Headache in Multiple Sclerosis: A Narrative Review.

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system characterized by autoimmune-mediated damage to oligodendrocytes and subsequent myelin destruction. Clinical implications: Clinically, the disease presents with many symptoms, often evolving over time. The insidious onset of MS often manifests with non-specific symptoms (prodromal phase), which may precede a clinical diagnosis by several years. Among them, headache is a prominent early indicator, affecting a significant number of MS patients (50-60%). Results: Headache manifests as migraine or tension-type headache with a clear female predilection (female-male ratio 2-3:1). Additionally, some disease-modifying therapies in MS can also induce headache. For instance, teriflunomide, interferons, ponesimod, alemtuzumab and cladribine are associated with an increased incidence of headache. Conclusions: The present review analyzed the literature data on the relationship between headache and MS to provide clinicians with valuable insights for optimized patient management and the therapeutic decision-making process.

The Comparison of the Selected Parameters of Brain Injury and Interleukins in the CSF in Patients Diagnosed De Novo with RRMS Compared to the Control Group.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS). Due to the different phenotypes of the disease and non-specific symptoms of MS, there is a great need for a validated panel of biomarkers to facilitate the diagnosis, predict disease progression, and evaluate treatment outcomes. METHODS: We determined the levels of the parameters of brain injury (NF-H, GPAF, S100B, and UCHL1) and the selected cytokines in the cerebrospinal fluid (CSF) in 101 patients diagnosed de novo with RRMS and 75 healthy controls. All determinations were made using the Bio-Plex method. RESULTS: We found higher levels of NF-H and GFAP in the relapsing-remitting multiple sclerosis (RRMS) group compared to the controls. The concentrations of both molecules were significantly increased in patients with Gd+ lesions on brain MRI. The level of S100B did not differ significantly between the groups. UCHL1 concentrations were higher in the control group. We found some correlations between the selected cytokines, the levels of the parameters of brain injury, and the time from the first symptoms to the diagnosis of MS. CONCLUSIONS: The role of the above molecules in MS is promising. However, further research is warranted to define their precise functions.

COVID-19 and autoimmune diseases of the nervous system - an update.

INTRODUCTION: Due to a similar pathomechanism, COVID-19 infection may significantly affect the course of autoimmune diseases (AIDs). In our review, we aimed to assess the severity of SARS-CoV-2 infection, response to treatment, and the impact of COVID-19 infection on the course of the underlying disease in patients with neuroimmune diseases. STATE OF THE ART: In the time of the COVID-19 pandemic, it was important to determine the influence of COVID-19 infection on the course of autoimmune diseases due to the weakened immune system and immunosuppressive therapies. CLINICAL IMPLICATIONS: Many reports have indicated that in patients with AIDs, the existence of the disease is not associated with a worse prognosis in the course of the viral infection. Patients in advanced stages of the disease, elderly patients, and those with comorbidities are at risk of more frequent hospitalisations and higher mortality in the course of COVID-19. Moreover, some drugs used in AIDs have been tested for their efficacy in SARS-CoV-2 infection. Episodes of newly diagnosed myasthenia gravis, Guillain-Barré syndrome, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica spectrum disorder (NMOSD) secondary to COVID-19 or vaccination have also been reported. Vaccination against this pathogen is highly recommended in most patients with AIDs. FUTURE DIRECTIONS: Despite many studies on the association between COVID-19 and neuroimmune diseases, more specific data is needed. The approach to patients with AIDs should be individual, since many issues remain unresolved despite the long-lasting pandemic.

The comparative analysis of selected interleukins and proinflammatory factors in CSF among de novo diagnosed patients with RRMS.

OBJECTIVES: Cytokines play a key role in neuroinflammation, which is present in every subset of multiple sclerosis (MS). The aim of the study was to assess levels of selected interleukins and proinflammatory factors in cerebrospinal fluid (CSF) among patients diagnosed with relapsing-remitting multiple sclerosis (RRMS). METHODS: One hundred eighteen patients diagnosed de novo with RRMS were enrolled in the study. We analysed the relationships between selected cytokines' levels depending on the age at diagnosis, time from the first symptoms to diagnosis and presence of MRI lesions. RESULTS: Among the study group the levels of IL-5 and IL-13 increased with the age at the diagnosis of MS. The concentration of IL-10 was lower in group of patients over the age of 35. The levels of IFN-γ, TNF-α, IL-5, IL-10 and IL-15 increased with the longer time from the first symptoms to diagnosis. Positive correlations were found between the levels of IL-2 and IL-12, IL-17, IL-4, IL-1RA as well as IL-1 and IL-4, IL-17. The concentration of IL-5 correlated positively with IL-4, IL-9 and IL-13. The level of IL-10 increased with IL-6 and IL-9 concentrations. A negative correlation was found for IL-10 and IL-4. In turn, between IL-13 and both IL-5 and IL-9, the relationship was positive. The level of IL-2 was significantly higher among patients without gadolinium-enhanced (Gd(+)) MRI lesions. CONCLUSIONS: The results of the study provide new insight into the role of selected molecules in the development of inflammation in MS. It might be crucial in planning the most adequate immunomodulatory therapy.

