Interferon beta-1a sc at 25 years: a mainstay in the treatment of multiple sclerosis over the period of one generation.

INTRODUCTION: Interferon beta (IFN beta) preparations are an established group of drugs used for immunomodulation in patients with multiple sclerosis (MS). Subcutaneously (sc) applied interferon beta-1a (IFN beta-1a sc) has been in continuous clinical use for 25 years as a disease-modifying treatment. AREAS COVERED: Based on data published since 2018, we discuss recent insights from analyses of the pivotal trial PRISMS and its long-term extension as well as from newer randomized studies with IFN beta-1a sc as the reference treatment, the use of IFN beta-1a sc across the patient life span and as a bridging therapy, recent data regarding the mechanisms of action, and potential benefits of IFN beta-1a sc regarding vaccine responses. EXPERT OPINION: IFN beta-1a sc paved the way to effective immunomodulatory treatment of MS, enabled meaningful insights into the disease process, and remains a valid therapeutic option in selected vulnerable MS patient groups.

Validity of an inertial sensor-based system for the assessment of spatio-temporal parameters in people with multiple sclerosis.

Background: Gait variability in people with multiple sclerosis (PwMS) reflects disease progression or may be used to evaluate treatment response. To date, marker-based camera systems are considered as gold standard to analyze gait impairment in PwMS. These systems might provide reliable data but are limited to a restricted laboratory setting and require knowledge, time, and cost to correctly interpret gait parameters. Inertial mobile sensors might be a user-friendly, environment- and examiner-independent alternative. The purpose of this study was to evaluate the validity of an inertial sensor-based gait analysis system in PwMS compared to a marker-based camera system. Methods: A sample N = 39 PwMS and N = 19 healthy participants were requested to repeatedly walk a defined distance at three different self-selected walking speeds (normal, fast, slow). To measure spatio-temporal gait parameters (i.e., walking speed, stride time, stride length, the duration of the stance and swing phase as well as max toe clearance), an inertial sensor system as well as a marker-based camera system were used simultaneously. Results: All gait parameters highly correlated between both systems (r > 0.84) with low errors. No bias was detected for stride time. Stance time was marginally overestimated (bias = -0.02 ± 0.03 s) and gait speed (bias = 0.03 ± 0.05 m/s), swing time (bias = 0.02 ± 0.02 s), stride length (0.04 ± 0.06 m), and max toe clearance (bias = 1.88 ± 2.35 cm) were slightly underestimated by the inertial sensors. Discussion: The inertial sensor-based system captured appropriately all examined gait parameters in comparison to a gold standard marker-based camera system. Stride time presented an excellent agreement. Furthermore, stride length and velocity presented also low errors. Whereas for stance and swing time, marginally worse results were observed.

Stability of sensor-based gait parameters reassessed after a period of one year in people with multiple sclerosis.

BACKGROUND: Currently, there are several studies showing that wearable inertial sensors are highly sensitive in the detection of gait disturbances in people with multiple sclerosis (PwMS), showing excellent reliability within one or 7-14 days. However, it is not known how stable these gait parameters remain over a longer period of time. This is surprising, because many treatments last longer than two weeks. Thus, the purpose of the current study was to examine gait parameters obtained by means of wearable inertial sensors during a 6-min walk and to reassess these parameters after a period of one year. METHODS: Fifty PwMS (without a relapse or a recent change in the Expanded Disability Status Scale (EDSS) or treatment) and 20 healthy participants were examined at two assessment points (interval between assessments: 14.4 ± 6.6 months). At each assessment point, all participants had to complete a 6-min walking test, an observer-rater test (Berg Balance Scale, BBS) and a Timed-up and Go Test (TUG). To measure mean gait parameters (i.e. walking speed, stride length, stride time, the duration of the stance and swing phase and minimum toe-to-floor distance), as well as the intraindividual standard deviation of each mean gait parameter, wearable inertial sensors were utilized. RESULTS: We found that even after one year all mean gait parameters showed excellent Intraclass Correlation Coefficients (ICC between 0.75 and 0.95) in PwMS. Looking at MS subgroups, the ICCs were slightly higher in MS subgroup 2 (EDSS 2.0-5.0) than those in MS subgroup 1 (EDSS 0.0-1.5) and healthy controls. Compared to the mean gait parameters, parameters of gait variability showed only good-to-fair ICC values in PwMS. Concerning BBS and TUG, the ICC values after one year were close to the ICC values of the measured mean gait parameters. CONCLUSIONS: Due to the excellent stability of mean gait parameters after one year, these sensor-based gait parameters can be identified as clinically relevant markers to evaluate treatment effects over a longer (several months) period of time in MS.

