Secondary Progressive Disease Course Research Articles

Multimodal diagnostics in multiple sclerosis: predicting disability and conversion from relapsing-remitting to secondary progressive disease course – protocol for systematic review and meta-analysis

BackgroundThe number of patients diagnosed with multiple sclerosis (MS) has increased significantly over the last decade. The challenge is to identify the transition from relapsing-remitting to secondary progressive MS. Since...

Ocular motor impairment in early-stage multiple sclerosis: a video-oculography assessment

BackgroundEye movement disorders in multiple sclerosis (MS) are frequently misdiagnosed and frequently overlooked during clinical examinations. Even at a preclinical state, these defects frequently cause impairment and weariness.MethodsWe conducted a cross-sectional observational study including 20 individuals with a confirmed MS diagnosis. The inclusion criteria were an EDSS score of 4 or less and a 6-month interval between the last relapse and enrolment. As part of the MS assessment, a routine ORL, neurology exam, eye exam, assessment of eye movement using Ulmer’s videonystagmography battery tests, and routine brain MRI were performed on the patient.ResultsA total of 75% of the patients in our series are female, with a mean age of 39 years and a range of 24 to 59 years. The average age of MS onset is 32 years. The relapsing-remitting type of multiple sclerosis (RRMS) accounts for 95% of all cases. There is only a single case of secondary progressive disease course (SPMS). Principal VNG manifestations are related to subclinical eye movements abnormalities. Rotatory vertigo caused by vestibular dysfunction was less prevalent than other balance disorders. There were found to be two types of nystagmus: pendular and central positional nystagmus.Discussion and conclusionVNG is sensitive for detecting vestibular system dysfunction in MS patients. It is also beneficial for diagnosing subtle eye movement abnormalities that are usually overlooked.

ECTRIMS 2021 – Oral Presentations

Multiple sclerosis (MS) is a complex disease in which the innate and adaptive immune systems play a fundamental role and treatment with disease-modifying therapies (DMTs) reduces relapses of neurologic symptoms. Immune modulatory therapies have provided novel insights into disease pathology, for example, that long-neglected B cells actually play a relevant role or that early consequent treatment in the relapsing phase of the disease is able to prevent a later conversion into a secondary progressive disease course. When starting or switching treatment, it is essential to continuously monitor patients and perform the necessary laboratory assessment and vaccination status check-currently in particular against SARS-CoV2-as well as a thorough neurological examination and MRI of the brain at regular intervals (Wiendl, Gold . . . Zipp, Multiple Sclerosis Treatment Consensus Group (MSTKG): Position statement on disease modifying therapies for multiple sclerosis (white paper). TAND 2021, in press). Here, we will discuss whether, when and with which monitoring steps MS patients on DMT with poor response to treatment should switch to higher efficacy DMTs versus similar efficacy DMTs. When possible, published evidence should be taken into account, however many questions have not yet been addressed by larger investigations;here, consensus statements should be considered. Efficacy and potential risks as well as the intervals between different treatment regimens should be included in the decision-making process. Novel blood-based biomarkers such as neurofilaments might additionally help in patient treatment stratification (Bittner, Jiwon, Havrdova, Tintore, Zipp, The potential of serum neurofilament as biomarker for multiple sclerosis. Brain 2021). The overall goal is to achieve little-or ideally no-evidence of disease activity and also no progression independent of relapses (PIRA). However, addressing axonal damage in MS remains the largest challenge faced by clinical research and patient care.

Epilepsy as a predictor of disease progression in multiple sclerosis

Background: Epilepsy development during the course of multiple sclerosis (MS) is considered to be the result of cortical pathology. However, no long-term data exist on whether epilepsy in MS also leads to increasing disability over time. Objective: To examine if epilepsy leads to more rapid disease progression. Methods: We analyzed the data of 31,052 patients on the German Multiple Sclerosis Register in a case–control study. Results: Secondary progressive disease course (odds ratio (OR) = 2.23), age (OR = 1.12 per 10 years), and disability (OR = 1.29 per Expanded Disability Status Scale (EDSS) point) were associated with the 5-year prevalence of epilepsy. Patients who developed epilepsy during the course of the disease had a higher EDSS score at disease onset compared to matched control patients (EDSS 2.0 vs 1.5), progressed faster in each dimension, and consequently showed higher disability (EDSS 4.4 vs 3.4) and lower employment status (40% vs 65%) at final follow-up. After 15 years of MS, 64% of patients without compared to 54% of patients with epilepsy were not severely limited in walking distance. Conclusion: This work highlights the association of epilepsy on disability progression in MS, and the need for additional data to further clarify the underlying mechanisms.

