Secondary Progressive Multiple Sclerosis Group Research Articles

Assessment of serum inflammatory parameters in RRMS and SPMS patients

ABSTRACT Objectives Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. Methods The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. Results The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. Discussion Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients.

Optical coherence tomography angiography in the diagnosis of multiple sclerosis

This study analyzes the main changes in retinal microcirculation in patients with multiple sclerosis (MS) and their relationship with the type of disease course. 159 patients (318 eyes) were examined. The groups were formed according to the type of course and duration of MS: group 1 - 37 patients (74 eyes; 23.27%) with relapsing-remitting MS (RRMS) less than 1 year; group 2 - 47 patients (94 eyes; 29.56%) with RRMS from 1 year to 10 years; group 3 - 44 patients (86 eyes; 27.05%) with RRMS >10 years; group 4 - 32 patients (64 eyes; 20.12%) with secondary progressive MS (SPMS). Subgroups A and B were allocated within each group depending on the absence or presence of optic neuritis (ON). Patients underwent standard ophthalmological examination, including optical coherence tomography angiography (OCTA). A decrease in the vessel density (wiVD) and perfusion density (wiPD) in the macular and peripapillary regions was revealed, progressing with the duration of the disease and with its transition to the progressive type. The minimum values were observed in patients with SPMS (group 4), with the most pronounced in the subgroup with ON (wiVD = 16.06±3.65 mm/mm2, wiPD = 39.38±9.46%, ppwiPD = 44.06±3.09%, ppwiF = 0.41±0.05). OCTA provides the ability to detect subclinical vascular changes and can be considered a comprehensive, reliable method for early diagnosis and monitoring of MS progression.

Role of Serum Zinc, Urinary Sodium and Urinary Uric Acid in Multiple Sclerosis in Egypt

Background Studies have suggested that zinc (Zn), sodium (Na) and uric acid (UA) have a role in multiple sclerosis (MS). Objectives Aim of study is to measure serum Zn, urinary Na and urinary UA levels in MS patients compared to healthy control (HC) subjects, and investigate the difference between the MS subtypes and correlate it with disease activity and disability. Patients and Methods It is a case control study was carried on 60 clinically definite MS patients, 30 Relapsing Remitting MS (RRMS) and 30 secondary progressive MS (SPMS), recruited from MS unit at Ain Shams University Hospitals, and 30 HC subjects. Results Regarding Zn level, there was no significance between MS and HC groups. However, significant higher level in SPMS group. There was significant higher Zn level in males of HC group only. Regarding Na level, there was significant higher level in MS group and higher level in SPMS group. There were positive correlations with duration of illness, number of relapses per year and EDSS. Regarding UA level, there was significant higher level in MS group and higher level in RRMS group. There was negative correlation with relapses rate. Conclusion The role of Zn level in MS is linked to disability, not its diagnosis nor its activity, due to its disturbed metabolism in CNS diseases. In addition, the role of Na level in MS is linked to higher disease activity and disability. However, the lower UA level in MS is linked to higher relapse rate, but its higher level may be a cause of disease or a consequence to effect of DMTs.

INVESTIGATION OF THE EFFECTS OF CX3CL1 ON IMMUNOPATHOGENESIS AND COGNITIVE FUNCTIONS IN RELAPSING REMITTINGAND SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS PATIENTS IN TERMS OF THE POSSIBILITY OF A BIOMARKER

