in whom a single measurement was performed. RESULTS: Serum levels of anti-NMDAR antibodies were higher in acute manic episodes than in lithium-treated patients. Serum levels of anti-GAD 450/620 antibodies were higher in acute manic and depressive episodes compared to remission after the respective episode. Their values in both acute manic and depressive episodes were higher than those in lithium-treated patients. Serum levels of IGF-1 were higher in acute manic episodes and in remission after mania than in lithium-treated patients. CONCLUSION: Higher levels of anti-NMDAR and anti-GAD antibodies during episodes may point to an abnormality in the glutamatergic system in BD. Increased levels of IGF-1 during an acute manic episode and in remission after mania may constitute a compensatory mechanism against excitotoxicity. Lower levels of anti-NMDAR, anti-GAD antibodies, and IGF-1 during long-term lithium treatment may reflect normalization of this processes, contributing to mood stabilization.

Cluster Headache in a 76-year-old Woman with Onset at the Age of 74: Case Report.

Cluster headache (CH) is a rare trigeminal autonomic cephalalgia. Although its pathophysiology is not entirely understood, the hypothalamus and trigeminal nociceptive and autonomic pathways seem to play a key role in its pathology. In the majority of cases, CH begins at a young age and affects mainly men. This article presents a case of a 76-year-old woman with CH that developed at the age of 74. This is one of the first documented reports of CH with such atypical features from an epidemiologic point of view. A possibility of symptomatic cluster-like headache (CLH) attributed to cerebrovascular disease in the patient is also discussed.

CXCL10 and CXCL13 chemokines in patients with relapsing remitting and primary progressive multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system characterized by a variable clinical course. Different pathogenic mechanisms responsible for relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS) are modulated by immunological process with important role of chemokine network. CXCL10 and CXCL13 chemokines act as chemoattractants and modulators of proinflammatory reactions promoting process of demyelination. In the present study, we investigated the concentrations of CXCL10 and CXCL13 in serum and cerebrospinal fluid (CSF) of patients with RRMS and PPMS. MATERIALS AND METHODS: The study groups comprised 25 RRMS patients (39,5±12years), 24 PPMS patients (49,9±10,5years), 31 healthy individuals (36±10,4years) with tension headache without symptoms of inflammatory diseases. A quantitive test kit based on ELISA has been used for chemokines measurement. Correlations analysis between the levels of CXCL10, CXCL13 and patient age, duration of MS, EDSS and IgG index were done. RESULTS: The mean concentration of CXCL10 in the CSF was statistically significantly higher in RRMS in comparison with the control group. The mean concentration of CXCL13 in the CSF was significantly higher in RRMS and PPMS than in the control group. The results have shown that in the stable phase of MS without relapse, mean concentration of CXCL10 and CXCL13 in CSF did not differ significantly between RRMS and PPMS. In PPMS a positive correlation between IgG index and CSF CXCL10 level or CSF CXCL13 level was observed. In RRMS a positive correlation between IgG index and CSF CXCL13 level was observed. CONCLUSIONS: These data indicate involvement of CXCL10 and CXCL13 chemokines in immunopathogenetic mechanisms in MS. There was no significant difference between mean CXCL10 or CXCL13 concentrations in the CSF in both RRMS and PPMS patients. No significant correlations were found between patient age and chemokines levels in theCSF in all groups. It suggest that these chemokines play similar role in inflammatory process despite more pronounced neurodegenerative process in PPMS.

Cognitive impairment in multiple sclerosis - a review of current knowledge and recent research.