Secondary Progressive Multiple Sclerosis: New Insights.

In most cases, multiple sclerosis (MS) begins with a relapsing-remitting course followed by insidious disability worsening that is independent from clinically apparent relapses and is termed secondary progressive MS (SMPS). Major differences exist between relapsing-remitting MS (RRMS) and SPMS, especially regarding therapeutic response to treatment. This review provides an overview of the pathology, differentiation, and challenges in the diagnosis and treatment of SPMS. We emphasize the criticality of conversion from a relapsing-remitting to a secondary progressive disease course not only because such conversion is evidence of disability progression, but also because, until recently, treatments that effectively reduced disability progression in relapsing MS were not proven to be effective in SPMS. Clear clinical, imaging, immunologic, or pathologic criteria marking the transition from RRMS to SPMS have not yet been established. Early identification of SPMS will require tools that, together with the use of appropriate treatments, may result in better long-term outcomes for the population of patients with SPMS.

Longitudinal Development of Peripapillary Hyper-Reflective Ovoid Masslike Structures Suggests a Novel Pathological Pathway in Multiple Sclerosis.

ObjectivePeripapillary hyper‐reflective ovoid masslike structures (PHOMS) are a new spectral domain optical coherence tomography (OCT) finding.MethodsThis prospective, longitudinal study included patients (n = 212) with multiple sclerosis (MS; n = 418 eyes), 59 healthy controls (HCs; n = 117 eyes), and 267 non‐MS disease controls (534 eyes). OCT and diffusion tensor imaging were used.ResultsThere were no PHOMS in HC eyes (0/117, 0%). The prevalence of PHOMS was significantly higher in patients with MS (34/212, p = 0.001) and MS eyes (45/418, p = 0.0002) when compared to HCs (0/59, 0/117). The inter‐rater agreement for PHOMS was 97.9% (kappa = 0.951). PHOMS were present in 16% of patients with relapsing–remitting, 16% of patients with progressive, and 12% of patients with secondary progressive disease course (2% of eyes). There was no relationship of PHOMS with age, disease duration, disease course, disability, or disease‐modifying treatments. The fractional anisotropy of the optic radiations was lower in patients without PHOMS (0.814) when compared to patients with PHOMS (0.845, p = 0.03). The majority of PHOMS remained stable, but increase in size and de novo development of PHOMS were also observed. In non‐MS disease controls, PHOMS were observed in intracranial hypertension (62%), optic disc drusen (47%), anomalous optic discs (44%), isolated optic neuritis (19%), and optic atrophy (12%).InterpretationThese data suggest that PHOMS are a novel finding in MS pathology. Future research is needed to determine whether development of PHOMS in MS is due to intermittently raised intracranial pressure or an otherwise impaired “glymphatic” outflow from eye to brain. ANN NEUROL 2020;88:309–319.

Atrophied Brain T2 Lesion Volume at MRI Is Associated with Disability Progression and Conversion to Secondary Progressive Multiple Sclerosis.