Objectives. CX3CL1 is a unique chemokine with direct relationship with its receptor to reduce expression of proinflammatory genes inactivated microglia.It is constitutively expressed by healty neurons and defined as neuroimmune regulatory protein.CX3CL1/CX3CR1signaling has been linked to human neurodegeneration. Under physiological conditions, disruption of this signaling leads to impairments inmotor learning, cognitive function, and synaptic plasticity. CX3CR1 also plays a role in the regulation of hippocampal-dependent memoryformation.Our aim in this study is to evaluate the role of CX3CL1 on immunopathogenesis and cognitive functions in Relapsing Remitting (RRMS) and Secondary Progressive Multiple Sclerosis (SPMS) patients in terms of biomarker possibility. Methods. Eight RRMS, 24 SPMS and 30 healty controls have been participated in this study. RRMS and SPMS were diagnosed according toMc Donald 2017 criteria. The degree of neurological deficits were assessed by EDSS.Serum levels of CX3CL1 were measured by ELISAmethod.The severity of cognitive impairment in patients were evaluate with MoCA test.Statistical analysis were performed using the IBMSPSS21. Results. When the RRMS, SPMS and control groups were compared,it was observed that the serum CX3CL1 levels in the SPMS groupwere decreased statistically significant.In addition,there was a positive correlation between MoCA score and serum CX3CL1 level in thepatients with RRMS and SPMS. Conclusion. Cytokines and chemokines play an important role in the immunopathogenesis of multiple sclerosis.Amongchemokines, serum levels of CX3CL1 was reported to be elevated in RRMS patients. However, it has not been observed in patients SPMS. CX3CL1 is an intrinsic neuroprotective chemokine and inhibitor against neurotoxicity. According to the results of our study, thedecrease in serum CX3CL1 levels serum CX3CL1 supports the development of neurodegeneration related neuroinflammation. In addition, thepositive correlation of MoCA test with CX3CL1 levels suggests that it has an important role in cognition. As a result, our study shows that CX3CL1 can be used as an early biomarker associated with disease progression and cognition, additionally it will be promising newtherapeutic target.

Stopping Interferon Beta 1b Does Not Influence the Risk of Disability Accrual in Non-Active SPMS: Results from an Italian Real-World Study.

Background: No consensus exists on the possibility to stop disease modifying therapies (DMTs) in Secondary Progressive Multiple Sclerosis (SPMS). Methods: The primary outcome was the time to reach 24-weeks confirmed Expanded Disability Status Scale (EDSS) 7.0. We enrolled all patients with a confirmed diagnosis of non-active SPMS (here, absence of clinical or radiological activity for at least 24 months before the conversion) between 1 January 2010 and 31 December 2015, at MS centers of Catania and Foggia, Italy. Patients were divided into two groups, according to the shared decision to stop DMTs (group A) or to maintain/switch to licensed interferon beta 1b for SPMS (group B). A Cox model adjusted with an inverse probability weighted propensity score (IPTW-PS) was employed. Results: A cohort of 311 patients was enrolled, 165 were in group A and 146 were in group B. Patients in the two groups were similar for baseline characteristics. The IPTW-PS adjusted Cox model for the event time to 24-weeks confirmed EDSS 7.0 did not show differences between the two groups (ExpB 0.96, CI 0.739–1.271, p = 0.819). Conclusions: In a real-world setting, in patients with non-active SPMS, the maintaining or switching to the licensed interferon beta 1b did not reduce the risk of reaching confirmed EDSS 7.0.

Inner and outer retina findings determined by optical coherence tomography in different subtypes of multiple sclerosis.

Integrity of outer retinal bands among multiple sclerosis (MS) subtypes remains unclear, however alterations of thickness in retinal layers is well described. The objective of the study was to determine the alterations in the thickness of the inner and outer layers of the retina and the findings in both layers detected by optical coherence tomography (OCT) among patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). A total of 132 eyes from 66 patients with multiple sclerosis (MS) (70 eyes from 35 patients with RRMS and 62 eyes from 31 patients with SPMS) and 72 eyes from 36 healthy controls were included in the study. The external structures of the retina, including the outer limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ), were examined using OCT in RRMS, SPMS, and healthy control groups. The correlation of neurological disability expressed by the Expanded Disability Study Scale (EDSS) score, best-corrected visual acuity, and duration of disease among OCT parameters was also analyzed. In eyes, with no history of previous optic neuritis (ON), the macular nerve fiber layer, the internal plexiform layer of ganglion cells (GCIPL), and the total thickness of the retinal layer were thinner in the SPMS group than in the RRMS group (P < 0.05, in each comparison). EZ was more vulnerable among the three hyperreflective external retinal zones in the retina of patients with SPMS than in patients with RRMS (P = 0.016). Alterations in retinal thickness in MS are not limited to the inner layers of the retina and also occur in the outer structures of the retina.