Multiple sclerosis (MS) is a chronic, progressive disease of the central nervous system that is characterised by inflammatory damage to the myelin sheath. Though often neglected, cognitive impairment is a common feature of MS that affects 43-70% of patients. It has a sophisticated neuroanatomic and pathophysiologic background and disturbs such vital cognitive domains as speed of information processing, memory, attention, executive functions and visual perceptual functions. In recent years there has been growing interest in neuroimaging findings with regard to cognitive impairment in MS. The possible options of managing cognitive dysfunction in MS are pharmacologic interventions, cognitive rehabilitation and exercise training; however, not enough evidence has been presented in this field. The aim of our article is to provide current knowledge on cognitive impairment in MS based on the most recent scientific results and conclusions with regard to affected cognitive domains, neuropsychological assessment, underlying mechanisms of this disturbance, neuroimaging findings and therapeutic options.

sNCAM as a specific marker of peripheral demyelination.

Adhesion molecules are involved in nerve growth, synaptic plasticity and myelin formation and maintenance process. Neural cell adhesion molecule (CD56 or NCAM) seems to play a crucial role in all the above-mentioned events. Having found poly-sialylated NCAM increased re-expression on demyelinated axons within multiple sclerosis plaques we assessed soluble NCAM (sNCAM) in sera of patients with various types of peripheral nerve affections - demyelinating, axonal "inflammatory", axonal metabolic polyneuropathies and healthy controls. These data were compared with the clinical state using Overall Neuropathy Limitations Scale (ONLS) and nerve conduction studies. We found significantly increased sNCAM concentration in demyelinating polyneuropathies in comparison to axonal group and healthy controls as well as significantly increased sNCAM level in axonal group in comparison to healthy subjects. We also found high positive correlation between sNCAM and ONLS and strong negative correlation between sNCAM level and the lowest conduction velocity (Vmin) found in a patient. We conclude that sNCAM might be thought as a specific marker of peripheral nerve demyelination and as a sensitive marker of peripheral nerve injuries.

Increased Serum CD14 Level Is Associated with Depletion of TNF-α in Monocytes in Migraine Patients during Interictal Period.

The aim of the present study was to investigate the levels of circulating CD14 in relation to the expression of tumor necrosis factor alpha (TNF-α) in monocytes, and serum levels of TNF-α and macrophage inflammatory protein-1 (MIP-1) in migraine patients. Numerous studies revealed controversial changes in the components of the immune system during attacks and the interictal period in migraine patients. Our study included 40 migraineurs and 39 controls. The levels of TNF-α, MIP-1 and CD14 were measured in peripheral monocytes and in sera with the Enzyme-Linked Immunosorbent Assay (ELISA) method, and the monocyte expression of TNF-α was also analysed by immunostaining. Serum CD14 concentrations were higher and the expression of TNF-α in monocytes was decreased in migraineurs. The serum MIP-1 level correlated with Verbal Rating Scale (VRS); the MIP-1:CD14 ratio in monocytes correlated with Visual Analogue Scale (VAS); the MIP-1:CD14 ratio correlated with Migraine Severity (MIGSEV)-Pain scores; and serum CD14 concentration correlated with migraine duration in years. Increased serum CD14 and depletion of TNF-α in monocytes can orchestrate other components of the immune system during the interictal period.

Serum sPECAM-1 and sVCAM-1 levels are associated with conversion to multiple sclerosis in patients with optic neuritis.

Platelet-Endothelial-Cell-Adhesion-Molecule-1 (PECAM-1) and Human-Vascular-CAM-1 (VCAM-1) are adhesion molecules involved in leukocyte-endothelial interaction. In our study serum levels of sPECAM-1 and sVCAM-1 were measured (ELISA) in twenty-nine patients during their first monosymptomatic optic neuritis (ON) episode. Anti-aquaporin-4-antibodies (AQP4-IgG) were detected with the cell-based assay. Patients were followed for seven years, during which 16/24 AQP4-IgG (-) patients developed MS and 2/5 AQP4-IgG (+) patients developed NMO. Patients who developed MS had significantly lower sPECAM-1 and sVCAM-1 than those who did not. Serum sPECAM-1 and sVCAM-1 may turn out to be useful biomarkers correlated with the risk of progression to MS after first ON incident.