Background Atrophied T2 lesion volume at MRI is an imaging measure that reflects the replacement of T2 lesions by cerebrospinal fluid spaces in patients with multiple sclerosis (MS). Purpose To investigate the association of atrophied T2 lesion volume and development of disability progression (DP) and conversion to secondary progressive MS (SPMS). Materials and Methods This retrospective study included 1612 participants recruited from 2006 to 2016 and followed up for 5 years with clinical and MRI examinations. Accumulation of T2 lesion volume, atrophied T2 lesion volume, percentage brain volume change (PBVC), and percentage ventricular volume change (PVVC) were measured. Disability progression and secondary progressive conversion were defined by using standardized guidelines. Analysis of covariance (ANCOVA) adjusted for age and Cox regression adjusted for age and sex were used to compare study groups and explore associations between MRI and clinical outcomes. Results A total of 1314 patients with MS (1006 women; mean age, 46 years ± 11 [standard deviation]) and 124 patients with clinically isolated syndrome (100 women; mean age, 39 years ± 11) along with 147 healthy control subjects (97 women; mean age, 42 years ± 13) were evaluated. A total of 336 of 1314 (23%) patients developed DP, and in 67 of 1213 (5.5%) the disease converted from clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS) to SPMS. Patients with conversion to DP had higher atrophied T2 lesion volume (+34.4 mm3; 95% confidence interval [CI]: 17.2 mm3, 51.5 mm3; d = 0.27; P < .001) and PBVC (-0.21%; 95% CI: -0.36%, -0.05%; d = 0.19; P = .042) but not PVVC (0.36%; 95% CI: -0.93%, 1.65%; d = 0.04; P = .89) or T2 lesion volume change (-64.5 mm3; 95% CI: -315.2 mm3, 186.3 mm3; d = 0.03; P = .67) when compared with DP nonconverters. ANCOVA showed that atrophied T2 lesion volume was associated with conversion from CIS or RRMS to SPMS (+26.4 mm3; 95% CI: 4.2 mm3, 56.9 mm3; d = 0.23; P = .002) but not PBVC (-0.14%; 95% CI: -0.46%, 0.18%; d = 0.11; P = .66), PVVC (+0.18%; 95% CI: -2.49%, 2.72%; d = 0.01; P = .75), or T2 lesion volume change (-46.4 mm3; 95% CI: -460.8 mm3, 367.9 mm3; d = 0.03; P = .93). At Cox regression analysis, only atrophied T2 lesion volume was associated with the DP (hazard ratio, 1.23; P < .001) and conversion to SPMS (hazard ratio, 1.16; P = .008). Conclusion Atrophied brain T2 lesion volume is a robust MRI marker of MS disability progression and conversion into a secondary progressive disease course. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chiang in this issue.

Patients With Epileptic Seizures and Multiple Sclerosis in a Multiple Sclerosis Center in Southern Germany Between 2003-2015.

Background: So far, many studies have shown that the risk of developing seizures and epilepsy is higher among patients with multiple sclerosis (MS) than in the general population. However, the causal link between these two diseases is still unclear. In addition, it is not clearly understood whether and to what extent the manifestation of seizures and epilepsy in patients with MS affects the clinical course and the long-term prognosis of the disease. We aimed to retrospectively identify and describe patients with MS and with seizures and epilepsy which were seen at the Department of Neurology of the University of Regensburg in Germany between the years 2003–2015.Methods: With the help of the electronic documentation system of hospital admitted patients followed by scrutinizing medical records of patients with MS for evidence of seizures and epilepsy, we identified patients with MS and seizures or epilepsy.Results: We identified 22 individuals (1.74%) out of 1,267 patients with MS with seizures or epilepsy. 18 of these 22 individuals met criteria for epilepsy (1.42%). Nine MS patients (40.9%) suffered from relapsing-remitting MS (RRMS) whereas 11 MS patients (50.0%) showed a secondary progressive disease course (SPMS). Five of those (45.5%) converted from RRMS to SPMS before they acquired epilepsy. None of the identified patients with MS and seizures or epilepsy suffered from primary progressive MS (PPMS). Moreover, two MS patients (9.1%) had a history of seizures before MS onset. Seizures were of focal onset in 17 patients with MS (77.3%). Fourteen out of these 17 MS patients presented with focal to bilateral tonic-clonic seizures (82.4%). Five MS patients (22.7%) showed tonic clonic seizures of unknown onset. Status epilepticus was reported in three patients with MS (13%), for one patient the data was inconclusive.Conclusion: The occurrence of seizures and epilepsy was higher than in the general population, suggesting a causal relationship between both diseases. In most cases, seizures occurred after the first manifestation of MS. The high frequency of focal seizures supports the concept of cerebral lesions in patients with MS playing an important role in precipitation of seizures and epilepsy.

Cortical grey matter sodium accumulation is associated with disability and secondary progressive disease course in relapse-onset multiple sclerosis

ObjectiveSodium (23Na)-MRI is an emerging imaging technique to investigate in vivo changes in tissue viability, reflecting neuroaxonal integrity and metabolism. Using an optimised 23Na-MRI protocol with smaller voxel sizes and...