Multiple sclerosis by phenotype in Germany

Background: A diagnosis of multiple sclerosis (MS) can be categorized based on its disease course into the following phenotypes: relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). With one exception, studies of MS by phenotype either provide only prevalence data or if describing drug utilization, the emphasis is on patients with RRMS; while drug utilization by phenotype tends to be examined over the course of a year. No recent studies have comprehensively evaluated MS phenotypes by prevalence, drug utilization, and comorbidities over time from a population-based perspective, which is essential for understanding the disease burden and identifying unmet needs in MS. Germany is one of the few countries where specific MS phenotypes are commonly recorded in routine clinical practice. The purpose of this study was to compare MS phenotypes with respect to changes in their population-based prevalence rates and the types of MS treatments prescribed over time, as well as the frequency of clinical conditions associated with MS based on data from a German health insurance database. Methods: This retrospective, observational, cohort study used data from a German health insurance database for the period 2010 to 2017. Patients aged 18+ years with a specified phenotype of MS based on ICD-10 diagnosis coding were included in the analysis. Results: In 2010, RRMS was reported in 73%, PPMS in 8%, and SPMS in 19% of patients with MS with a known phenotype. The mean ages of patients were 41.4, 53.6, and 52.8 years, respectively, and all phenotypes were associated with a female predominance (69%, 63% and 63%, respectively). The prevalence rate of each phenotype markedly increased during the study period (RRMS +113%, PPMS +40%, SPMS +54%; in 2017 the rates were 183, 14, and 34 per 100,000, respectively). The mean age of patients reporting each phenotype also increased (p<0.01), while the female:male proportion remained stable in RRMS and SPMS, the proportion of females significantly declined over time in the PPMS group. The overall percentage of patients prescribed a disease-modifying drug increased across the phenotypes from 51% to 57%. Prescription of interferon-based therapies declined in each phenotype, with the greatest declines observed in RRMS and PPMS. The PPMS and SPMS groups had significantly more prescriptions for symptom management than the RRMS group. Depression was the most prevalent clinical condition associated with each phenotype. There was a significant difference in the percentage of patients with depression across the phenotypes (p = 0.03), with the highest among SPMS (44%) compared with RRMS (35%) or PPMS (37%). Significant differences (p<0.05) across the phenotypes were also observed for the composite prevalence of cardiovascular conditions (highest in PPMS) and cognitive dysfunction (highest in SPMS). Conclusion: The increasing numbers of patients across each MS phenotype, aging population in patients with MS regardless of phenotype, gender differences and variations across the types of treatments prescribed, and clinical conditions associated with each MS phenotype present new insight into the disease burden and treatment strategies of MS. These should be considered when developing healthcare strategies and optimizing care for patients with MS.

Real-world experience of ocrelizumab initiation in a diverse multiple sclerosis population