The reciprocal links between synaptophysin serum levels and the prevalence of metabolic syndrome according to selected low-grade inflammation indices and age-related androgen serum level changes in men.

UNLABELLED: The correlations between synaptophysin (SYP) plasma levels and the brain neurotransmission activity are still not strictly identified. However, the efficiency of neurotransmission depends, inter alia, on the age, hormonal status, and coexistence of a low-grade systemic inflammation (LGSI) which is regarded as a pathogenic link with obesity and insulin resistance, atherogenesis and aging per se. AIM: The aim of this study was to investigate the associations between synaptophysin serum levels and age, LGSI indices, homocysteine and selected hormonal parameters (dehydroepiandrosterone and its sulfate, free-testosterone, SHBG) and the prevalence of metabolic syndrome (MS) in men over the age of 40. MATERIALS AND METHODS: After randomization, 157 male volunteers aged 40-80 years were included in a retrospective study. MS was diagnosed according to the International Diabetes Federation criteria. For the diagnosis of late-onset hypogonadism (LOH) we adopted the criteria proposed by the European Male Aging Study (EMAS). RESULTS: Synaptophysin plasma concentrations in respondents decreased with age, but only between the ages of 40 to 70 years. There were no differences in SYP plasma concentrations in men suffering from MS compared to healthy subjects (p=0.845). Men suffering from MS demonstrated while higher hs-CRP (high sensitive C - reactive protein) levels than healthy (p=0.019), contrary to the α1-antichymotrypsin and transferrin. A positive monotonic correlation between synaptophysin and hs-CRP was demonstrated (r=0.235; p=0.003). No statistically significant relationships between SYP and homocysteine plasma levels were presented (r=0.047; p=0.562), although in men diagnosed with MS higher homocysteine levels compared to healthy subjects were demonstrated. No correlations between synaptophysin and free testosterone (r=-0.036; p=0.651), DHEA (r=-0.122; p=0.128) and its sulphate (r=-0.024; p=0.764) as well as SHBG (r=-0.088; p=0.288) were demonstrated. CONCLUSIONS: Although the correlations between synaptophysin plasma levels and age as well as strong LGSI indicator (hs-CRP) have been demonstrated, the usefulness of determining SYP serum concentration as a marker of age-related studied diseases (MS, LOH) seems to be significantly limited.

Immunological differences between classical phenothypes of multiple sclerosis.

Multiple sclerosis (MS), one of the most serious inflammatory and neurodegenerative conditions, is characterized by variable clinical courses - relapsing-remitting (RRMS), primary progressive (PPMS) and secondary progressive (SPMS). Although PPMS affects only 10-15% of the patient population, its course and pathophysiological and immunological background are distinct. In this review we present and discuss main differences between different types of MS, with particular focus on the underlying immunological mechanisms.

Assessment of Vitamin D Level in Autoimmune Thyroiditis Patients and a Control Group in the Polish Population.

BACKGROUND: Vitamin D, known for its role in calcium-phosphorus homeostasis, is also a significant immunomodulatory factor. Vitamin D deficiency has been reported in some autoimmune disorders. Recently, vitamin D level in autoimmune thyroiditis (HT - Hashimoto's thyroiditis) has become the subject of researchers' interest. OBJECTIVES: This study aims to assess vitamin 25-OH-D3 levels in HT patients in comparison to a control group in the Polish population. This would be the first attempt conducted in this region with such poor sunlight exposure. MATERIAL AND METHODS: The group we studied consisted of 62 subjects diagnosed with HT (mean age 49.15±15.51) and 32 healthy controls matched with age and sex (mean age 46.09±14.32). All blood samples were collected in the first quarter of the year to minimize the impact of seasonal fluctuations of vitamin D concentrations. RESULTS: In the HT group the mean vitamin D level was 20.09 nmol/L (SD±12.66), compared to 30.31 nmol/L (SD±19.49) in the controls, p=0.014. None of the patients and the controls was vitamin D sufficient (75-125 nmol/L). The deficiency (<50 nmol/L) was significantly more common among HT patients compared to the controls (61-98.4% vs. 27- 84.4%, p=0.029). CONCLUSIONS: In conclusion, we found that serum vitamin D concentration is significantly lower in HT patients in comparison to the control group. This suggests vitamin D deficit as one of the risk factors for HT development. Observed vitamin D level was also low in the control group, therefore wider supplementation in general population should be recommended.