The congruency of neuropsychological and F18-FDG brain PET/CT diagnostics of Alzheimer's Disease (AD) in routine clinical practice: insights from a mixed neurological patient cohort.

BACKGROUND: Diagnostics of Alzheimer's Disease (AD) require a multimodal approach. Neuropsychologists examine the degree and etiology of dementia syndromes and results are combined with those of cerebrospinal fluid markers and imaging data. In the diagnostic process, neuropsychologists often rely on anamnestic and clinical information, as well as cognitive tests, prior to the availability of exhaustive etiological information. The congruency of this phenomenological approach with results from FDG-PET/CT examinations remains to be explored. The latter yield highly accurate diagnostic information. METHOD: A mixed sample of N = 127 hospitalized neurological patients suspected of displaying a dementia syndrome underwent extensive neuropsychological and FDG-PET/CT examinations. Neuropsychological examinations included an anamnestic and clinical interview, and the CERAD cognitive test battery. Two decisional approaches were considered: First, routine diagnostic results were obtained, i.e. the final clinical decision of the examining neuropsychologist (ADClinical vs. non-ADClinical). Secondly, a logistic regression model was implemented, relying on CERAD profiles alone. CERAD subscales that best predicted AD based on FDG-PET/CT were identified and a nominal categorization obtained (ADTest vs. non-ADTest). Congruency of results from both approaches with those of the FDG-PET/CT (ADPET vs. non-ADPET) were estimated with Cohen's Kappa (κ) and Yule's Y coefficient of colligation. Descriptive estimates of accuracy, sensitivity and specificity of CERAD relative to FDG-PET/CT diagnostics were derived. RESULTS: ADPET patients constituted N = 33/127 (26%) of the sample. The clinical decision approach (ADClinical vs. non-ADClinical) showed substantial agreement with the FDG-PET/CT classification (κ = .69, Y = .72) involving good accuracy (84.2%), moderate sensitivity (75.8%) and excellent specificity (92.6%). In contrast, the decisional approach that relied on CERAD data alone (ADTest vs. non-ADTest) involved only moderate agreement with the FDG-PET/CT (κ = .54, Y = .62) with lower accuracy (74.8%), attributable to decreased sensitivity (56.3%) and comparable specificity (93.3%). CONCLUSIONS: It is feasible to identify AD through a comprehensive neuropsychological examination in a mixed sample of neurological patients. However, within the boundaries of methods applied here, decisions based on cognitive test results alone appear limited. One may conclude that the clinical impression based on anamnestic and clinical information obtained by the neuropsychological examiner plays a crucial role in the identification of AD patients in routine clinical practice.

Mindfulness training during brief periods of hospitalization in multiple sclerosis (MS): beneficial alterations in fatigue and the mediating role of depression.