BackgroundOcrelizumab (OCR) is a humanized monoclonal antibody directed against CD20 positive B-lymphocytes. It was approved for use in 2017 by the U.S. Food and Drug Administration (FDA) for both the relapsing-remitting and primary progressive forms of multiple sclerosis (MS). ObjectiveTo provide real-world data for patients with MS treated with OCR in our center and evaluate both the safety and efficacy across different ethnic groups not studied in previous clinical trials. MethodsWe performed a retrospective observational analysis of MS patients who were treated with OCR from March 31, 2017 to April 30, 2020. We collected data on patients who had received at least a one dose infusion of OCR at our MS center. Patient characteristics, including demographics, clinical disease course, and documented side effects, were collected and analyzed. ResultsA total of 82 patients were eligible for this study, of which 72% had relapsing-remitting MS (RRMS), 14% had primary progressive MS (PPMS), and 11% active/relapsing secondary progressive MS (SPMS). 22% of our patients were of African American descent, 61% Caucasian, and 17% of Hispanic descent. The mean age of starting OCR was 41 ± 11 years. 47% were treatment naïve when started on OCR, 24% were previously treated with one disease-modifying therapy (DMT), 14% were treated with two DMTs, and 15% were treated with more than two DMTs prior to OCR. 50% of patients had at least one adverse event while on OCR; 4.8% had adverse events requiring to OCR discontinuation, 36% had infusion-related reactions, and 7.3% had viral infections. We found two cases of severe babesiosis along with index cases of re-activation of lichen planus, agranulocytosis, severe lymphopenia, and ectopic pregnancy. There were no cases of malignancy, progressive multifocal leukoencephalopathy, or death within our cohort. The mean time after OCR initiation was 17.3 months in the RRMS group, 22.2 months in the PPMS group, and 28.2 months in SPMS group. The annualized relapse rate reduced from 1.33 to 0.15 in the RRMS group. The mean extended disability status scale (EDSS) scores did not worsen across MS phenotypes and ethnic groups while being treated with OCR. ConclusionsIn a diverse patient population, OCR was well-tolerated without significant adverse events. There were novel cases of severe babesiosis, re-activation of lichen planus, lymphopenia, agranulocytosis, and ectopic pregnancy. It is vital to consider geographic risk factors that may expose patients to Babesia microti (B. microti) when either considering or initiating OCR therapy. There were an additional six cases of severe B. microti cases associated with OCR that were reported to the FDA adverse event reporting system (FAERS) along with multiple babesiosis cases associated with other DMTs, including rituximab. OCR was found in our cohort to be effective by decreasing relapse rates and maintaining EDSS scores. Our study extends the generalizability of OCR from clinical trials to a real-world setting consisting of a diverse population.

Efficacy and Safety of Rituximab in Central Nervous System Demyelinating Disorders.

Background:Rituximab, an anti-CD20 monoclonal antibody, has been used worldwide as an off-label therapy in patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD).Objective:The aim of the present study was to evaluate the efficacy and safety of rituximab in central nervous system demyelinating disorders in the Indian context.Methods:We conducted a retrospective analysis of patients with MS, NMOSD, and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) who were treated with rituximab at a single tertiary care centre in Mumbai.Results:The study enrolled 102 patients (61 MS, 37 NMOSD and 4 MOGAD) from June 2008 to January 2020. Following rituximab therapy, 96.7% of MS, 67% of NMOSD, and 50% of MOGAD patients were free of relapses. The mean annualized relapse rate reduced from 2.17 to 0 for patients with relapsing remitting MS (RRMS), from 0.8 to 0 for secondary progressive MS (SPMS), from 2.5 to 0.14 for NMOSD, and from 3.43 to 1.04 for MOGAD. The median expanded disability status scale improved significantly in RRMS patients, worsened non-significantly in the SPMS group, and remained unchanged in NMOSD and MOGAD patients. On follow-up magnetic resonance imaging, there was a significant reduction in the number of MS patients developing new contrast enhancing lesions or new T2 lesions. Adverse events (infusion reactions or severe infections) occurred in 12 patients.Conclusion:Rituximab is effective and safe in Indian patients with MS and NMOSD.

Rituximab in the treatment of multiple sclerosis in the Hospital District of Southwest Finland

BackgroundThere are already numerous B-cell depleting monoclonal anti-CD20 antibodies which have been used to reduce the inflammatory burden associated with multiple sclerosis (MS). We describe here our experience of treating MS-patients with B-cell depleting rituximab. Patients and methodsAll MS-patients (n = 72) who had received rituximab treatment for at least six months by January 2019 were identified from the patient charts at the Turku University Hospital. Information about MS disease subtype, disease severity, MR-imaging outcomes and B-cell counts were collected from the charts. ResultsRituximab was well received and well tolerated by the patients. There were no serious infusion-related side effects. The most serious adverse event that led to treatment discontinuation was neutropenia. After rituximab initiation the annual number of relapses was decreased in the relapsing remitting and secondary progressive MS groups and the mean number of gadolinium-enhancing lesions was decreased in relapsing remitting MS. Our study confirms the usability of rituximab treatment for MS in the Finnish health care environment. ConclusionsOff-label rituximab-treatment can be successfully used to reduce MS disease burden for the benefit of MS patients.