The Rate of Hospitalization of Pregnant Women with Multiple Sclerosis in Poland.

Multiple sclerosis (MS) is most often diagnosed in women of childbearing age. Therefore, it is important to examine the impact of pregnancy on the course of MS and to enable patients to make decisions about motherhood based on reliable data. The main objective of this study was to assess the impact of pregnancy on the course of MS by comparing the frequency of MS-related hospitalizations during pregnancy and 40 weeks postpartum versus 40 weeks before pregnancy. We used administrative health claims to identify female patients with MS, their deliveries, and their MS-related hospital admissions and calculated the frequency of MS-related hospital admissions before, during, and after pregnancy. We observed that MS is diagnosed approximately three times less often during pregnancy than before or after pregnancy. The number of MS-related hospital admissions decreased during pregnancy, especially in the third trimester. In contrast with other studies, we did not observe an increased level of MS-related admissions postpartum. The number of hospitalizations reported with steroid injections and emergency department visits also decreased during pregnancy. Our results show that pregnancy has a protective effect on the course of MS.

Bilateral paralysis of peroneal nerve after COVID-19 disease: a case report.

BACKGROUND: COVID-19, caused by a novel coronavirus SARS-CoV 2 has rapidly developed into pandemic. This infectious disease affecting mainly respiratory system may cause multiple systemic disorders. With increasing number of new infected patients there are more and more cases with neurological complications secondary to COVID-19. CASE PRESENTATION: Here we present a case of 67-years old Polish male with previously no comorbidities, who has developed bilateral paralysis of peroneal nerve after SARS-CoV 2 infection. Prior to the hospitalization he presented cough and fever and weakness. RT-PCR was reported positive for COVID-19 infection. Then he developed pneumonia and respiratory failure with bilateral lung consolidations on radiological examination. Laboratory findings revealed elevated levels of D-dimer, CRP, AspAT, GGTP, PCT and serum glucose. After discharge from hospital he was diagnosed with thrombophlebitis and prediabetes on follow-up visits. Due to problems with walking, numbness of toes and involuntary muscle spasms in hands, the patient went to the Neurological Outpatient Clinic. After neurological examination bilateral paralysis of peroneal nerve was revealed. CONCLUSIONS: In this report we want to highlight one of the unexpected presentations of SARS-CoV 2 infection and emphasize the importance of neurological examination in COVID-19 patients.

Multiple sclerosis immunomodulatory therapies tested for effectiveness in COVID-19.

INTRODUCTION: The global pandemic of COVID-19 began in Wuhan, China in December 2019. Research into effective therapies has been conducted worldwide. Currently, there is no antiviral treatment and many patients develop a severe course of the disease, including severe respiratory failure. Due to similar pathomechanisms of inflammation in multiple sclerosis (MS) and COVID-19, immunomodulatory drugs that are registered for the treatment of MS are under study in the SARS-CoV-2 infection in clinical trials. MATERIALS AND METHODS: Using clinicaltrials.gov, we found information related to ongoing clinical studies on potential drugs for COVID-19 which are also used in MS therapy. The outcomes of several trials were published on pubmed.ncbi.nlm.nih.gov. RESULTS: There were 18 clinical trials evaluating the effectiveness and safety of interferon-ß, fingolimod, or leflunomide in COVID-19. Some trial outcomes available at pubmed.ncbi.nlm.nih.gov suggested an association of these drug treatments with improvements in signs and symptoms, and the disease course. CONCLUSION: The administration of immunomodulatory drugs in COVID-19 may result in potential beneficial effects probably associated with their anti-inflammatory and antiviral properties. Further research is warranted to confirm the long-term effects of immunomodulatory therapies in patients with COVID-19.

The course of COVID-19 infection in patients with multiple sclerosis-The experience of one center based on the population of Upper Silesia.