Progressive multiple sclerosis: latest therapeutic developments and future directions.

Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system leading to demyelination and neurodegeneration. While the initial presentation is mostly characterized by a relapsing–remitting disease, patients often progress naturally after 10–15 years to a secondary-progressive disease course. Another 10–15% present with an initial, primary-progressive MS course. Pathogenic mechanisms possibly driving progression include continued compartmentalized inflammation by T- and B-lymphocytes and cells of innate immunity, oxidative stress, iron accumulation, and consecutive mitochondrial damage, altogether leading to neurodegeneration with accumulation of disability. Increasing knowledge about pathogenic mechanisms involved in progressive MS helps to design more specific and precise therapeutic approaches. Successful examples are the B-cell targeting monoclonal antibody ocrelizumab, effective in primary progressive MS, and the sphingosine-1-receptor modulator siponimod, effective in active forms of secondary-progressive MS. Apart from that, other medications such as the B-cell targeted antibody ofatumumab, cladribine due to T- and B-cell depletion, and other sphingosine-1-receptor modulators such as ozanimod and ponesimod are under development. Moreover, some therapeutic approaches in preclinical stages are under development. In this review, we will summarize the newest therapeutic development in the field of progressive MS of the last 3 years, and shed light on auspicious substances with similar mechanisms and new developments in the therapeutic pipeline, presumably supporting a bright future for progressive MS treatment.

Therapeutic Application of Monoclonal Antibodies in Multiple Sclerosis.

Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disorder of the central nervous system (CNS). People with MS typically have a relapsing remitting disease course, with episodic neurological dysfunction corresponding to inflammation in the brain or spinal cord. Some relapsing patients develop a secondary progressive disease course, with accumulation of disability over time, yet other people with MS only experience a primary progressive course. Over the past 20 years, 14 immunomodulatory therapies have been approved in MS in order to reduce the frequency of inflammatory relapses and prevent CNS damage. Of the available types of therapies, the monoclonal antibodies are generally the most effective at dampening MS disease activity. In this review we will discuss the development of effective monoclonal antibody therapies coinciding with a better understanding of the complex immunopathogenesis of MS, both successes and failures, as well as targets for future development that address the mechanisms underlying progressive disease.

Ongoing Oxidative Stress Causes Subclinical Neuronal Dysfunction in the Recovery Phase of EAE.

Most multiple sclerosis (MS) patients develop over time a secondary progressive disease course, characterized histologically by axonal loss and atrophy. In early phases of the disease, focal inflammatory demyelination leads to functional impairment, but the mechanism of chronic progression in MS is still under debate. Reactive oxygen species generated by invading and resident central nervous system (CNS) macrophages have been implicated in mediating demyelination and axonal damage, but demyelination and neurodegeneration proceed even in the absence of obvious immune cell infiltration, during clinical recovery in chronic MS. Here, we employ intravital NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX1–4, DUOX1, 2) and, thus, to identify the cellular source of oxidative stress in the CNS of mice affected by experimental autoimmune encephalomyelitis (EAE) in the remission phase of the disease. This directly affects neuronal function in vivo, as monitored by cellular calcium levels using intravital FRET–FLIM, providing a possible mechanism of disease progression in MS.

Prognostic indicators of secondary progression in a paediatric-onset multiple sclerosis cohort in Kuwait

Background: The frequency of paediatric-onset multiple sclerosis (POMS) and the precise risk of secondary progression of disease are largely unknown in the Middle East. This cross-sectional cohort study assessed the risk and examined prognostic factors for time to onset of secondary progressive multiple sclerosis (SPMS) in a cohort of POMS patients. Methods: The Kuwait National MS Registry database was used to identify a cohort of POMS cases (diagnosed at age <18 years) from 1994 to 2013. Data were abstracted from patients’ records. A Cox proportional hazards model was used to evaluate the prognostic significance of the variables considered. Results: Of 808 multiple sclerosis (MS) patients, 127 (15.7%) were POMS cases. The median age (years) at disease onset was 16.0 (range 6.5–17.9). Of 127 POMS cases, 20 (15.8%) developed SPMS. A multivariable Cox proportional hazards model showed that at MS onset, brainstem involvement (adjusted hazard ratio 5.71; 95% confidence interval 1.53–21.30; P=0.010), and POMS patient age at MS onset (adjusted hazard ratio 1.38; 95% confidence interval 1.01–1.88; P=0.042) were significantly associated with the increased risk of a secondary progressive disease course. Conclusions: This study showed that POMS patients with brainstem/cerebellar presentation and a relatively higher age at MS onset had disposition for SPMS and warrant an aggressive therapeutic approach.