Restless Legs Syndrome in Multiple Sclerosis.

The co-existence of Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED/WED) and multiple sclerosis (MS) is a common condition. For this reason, we aimed to evaluate the effects of RLS/WED and its relationship with MS. We evaluated the clinical features of 102 patients diagnosed with MS who were in follow-up between 2010 and 2015 in outpatient clinic. All the patients were evaluated for RLS/WED according to the revised International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria. The Expanded Disability Status Scale (EDSS), Beck Depression Inventory, Beck Anxiety Inventory and Fatigue Severity Scale scores of all the patients were recorded. The IRLSSG 2003 severity scale was used to determine the degree of RLS/WED. RLS/WED was detected in 30.4% (n=31) of the patients (MS-RLS/WED+), but not in 69.6% (n=71) (MS-RLS/WED-). The mean EDSS score of the MS-RLS/WED+ patients were 3.2±2.1 while the MS-RLS/WED-patients were 2.0±1.6. The incidences of depression, moderate or severe anxiety, fatigue and intestinal and bladder dysfunction in the MS-RLS/WED+ patients were significantly higher. Regarding to RLS/WED complaints, 32.2% were mild, 35.4% were moderate, 19.3% were severe and 12.9% were very severe. When the MS subgroups were evaluated the highest RLS/WED severity score was found in the secondary progressive MS group. In the patients with pyramidal symptoms and intestinal and bladder dysfunction, the mean RLS/WED severity was significantly higher. The mean RLS/WED severity score was also significantly higher in those with depression and anxiety. The RLS/WED severity was significantly correlated with the number of pyramidal attacks and the EDSS score. Restless legs syndrome is a cause of depression, anxiety and fatigue and has negative effects on MS patients. Therefore, after the diagnosis of MS, the RLS/WED symptoms and signs should be determined, as soon as possible, in addition to the other MS symptoms. The treatment of this condition should be started early.

Efficacy of alemtuzumab and natalizumab in the treatment of different stages of multiple sclerosis patients.

Background:Multiple sclerosis (MS) is an autoimmune disease, in which the insulating covers of nerve cells in the brain and spinal cord are demyelinated. This study was conducted to compare the efficacy of alemtuzumab and natalizumab in the treatment of different stages of MS patients.Methods:A total of 585 patients diagnosed with MS and hospitalized were included and analyzed after which they were divided into the primary progressive MS A and B groups, the relapsing-remitting MS (RRMS) C and D groups, and the secondary progressive MS E and F groups. Patients in A, C, and E groups were administered alemtuzumab while those in B, D, and F groups were administered natalizumab for the treatment. The expanded disability status scale (EDSS) scores and the EDSS difference were calculated before and after treatment. The number of head magnetic resonance imaging enhanced lesions in the patients, recurrence time and recurrence rate were measured before and after treatment.Results:The EDSS score of the RRMS group was significantly lower than that of the primary progressive MS group and the secondary progressive MS group. After 12 months of treatment, the EDSS score of RRMS patients treated with natalizumab was significantly lower compared with the patients with alemtuzumab, and the difference before and after treatment was significantly higher than alemtuzumab. The recurrence rate of the RRMS-D group was significantly lower than the RRMS-C group. After 12 months of treatment, compared with the RRMS-C group, a significant reduction was observed in the number of head magnetic resonance imaging enhanced lesions and longer recurrence time in the RRMS-D group.Conclusion:The efficacy of natalizumab was better than alemtuzumab in the treatment of patients in the RRMS group, while there was no significant difference among other stages of MS patients, which provided the theoretical basis and clinical guidance for the treatment of different stages of MS.

Comparison of Brain Atrophy, Cognition and Optical Coherence Tomography Results Between Multiple Sclerosis Patients and Healthy Controls.