BACKGROUND: It is suspected that patients with multiple sclerosis (MS) are at greater risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to disability and immunotherapy. The relationship between MS and coronavirus disease 2019 (COVID-19) is uncertain. The aim of the study was to collect and analyze this relationship. METHODS: All MS patients of the Neurological Outpatient Clinic in Zabrze, Poland, were regularly questioned for the symptoms of COVID-19 and contact with an infected person. Patients that presented with COVID-19 symptoms or confirmed contact with an infected person were referred for the COVID-19 test. All patients with confirmed SARS-CoV-2 infection (n = 41) were included in the analysis. Medical records of the study group were analyzed. Patient condition was monitored in the outpatient clinic after recovery. In 26 subjects, additional examinations, including brain magnetic resonance imaging (MRI), electroneurography (ENG), electroencephalography (EEG), color duplex Doppler (CDD), visual evoked potentials (VEPs), brainstem auditory evoked potentials (BAEPs) and psychological assessment were performed following recovery. RESULTS: Only one patient required hospitalization during COVID-19 infection, whereas 87.80% of patients did not require treatment for COVID-19. In all patients, C-reactive protein (CRP) levels were below 10 mg/L. In 2.44% of patients, oxygen partial pressure was below 95%. In most MS patients, the results of further examinations after COVID-19 infection were similar to those prior to infection. Psychological assessment revealed that anxiety was found in 42.31% of patients. CONCLUSIONS: A mild course of COVID-19 in MS patients seems common despite disease-modifying drug treatment and disability. Self-isolation is recommended to reduce the number of infected patients. COVID-19 infection did not worsen the course of MS in most subjects. Patients with MS may require additional psychological support during the pandemic due to their susceptibility to anxiety.

The Most Common Lesions Detected by Neuroimaging as Causes of Epilepsy.

Epilepsy is a common neurological disorder characterized by chronic, unprovoked and recurrent seizures, which are the result of rapid and excessive bioelectric discharges in nerve cells. Neuroimaging is used to detect underlying structural abnormalities which may be associated with epilepsy. This paper reviews the most common abnormalities, such as hippocampal sclerosis, malformations of cortical development and vascular malformation, detected by neuroimaging in patients with epilepsy to help understand the correlation between these changes and the course, treatment and prognosis of epilepsy. Magnetic resonance imaging (MRI) reveals structural changes in the brain which are described in this review. Recent studies indicate the usefulness of additional imaging techniques. The use of fluorodeoxyglucose positron emission tomography (FDG-PET) improves surgical outcomes in MRI-negative cases of focal cortical dysplasia. Some techniques, such as quantitative image analysis, magnetic resonance spectroscopy (MRS), functional MRI (fMRI), diffusion tensor imaging (DTI) and fibre tract reconstruction, can detect small malformations-which means that some of the epilepsies can be treated surgically. Quantitative susceptibility mapping may become the method of choice in vascular malformations. Neuroimaging determines appropriate diagnosis and treatment and helps to predict prognosis.

Modified Rio Score with Platform Therapy Predicts Treatment Success with Fingolimod and Natalizumab in Relapsing-Remitting Multiple Sclerosis Patients.

BACKGROUND: Reliable markers of disease outcomes in multiple sclerosis (MS) would help to predict the response to treatment in patients treated with high efficacy drugs. No evidence of disease activity (NEDA) has become a treatment goal whereas the modified Rio score (MRS) predicts future suboptimal responders to treatment. The aim of our study was to identify factors that would predict poor response to treatment with natalizumab and fingolimod. METHODS: In the multicenter prospective trial, 336 subjects were enrolled, initiating therapy with natalizumab (n = 135) or fingolimod (n = 201). Data on relapse rate, the expanded disability status scale, and MRI results were collected, and MRS was estimated. RESULTS: NEDA-3 after the first year of therapy was 73.9% for natalizumab and 54.8% for fingolimod (p < 0.0001). Patients with MRS = 0 in the last year on platform therapy had the best NEDA-3 (71%) and patients with MRS = 3 had the worst NEDA-3 (41%) in the first year of treatment with the second-line therapy. CONCLUSION: We conclude that switching to the second-line therapy should occur earlier to enable better results for patients treated with natalizumab or fingolimod. The outcome on both drugs is better with better neurological conditions and lower MRS of the patient on the platform therapy.

Secondary progressive multiple sclerosis - from neuropathology to definition and effective treatment.