OBJECTIVES: Persons with MS (PwMS) are frequently affected by fatigue and depression. Mindfulness-based interventions may reduce these symptoms in PwMS and consequently their application has been extended to various settings. Only few efforts have been made to explore effects of short-term mindfulness training during brief periods of hospitalization. In the current study, the feasibility and potential effects of short-term mindfulness training on depression, fatigue, rumination and cognition were explored in PwMS in an acute-care hospital setting. Based on previous work, it was further examined whether the relation between trait mindfulness and fatigue prior to and following the intervention was mediated by depression and whether a mediation effect was also observable throughout the intervention. METHODS: A short-term mindfulness training protocol was developed, tailored to the requirements of the acute-care setting. Subsequently, 30 PwMS were recruited sequentially and received mindfulness training during the routine clinical process (median duration in hospital: eight days, number of sessions: four). Participants completed relevant self-report measures (depression, fatigue, rumination) and a neuropsychological assessment before and after training. RESULTS: Participants reported significantly increased trait mindfulness and decreased depression and fatigue following the intervention. Respective change scores were highly correlated so that increased trait mindfulness was associated with decreased symptoms. In the rumination domain, patients reported a tendency for an increased adaptive ability to engage in distractive behavior during arising negative mood. Other measures of trait rumination and cognition remained relatively stable. Results of the mediation analyses indicated that depression mediated the negative relationship between trait mindfulness and fatigue symptoms at pre and post assessments. With regards to the change scores, an association between mindfulness and cognitive fatigue ceased to be significant when depression was controlled, albeit in this case, the mediation effect did not reach significance. CONCLUSION: Results of the current study indicate that short-term mindfulness training during brief periods of hospitalization may be beneficial for PwMS. They further complement previous work by identifying depression as a potential mediator of the antagonistic relationship between mindfulness and fatigue. Based on the current exploratory study, future trials are warranted to address this mechanism of mindfulness training in more detail.

Wearable inertial sensors are highly sensitive in the detection of gait disturbances and fatigue at early stages of multiple sclerosis.

BACKGROUND: The aim of the current study was to examine multiple gait parameters obtained by wearable inertial sensors and their sensitivity to clinical status in early multiple sclerosis (MS). Further, a potential correlation between gait parameters and subjective fatigue was explored. METHODS: Automated gait analyses were carried out on 88 MS patients and 31 healthy participants. To measure gait parameters (i.e. walking speed, stride length, stride duration, duration of stance and swing phase, minimal toe-to-floor distance), wearable inertial sensors were utilized throughout a 6-min 25-ft walk. Additionally, self-reported subjective fatigue was assessed. RESULTS: Mean gait parameters consistently revealed significant differences between healthy participants and MS patients from as early as an Expanded Disability Status Scale (EDSS) value of 1.5 onwards. Further, MS patients showed a significant linear trend in all parameters, reflecting continuously deteriorating gait performance throughout the test. This linear deterioration trend showed significant correlations with fatigue. CONCLUSIONS: Wearable inertial sensors are highly sensitive in the detection of gait disturbances, even in early MS, where global scales such as the EDSS do not provide any clinical information about deviations in gait behavior. Moreover, these measures provide a linear trend parameter of gait deterioration that may serve as a surrogate marker of fatigue. In sum, these results suggest that classic timed walking tests in routine clinical practice should be replaced by readily and automatically applicable gait assessments, as provided by inertial sensors.

Measuring Gait Stability in People with Multiple Sclerosis Using Different Sensor Locations and Time Scales.

The evaluation of local divergence exponent (LDE) has been proposed as a common gait stability measure in people with multiple sclerosis (PwMS). However, differences in methods of determining LDE may lead to different results. Therefore, the purpose of the current study was to determine the effect of different sensor locations and LDE measures on the sensitivity to discriminate PwMS. To accomplish this, 86 PwMS and 30 healthy participants were instructed to complete a six-minute walk wearing inertial sensors attached to the foot, trunk and lumbar spine. Due to possible fatigue effects, the LDE short (~50% of stride) and very short (~5% of stride) were calculated for the remaining first, middle and last 30 strides. The effect of group (PwMS vs. healthy participants) and time (begin, mid, end) and the effect of Expanded Disability Status Scale (EDSS) and time were assessed with linear random intercepts models. We found that perturbations seem to be better compensated in healthy participants on a longer time scale based on trunk movements and on a shorter time scale (almost instantaneously) according to the foot kinematics. Therefore, we suggest to consider both sensor location and time scale of LDE when calculating local gait stability in PwMS.

Subcutaneous Interferon Beta Therapy in Multiple Sclerosis Patients - Characterization of Injection Site Reactions and Flu-Like Symptoms in a Daily Practice Setting - Results from the Non-Interventional Study PERFECT.