Cognitive impairment is also an important cause of disability in MS in addition to motor, sensory, visual, and cerebellar affections. The aim of this study is to show the relation between the cognitive disability in MS with brain atrophy and retinal nerve fiber layer (RNFL). Forty-three multiple sclerosis (MS) patients, and 15 healthy individuals as controls were included in the study. MS patients were divided into three groups as relapsing-remitting MS (RRMS), relapsing-remitting with optic neuritis (RRMS+ON), and secondary-progressive MS (SPMS). An experienced psychologist performed modified Wechsler Memory Scale Revised form (WMS-R), Lines Orientation test, Stroop Color Word Interference test (STROOP), Standard Raven Progressive Matrices (SRPM), Benton Facial Recognition Test, verbal fluency test, and Paced Auditory Serial Addition tests in all cases. Optic coherence tomographies (OCT) were done. Cranial subcortical volumes of all subjects were measured using 3-dimensonal T1A imagines obtained by the cranial subcortical 1.5 tesla MR device (fully automatic Freesurfer program). Brain parenchymal fractions were calculated by proportioning the obtained volume measurements to the total intracranial volume. Fifty-eight subjects (65.5% female, 34.5% male) were enrolled in the study. There were significant differences among the groups in terms of parenchymal thickness, volumes of third ventricle, and white matter. There was a significant correlation between the volumes of the deep gray matter, mesial temporal structures and lateral ventricular volumes, and the test results of the WMS-R. OCT scores of all MS patients, whether or not they experienced optic neuritis, had increased, being worse especially in the SPMS group. Correlation between RNFL and the brain parenchymal fractions of the patients were statistically significant. Manual methods instead of automatic segmentation method are being more commonly used in the studies with brain atrophy and MS in our country. A significant correlation between OCT scores and brain atrophy is shown with our present study, and this is followed as a reflection of decrease in cognitive tests that provides valuable and reliable knowledge for the literature.

MRI Analysis of White Matter Myelin Water Content in Multiple Sclerosis: A Novel Approach Applied to Finding Correlates of Cortical Thinning.

A novel lesion-mask free method based on a gamma mixture model was applied to myelin water fraction (MWF) maps to estimate the association between cortical thickness and myelin content, and how it differs between relapsing-remitting (RRMS) and secondary-progressive multiple sclerosis (SPMS) groups (135 and 23 patients, respectively). It was compared to an approach based on lesion masks. The gamma mixture distribution of whole brain, white matter (WM) MWF was characterized with three variables: the mode (most frequent value) m1 of the gamma component shown to relate to lesion, the mode m2 of the component shown to be associated with normal appearing (NA) WM, and the mixing ratio (λ) between the two distributions. The lesion-mask approach relied on the mean MWF within lesion and within NAWM. A multivariate regression analysis was carried out to find the best predictors of cortical thickness for each group and for each approach. The gamma-mixture method was shown to outperform the lesion-mask approach in terms of adjusted R2, both for the RRMS and SPMS groups. The predictors of the final gamma-mixture models were found to be m1 (β = 1.56, p < 0.005), λ (β = −0.30, p < 0.0005) and age (β = −0.0031, p < 0.005) for the RRMS group (adjusted R2 = 0.16), and m2 (β = 4.72, p < 0.0005) for the SPMS group (adjusted R2 = 0.45). Further, a DICE coefficient analysis demonstrated that the lesion mask had more overlap to an ROI associated with m1, than to an ROI associated with m2 (p < 0.00001), and vice versa for the NAWM mask (p < 0.00001). These results suggest that during the relapsing phase, focal WM damage is associated with cortical thinning, yet in SPMS patients, global WM deterioration has a much stronger influence on secondary degeneration. Through these findings, we demonstrate the potential contribution of myelin loss on neuronal degeneration at different disease stages and the usefulness of our statistical reduction technique which is not affected by the typical bias associated with approaches based on lesion masks.

Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis

The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). After AHSCT, 7 patients (22.6%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.