INTRODUCTION: There is no single, commonly accepted, standard definition of secondary progressive multiple sclerosis (SPMS), an absence that poses a challenge for clinicians. STATE OF THE ART: SPMS is characterised by inflammation, neurodegeneration and disease progression with the presence or absence of relapses. No biochemical or radiological biomarkers are currently available to indicate the precise secondary progressive course in individual patients. The retrospective approach to identifying SPMS patients raises many difficulties, especially in terms of determining the time point of progression. Currently, the most precise diagnosis of SPMS is based on the definition proposed by Lorscheider et al., where SPMS is defined as a disability progression by 1 step on the Expanded Disability Status Scale (EDSS) in patients with EDSS ≤ 5.5 or of 0.5 EDSS steps in patients with EDSS ≥ 6 in the absence of a relapse, a minimum EDSS score of 4 and pyramidal functional system (FS) score of 2, and confirmed progression over ≥ 3 months, including confirmation within the leading FS. CLINICAL IMPLICATIONS: The need to establish criteria for the diagnosis of SPMS is currently of crucial importance due to emerging treatment opportunities including siponimod, a sphingosine 1-phosphate (S1P) receptor modulator selective for S1P1 and S1P5 receptors. It is reasonable to introduce drugs at the earliest possible stage of lesion progression to reduce inflammation a nd t o p rotect t he c entral n ervous s ystem ( CNS) a gainst i rreversible n eurodegeneration. FUTURE DIRECTIONS: Further studies with prospective, multicentre and long term follow-up design are needed to provide better insights into SP course in MS patients. This should be supported by radiological, biochemical and pathological evaluations to help establish reliable and sensitive biomarkers to guide clinical practice.

Evaluation of serum human epididymis protein 4 in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: So far, little is known about the properties of human epididymis protein 4 (HE4) in multiple sclerosis (MS). This type 4 glycoprotein belongs to a family of genes encoding proteins whose expression is associated with the process of spermatogenesis in the epididymis. The biological function of HE4 is not fully understood. Overexpression of HE4 has been found in several malignant tumors, particularly in ovarian cancer, as well as in mesothelioma, lung, endometrial, breast, and kidney cancers. OBJECTIVES: To evaluate serum HE4 in patients with relapsing-remitting multiple sclerosis (RRMS) as compared to healthy controls. MATERIAL AND METHODS: Fifty patients with RRMS undergoing first-line immunomodulatory treatment were enrolled in the prospective study. We analyzed correlations between serum HE4 levels and gender, age, disease duration, the Expanded Disability Status Scale (EDSS), annualized relapse rate (ARR), and magnetic resonance imaging (MRI) lesions. RESULTS: The patients from the study group had higher concentrations of HE4 than the subjects from the control group. Patients with EDSS > 2 had significantly higher concentrations of HE4. Positive correlations were found between HE4 concentrations and age as well as between HE4 concentrations and disease duration. No significant correlations were found between HE4 concentrations and EDSS or between HE4 concentrations and ARR. CONCLUSIONS: The results of the study indicate a novel aspect of the HE4 protein in the pathomechanisms of MS.

Are antioxidant parameters in serum altered in patients with relapsing-remitting multiple sclerosis treated with II-line immunomodulatory therapy?

So far little has been known about antioxidant properties of immunomodulatory drugs. The aim of the study was to evaluate the antioxidant status in serum of relapsing-remitting multiple sclerosis (RRMS) patients treated with II-line immunomodulatory therapy compared to de novo diagnosed patients, subjects treated with interferon (IFN) beta and healthy controls. We analyzed the relationships depending on the gender, age, disease duration, the Expanded Disability Status Scale, the annualised relapse rate, and MRI lesions in patients treated with II-line. One hundred and twenty one RRMS patients were enrolled in the prospective study. Patients were divided into the following groups: de novo, IFN, fingolimod (FG), natalizumab (NT), and the control. The total antioxidant capacity, sulfhydryl groups (SH groups, PSH groups), ceruloplasmin, and superoxide dismutase (SOD) activity were determined in serum. NT and FG groups presented with lower SOD activity compared to controls. The levels of antioxidants in NT- and FG-treated patients were not different from the IFN group. Antioxidant parameters increased with disease duration in the FG group. FG and NT could have an effect on the antioxidant system in multiple sclerosis (MS) patients. The results of this study propose a novel aspect of antioxidative properties of II-line immunomodulatory therapy in MS.

The Evaluation of Oxidative Stress Parameters in Serum Patients with Relapsing-Remitting Multiple Sclerosis Treated with II-Line Immunomodulatory Therapy.