Contingent negative variation is associated with cognitive dysfunction and secondary progressive disease course in multiple sclerosis.

Background and PurposeThe relationship between contingent negative variation (CNV), which is an event-related potential, and cognition in multiple sclerosis (MS) has not been examined previously. The primary objective of the present study was thus to determine the association between CNV and cognition in a sample of MS patients.MethodsThe subjects of this study comprised 66 MS patients [50 with relapsing-remitting MS (RRMS) and 16 with secondary progressive MS (SPMS)] and 40 matched healthy volunteers. A neuropsychological battery was administered to all of the subjects; CNV recordings were made from the Cz, Fz, and Pz electrodes, and the amplitude and area under the curve (AUC) were measured at each electrode.ResultsRRMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls at Pz. SPMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls, and CNVs with a smaller amplitude than the RRMS patients at both Cz and Pz. After correcting for multiple comparisons, a lower CNV amplitude at Pz was significantly associated with worse performance on measures of speed of information processing, verbal fluency, verbal learning, and verbal recall.ConclusionsCNV may serve as a marker for disease progression and cognitive dysfunction in MS. Further studies with larger samples and wider electrode coverage are required to fully assess the value of CNV in these areas.

Modeling of cognitive impairment by disease duration in multiple sclerosis: a cross-sectional study.

Background/AimsLarge-scale population studies measuring rates and dynamics of cognitive decline in multiple sclerosis (MS) are lacking. In the current cross-sectional study we evaluated the patterns of cognitive impairment in MS patients with disease duration of up to 30 years.Methods1,500 patients with MS were assessed by a computerized cognitive battery measuring verbal and non-verbal memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Cognitive impairment was defined as below one standard deviation (SD) and severe cognitive impairment as below 2SD for age and education matched healthy population norms.ResultsCognitive performance in our cohort was poorer than healthy population norms. The most frequently impaired domains were information processing speed and executive function. MS patients with secondary-progressive disease course performed poorly compared with clinically isolated syndrome, relapsing-remitting and primary progressive MS patients. By the fifth year from disease onset, 20.9% of patients performed below the 1SD cutoff for impairment, p = 0.005, and 6.0% performed below the 2SD cutoff for severe cognitive impairment, p = 0.002. By 10 years from onset 29.3% and 9.0% of patients performed below the 1SD and 2SD cutoffs, respectively, p = 0.0001. Regression modeling suggested that cognitive impairment may precede MS onset by 1.2 years.ConclusionsThe rates of cognitive impairment in this large sample of MS patients were lower than previously reported and severe cognitive impairment was evident only in a relatively small group of patients. Cognitive impairment differed significantly from expected normal distribution only at five years from onset, suggesting the existence of a therapeutic window during which patients may benefit from interventions to maintain cognitive health.

Changes in CD4+ T cell affinity for MOG do not correlate with symptom relapse or remission in secondary progressive demyelinating disease (P4109)

Abstract We investigated the role of CD4 T cell frequency and affinity in the nonobese diabetic (NOD) mouse model of EAE. This model is clinically relevant in its MHC-class II-associated proclivity to autoimmune disease and its tendency to follow a secondary progressive disease course that resembles that seen in the majority of MS patients. Using the NOD model, we quantified the affinity of CD4 T cells for myelin oligodendrocyte glycoprotein (MOG) at initial peak of disease, symptom remission and at chronic disease time points. We used the micropipette adhesion frequency assay to obtain a sensitive and physiologically relevant two dimensional measurement of T-cell receptor affinity for peptide:MHC in a cell-anchored system. This assay allows us to quantify both frequency and affinity of antigen-specific CD4 T cells that are minimally detected by MHC-class II tetramer-based assays. Our data demonstrated that CD4 T cells isolated from the CNS at the initial peak of disease have similar affinities to those isolated at remission and chronic time points. However, CNS-infiltrating Tregs were roughly twice as frequent at disease remission as compared to initial peak of disease (p&amp;lt;0.0001). Additionally, changes in the distribution of cytokine-producing CD4 T cells seemed to contribute to the remission of symptomatic disease. Thus, Treg frequency and effector cytokine profile determined remission and relapse of symptoms and this progression was independent of changes in T cell affinity.