Long-Term Remissions With Use of High Dose Cyclophosphamide in Multiple Sclerosis

Background: In this study, the results of high dose intravenous monthly pulse CYC on patients with worsening relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) were evaluated. Methods: Fifty-six patients who presented with worsening RRMS (30) or SPMS (26) were to be treated with intravenous (IV) monthly pulse of 800 mg/m² CYC in the first year and bimonthly in the second year. We evaluated the results before treatment and after 12 and 24 months. Results: In the RRMS patients, after 2 years baseline EDSS had improved in 18, was unchanged in 5 and worse in 3. In RRMS group annual relapse rate was 0.92 at the beginning. it decreased to 0.23 in first year and to 0.23 in second year. The SPMS patients after 2 years baseline EDSS had improved in 5, was unchanged in 15 and worse in 3. In SPMS group annual relapse rate was 0.26 at the beggining. It decreased 0.13 in the first year and 0.04 in the second year. Conclusion: This study showed that high dose CYC treatment for two years was well tolerated and seemed effective for both RRMS and SPMS.

Evaluation of the Adherence to Immunmodulatory Treatment in Patients with Multiple Sclerosis.

In this article, we report the data regarding treatment adherence of a group of patients with multiple sclerosis (MS) and relapsing-remitting or secondary progressive disease who were followed in the MS outpatient clinic of Bozyaka Education and Research Hospital, Izmir. We collected the demographic data of 219 patients with MS who were treated with immunomodulatory drugs and the documentary data on the disease characteristics from the patient' files. Each patient was provided a detailed questionnaire regarding treatment adherence in addition to the Beck depression scale (BDS) and Paced Auditory Serial Addition Test (PASAT). Nonadherence was defined as the discontinuation of the drug, i.e., more than one dose a month for intramuscular interferon, six doses a month for glatiramer acetate, and four doses a month for subcutaneous interferons. Statistical analyses were performed using Medcalc statistics package. For those parameters with an even distribution, the paired samples t-test was used to compare the results. Of the 219 [183 relapsing remitting multiple sclerosis (RRMS) and 36 secondary progressive multiple sclerosis (SPMS)] patients included in the study, 143 patients were women and 76 were men. The mean age of the patients was 40.77±10.36 years. The mean expanded disability status scale (EDSS) score was 2.90±1.88, and mean annualized attack rate (ARR) was .65±.55. Of the 219 patients, 75.1% continued the immunomodulatory treatment. Thirty-three patients in the RRMS group and 23 patients in the SPMS group abandoned the immunomodulatory treatment. Treatment adherences were similar between patients with RRMS and SPMS (53%). Adherence revealed no correlation with age, ARR, PASAT score, and disease duration. However, higher EDSS and depression scores had significant positive correlation with adherence. Moreover, treatment adherence was noted to be lower in the group with higher education levels. Treatment discontinuation did not correlate with age, ARR, BDS, or PASAT scores. The disease duration and EDSS scores were found to be significantly correlated with treatment discontinuation. In this extensively followed up patients' group with multiple sclerosis, the ones with extended disease duration, higher disability, and more educated had higher rates of treatment discontinuation and lower levels of treatment adherence. The patient-reported outcomes and well-documented treatment adherence data will contribute to the neurologists' understanding of the patients' inclinations regarding the injectable treatments and help in better management of the immunomodulatory treatments.

Magnetization transfer ratio measures in normal-appearing white matter show periventricular gradient abnormalities in multiple sclerosis.