OBJECTIVES: The assessment of oxidative stress (OS) in serum relapsing-remitting multiple sclerosis patients treated with II-line immunomodulatory therapy (fingolimod, natalizumab) compared to newly diagnosed patients (de novo group) treated with interferon (IFN) beta and controls. The relationship between OS parameters and gender, age, disease duration, Expanded Disability Status Scale, annualized relapse rate, MRI lesions in patients treated with II-line. MATERIALS AND METHODS: One hundred and twenty-one patients with RRMS were enrolled in the study. Patients were divided into groups: de novo group, IFN, fingolimod (FG), natalizumab (NT), and controls. Lipid hydroperoxides (LHP), malondialdehyde (MDA), lipofuscin (LPS), and total oxidative status (TOS) were determined. RESULTS: LHP, MDA, and TOS were lower in NT and FG groups compared to the de novo group. Levels of OS were different between NT and FG patients and the IFN group. Women treated with FG and NT had lower MDA, LPH, and TOS than women who were not treated while in men only LPH was lowered. Positive correlations were found between MDA, LHP, TOS, and ARR in the NT group. CONCLUSION: The II-line immunomodulatory treatment decreased OS particularly among women. No difference in OS levels was observed between II-line therapy and IFN beta.

New Insights into the Role of Oxidative Stress Mechanisms in the Pathophysiology and Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a multifactorial disease of the central nervous system (CNS) characterized by an inflammatory process and demyelination. The etiology of the disease is still not fully understood. Therefore, finding new etiological factors is of such crucial importance. It is suspected that the development of MS may be affected by oxidative stress (OS). In the acute phase OS initiates inflammatory processes and in the chronic phase it sustains neurodegeneration. Redox processes in MS are associated with mitochondrial dysfunction, dysregulation of axonal bioenergetics, iron accumulation in the brain, impaired oxidant/antioxidant balance, and OS memory. The present paper is a review of the current literature about the role of OS in MS and it focuses on all major aspects. The article explains the mechanisms of OS, reports unique biomarkers with regard to their clinical significance, and presents a poorly understood relationship between OS and neurodegeneration. It also provides novel methods of treatment, including the use of antioxidants and the role of antioxidants in neuroprotection. Furthermore, adding new drugs in the treatment of relapse may be useful. The article considers the significance of OS in the current treatment of MS patients.

A novel approach to crystallisation of nanodispersible microparticles by spray drying for improved tabletability.

High-dose API powders which are to be tableted by direct compression should have high compactibility and compressibility. This note reports on a novel approach to the manufacture of crystalline powders intended for direct compaction with improved compactibility and compressibility properties. The poorly compactable API, chlorothiazide, was spray dried from a water/acetone solvent mix producing additive-free nanocrystalline microparticles (NCMPs) of median particle size 3.5 µm. Tablets compacted from NCMPs had tensile strengths ranging from 0.5 to 4.6 MPa (compared to 0.6-0.9 MPa for tablets of micronised CTZ) at compression forces ranging from 6 kN to 13 kN. NCMP tablets also had high porosities (34-20%) and large specific surface areas (4.4-4.8m(2)/g). The time taken for tablets made of NCMPs to erode was not statistically longer (p>0.05) than for tablets made of micronised CTZ. Fragmentation of NCMPs on compression was observed. The volume fraction of particles below 1 µm present in the suspension recovered after erosion of NCMP tablets was 34.8±3.43%, while no nanosized particles were detected in the slurry after erosion of compacted micronised CTZ.

Oral delivery of macromolecules: rationale underpinning Gastrointestinal Permeation Enhancement Technology (GIPET).

Oral delivery of macromolecular drugs, particularly peptides and proteins, is the focus of many academic and industrial laboratories. Armed with an increased understanding of the structure and regulation of intestinal epithelial junctional complexes of the paracellular barrier, the development of permeation enhancement technology initially focused on the specific and reversible opening of tight junctions in order to enable oral delivery. Despite intense research, none of these specific tight junction-opening technologies has yet been approved in an oral drug product, likely because of poor efficacy. Less specific enhancer technologies with a long history of safe use in man have additional surfactant-like effects on the transcellular pathway that lead to improved efficacy. These are likely to be the first to market for selected poorly permeable peptides. This review presents a summary of some approaches taken to intestinal permeation enhancement and explores in detail the oral delivery system developed by Merrion Pharmaceuticals, Gastrointestinal Permeation Enhancement Technology (GIPET).