Neurobiology and temperament in the offspring of excellent lithium responders.

OBJECTIVES: The aim of the study was to assess neurobiological and temperamental correlates in offspring of lithium-treated patients, related to parental lithium response. METHODS: The study comprised 27 female and 23 male subjects, aged 17-54 years, the offspring of 36 bipolar patients receiving lithium for 5-38 years. Thirteen subjects were offspring of excellent lithium responders (ELR), 25 of partial lithium responders and 12 of lithium non-responders. In all subjects, serum brain-derived neurotrophic factor (BDNF), matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured, and the subjects were assessed by the Temperament Scale of Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A) and the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) scale. RESULTS: In offspring of the ELR, the percentage of persons treated for mood disorder was higher (46 vs. 16%), and higher mean BDNF and MMP-9 levels and lower IL-6 levels were found, compared with the remaining subjects. There were also differences between the ELR and the remaining patients on the TEMPS-A and O-LIFE scale, and within the ELR, between subjects treated for mood disorders and the healthy ones. CONCLUSIONS: The offspring of ELR show distinct neurobiological and temperamental profiles compared to other lithium-treated patients.

Restless legs syndrome in multiple sclerosis.

Restless legs syndrome (RLS) is a sleep-related sensory-motor disorder characterized by an irresistible urge to move the legs accompanied by unpleasant sensations in the lower extremities. According to many recent studies patients with multiple sclerosis (MS) suffer frequently from symptoms of RLS. The prevalence of RLS in MS patients varies 13.3%-65.1%, which is higher than the prevalence of RLS in people of the same age in the general population. MS patients with RLS have higher scores in the Expanded Disability Status Scale compared to MS patients without RLS. Presence of RLS has a negative impact on sleep quality and fatigue of MS patients. Iron deficiency and chronic inflammation may be factors contributing to development of RLS in MS. The relationship between the course and treatment of MS and RLS requires further prospective studies.

Concentration of Il-1ß, Il-2, Il-6, TNFα in the blood serum in children with generalized epilepsy treated by valproate.

BACKGROUND: The aim of the study was the comparison of concentrations of IL-1ß, IL-2, IL-6 and TNFα before and after valproate (VPA) treatment in blood serum in patients with generalized seizures diagnosed and treated in the Department of Developmental Neurology, Poznan University of Medical Sciences from January 2006 to May 2007. METHODS: The analysis was conducted in a group of 21 patients with well controlled, generalized seizures (mean age 7.7±4.7 years) before and after 4-6 months of VPA therapy. Quantitative determination IL-1ß, IL-2, IL-6 and TNFα were performed with method of enzyme-linked immunosorbent assay (ELISA). The serum drug concentration was determined with the use of fluorescence-polarization-immunoassay system (FPIA). RESULTS: The concentration of IL-6 in blood serum of patients decreased significantly (p<0.001) after 4-6 months of VPA therapy, but concentration of IL-1ß (p=0.732), IL-2 (p=0.865), TNFα (p=0.079) did not change significantly. The serum concentration of VPA in all of patients was in therapeutic range (mean 77.53±19.71µg/ml). CONCLUSIONS: The serum level of pro-inflammatory IL-6 in patients with generalized epilepsy decreased in statistically significant way during VPA therapy, so the anti-inflammatory properties of VPA are also important for the effective control of seizure. Due to the incompatibility of reports on the influence of VPA on cytokine system in patients with generalized epilepsy, this problem needs more investigations, especially in the group of children.