In multiple sclerosis, there is increasing evidence that demyelination, and neuronal damage occurs preferentially in cortical grey matter next to the outer surface of the brain. It has been suggested that this may be due to the effects of pathology outside the brain parenchyma, in particular meningeal inflammation or through cerebrospinal fluid mediated factors. White matter lesions are often located adjacent to the ventricles of the brain, suggesting the possibility of a similar outside-in pathogenesis, but an investigation of the relationship of periventricular normal-appearing white matter abnormalities with distance from the ventricles has not previously been undertaken. The present study investigates this relationship in vivo using quantitative magnetic resonance imaging and compares the abnormalities between secondary progressive and relapsing remitting multiple sclerosis. Forty-three patients with relapsing remitting and 28 with secondary progressive multiple sclerosis, and 38 healthy control subjects were included in this study. T1-weighted volumetric, magnetization transfer and proton density/T2-weighted scans were acquired for all subjects. From the magnetization transfer data, magnetization transfer ratio maps were prepared. White matter tissue masks were derived from SPM8 segmentations of the T1-weighted images. Normal-appearing white matter masks were generated by subtracting white matter lesions identified on the proton density/T2 scan, and a two-voxel perilesional ring, from the SPM8 derived white matter masks. White matter was divided in concentric bands, each ∼1-mm thick, radiating from the ventricles toward the cortex. The first periventricular band was excluded from analysis to mitigate partial volume effects, and normal-appearing white matter and lesion magnetization transfer ratio values were then computed for the 10 bands nearest to the ventricles. Compared with controls, magnetization transfer ratio in the normal-appearing white matter bands was significantly lower in patients with multiple sclerosis. In controls, magnetization transfer ratio was highest in the band adjacent to the ventricles and declined with increasing distance from the ventricles. In the multiple sclerosis groups, relative to controls, reductions in magnetization transfer ratio were greater in the secondary progressive multiple sclerosis compared with relapsing remitting multiple sclerosis group, and these reductions were greatest next to the ventricles and became smaller with distance from them. White matter lesion magnetization transfer ratio reductions were also more apparent adjacent to the ventricle and decreased with distance from the ventricles in both the relapsing remitting and secondary progressive multiple sclerosis groups. These findings suggest that in people with multiple sclerosis, and more so in secondary progressive than relapsing remitting multiple sclerosis, tissue structural abnormalities in normal-appearing white matter and white matter lesions are greatest near the ventricles. This would be consistent with a cerebrospinal fluid or ependymal mediated pathogenesis.

Leptin hormone level in serum of opticospinal, neuromyelitisoptica and multiple sclerosis patients

AbstractObjectivesA growing body of evidence shows that leptin acts as a pro‐inflammatory cytokine in autoimmune disorders and is related to multiple sclerosis (MS) pathogenesis. The present study was an analysis of serum leptin levels among healthy volunteers and patients with different subtypes of MS, opticospinal MS (OSMS) and neuromyelitis optica (NMO).MethodsLeptin concentrations in the sera of 121 healthy volunteers and 201 patients with different subtypes of MS, as well as in 27 NMO and 27 OSMS, were measured.ResultsSignificant differences in leptin serum levels were observed between healthy volunteers, and MS, OSMS and NMO patients (P &lt; 0.001). Furthermore, leptin serum concentration was in correlation with expanded disability status scale (EDSS) in primary progressive MS and secondary progressive MS groups. Interestingly, while the female‐to‐male ratio of leptin was approximately 2 in each group, the NMO female patients showed sevenfold higher levels of leptin than males.ConclusionThe present results show that leptin concentration is important in the pathogenesis of different neuroinflammatory diseases of the central nervous system, in particular NMO.

Functional connectivity changes within specific networks parallel the clinical evolution of multiple sclerosis

Background: In multiple sclerosis (MS), the location of focal lesions does not always correlate with clinical symptoms, suggesting disconnection as a major pathophysiological mechanism. Resting-state (RS) functional magnetic resonance imaging (fMRI) is believed to reflect brain functional connectivity (FC) within specific neuronal networks. Objective: RS-fMRI was used to investigate changes in FC within two critical networks for the understanding of MS disabilities, namely, the sensory-motor network (SMN) and the default-mode network (DMN), respectively, implicated in sensory-motor and cognitive functions. Methods: Thirty-four relapsing–remitting (RR), 14 secondary progressive (SP) MS patients and 25 healthy controls underwent MRI at 3T, including conventional images, T1-weighted volumes, and RS-fMRI sequences. Independent component analysis (ICA) was employed to extract maps of the relevant RS networks for every participant. Group analyses were performed to assess changes in FC within the SMN and DMN in the two MS phenotypes. Results: Increased FC was found in both networks of MS patients. Interestingly, specific changes in either direction were observed also between RR and SP MS groups. Conclusions: FC changes seem to parallel patients’ clinical state and capability of compensating for the severity of clinical/cognitive disabilities.