Pediatric Multiple Sclerosis

Pediatric multiple sclerosis has been increasingly recognized in the past 10 to 15 years; 3% to 5% of all multiple sclerosis patients experience their first attack in childhood. Childhood multiple sclerosis has a relapsing-remitting disease course. The first attack, or "acquired demyelinating syndrome," consists of optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, and monofocal or polyfocal neurological deficits. The diagnosis of multiple sclerosis necessitates the clinical or magnetic resonance imaging confirmation of dissemination in space and time and exclusion of other disorders. The morbidity of childhood multiple sclerosis is significant; within the first 2 years from onset, 30% of children have significant cognitive impairment, 50% show signs of depression, and 75% are fatigued. The relapse rate in children with multiple sclerosis is higher than in adult-onset disease. Following acute treatment, recovery after the first attacks is usually excellent, but patients with childhood-onset multiple sclerosis reach permanent disability or enter the secondary progressive disease course 10 years younger than patients with adult-onset multiple sclerosis.

3D GRASE arterial spin labelling reveals an inverse correlation of cortical perfusion with the white matter lesion volume in MS

Background: We hypothesized that in multiple sclerosis (MS) patients, reduced cortical perfusion is associated with chronic white matter injury. Objective: To investigate the influence of different clinical and magnetic resonance imaging characteristics on cortical perfusion. Methods: Cerebral blood flow (CBF) was assessed by applying a pulsed arterial spin labelling (ASL) technique combined with single-shot 3D-GRASE (gradient-spin echo) in a cohort of 165 MS patients with a relapsing–remitting (n=123) or secondary progressive disease course (n=42). Mean age was 45.4 years (20–68 years), mean disease duration was 14.2 years (1–48 years). Results: Mean cortical CBF was 45.6 ml/100g per min (SD: 7.8 ml/100g per min). Stepwise multiple linear regression models were calculated to investigate the relationship between different factor sets and mean CBF. The model with the highest adjusted coefficient of determination included T2 lesion load, age, gender and disease duration as significant factors. Post-hoc Spearman rank correlation revealed significant correlation of adjusted CBF with T2 lesion load (t=−0.35, p=1*10–6), with age (t =−0.34, p=4*10–6), and with disease duration (t=0.16, p=0.03), while Expanded Disability Status Scale (EDSS) did not reach significance in either model. Conclusion: This study suggests that the amount of white matter lesions indicates a reduced metabolic demand and reduced perfusion at a cortical level.

Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience

Background: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. Objectives: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. Methods: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8–126) months. Results: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing–remitting course (31%) had a 6–12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. Conclusions: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing–remitting phase of the disease.

Effects of whole-body cryotherapy on a total antioxidative status and activities of antioxidative enzymes in blood of depressive multiple sclerosis patients

Objectives. Oxidative stress (OS) plays an important role in the pathogenesis of multiple sclerosis (MS). In MS patients depression is often observed. Cryotherapy might have an effect on OS. The aim of this study was to compare the effects of whole body cryotherapy (WBCT) on changes in total antioxidative status (TAS) of plasma and activities of antioxidative enzymes in erythrocytes from depressive and non depressive MS patients. Methods. Twenty-two MS patients with secondary progressive disease course (12 depressive and 10 non depressive) were treated with 10 exposures in a cryochamber. Before and after WBCT the plasma TAS and the activities of superoxide dismutase (SOD) and catalase (CAT) in the erythrocytes were measured. Results. The level of TAS in depressive MS group was significantly lower than in non depressive MS (P < 0.0003). WBCT increased the level of TAS in depressive (P < 0.002) more than in non depressive MS patients (P < 0.01). WBCT treatment of MS patients resulted in the significant increase of TAS level in plasma but had no effects on activities of SOD and CAT. Conclusions. Our results indicate that WBCT suppresses OS in MS patients, especially in depressive patients.