PURPOSE: The purpose of this study was to assess the prevalence of injection site reactions (ISR) and flu-like symptoms (FLS) during treatment with subcutaneous (SC) interferon (IFN) beta therapies and to document measures to mitigate and prevent ISR and FLS. PATIENTS AND METHODS: The cross-sectional post-authorization safety study PERFECT was conducted from 11/2017 to 7/2019 in neurology practices in Germany. Adult patients with relapsing-remitting multiple sclerosis (MS) receiving SC IFN beta for ≥3 months were eligible. The primary endpoints were patient-reported prevalence of ISR and FLS. Additional endpoints reported by patients, MS nurses, and neurologists included type, frequency, duration, time of occurrence, and management of ISR and FLS. RESULTS: In total, 603 patients (median age 45 years [range 36-53], 74% female) were included in the analysis. Time since MS diagnosis was >5 years in most patients. The majority had received none (64%) or 1 (22%) prior therapy. Current MS therapy in 36%, 32%, and 30% of patients was IFN beta-1b, IFN beta-1a, and peginterferon beta-1a, respectively. ISR and FLS under current therapy were reported by 84% and 68% of patients, respectively. ISR developed within 5 days after injection (84%) and lasted for 2-14 days (53%) in most patients. The most frequent patient-reported symptom was erythema (39%). ISR resolved or abated with systemic treatments or topical ointments. Most frequent preventive measures included alternating injection sites (58%). Occurrence of ISR rarely resulted in treatment interruption (5%). FLS occurred predominantly up to 6 h after injection (40%) and lasted <12 h (26%). The most frequent patient-reported symptoms were fatigue (15%) and aching limbs (15%). Assessments by physicians and MS nurses differed from patient-reported results. CONCLUSION: Although ISR were experienced by the majority of patients, they rarely resulted in treatment interruption. In this real-world setting, ISR and FLS management was in line with published expert recommendations.

Trait mindfulness is primarily associated with depression and not with fatigue in multiple sclerosis (MS): implications for mindfulness-based interventions.

OBJECTIVES: Persons with MS (PwMS) often display symptoms of depression and fatigue. Mindfulness-based interventions are known to counteract these symptoms. However, to-date the exact relations between trait mindfulness, depression and fatigue remain to be examined. Fatigue is generally regarded as a symptom immanent to the disease and as a direct neurobiological consequence of increased cytokine levels and cortical atrophy. In depression on the other hand, psychosocial factors in the context of adaptation difficulties are probably of higher relevance. Hence, one may argue that mindfulness, as a trait that promotes successful adaption, may show a strong negative association with depression and a relatively minor negative association with fatigue in PwMS. METHODS: In the current study, the association between self-reported trait mindfulness, fatigue and depression was examined in a sample of 69 PwMS. RESULTS: Trait mindfulness showed highly significant negative correlations with both, depression and fatigue. Mediation analyses however, revealed that depression mediated the relation between mindfulness and fatigue. CONCLUSION: It may be concluded that in PwMS, trait mindfulness shows a genuine negative association with depression, but that it is only secondarily associated with fatigue. Implications for mindfulness-based interventions in MS are discussed. Based on the results of the current study, it may be feasible to promote the acceptance of default fatigue symptoms, instead of an actual reduction of fatigue symptoms.

Frontal brain activity and cognitive processing speed in multiple sclerosis: An exploration of EEG neurofeedback training.

BACKGROUND: Cognitive deficits including impaired information processing speed as assessed by the Symbol Digit Modalities Test (SDMT) are common in multiple sclerosis (MS). Oscillatory markers of processing speed may be extracted from magnetoencephalographic (MEG) and electroencephalographic (EEG) resting-state recordings. In this context, an increased proportion of frontal slow-wave (theta, 4-8 Hz) to fast-wave (beta, 13-30 Hz) EEG activity was indicative of impaired SDMT performance. Such an increased theta/beta ratio may reflect oscillatory slowing associated with deficits in attention control. Therapeutic approaches that consider atypical oscillatory activity in MS remain sparse. OBJECTIVES: In a cross-sectional design, we examined the relation between SDMT performance, the EEG theta/beta ratio and its components. We also explored longitudinally, whether EEG neurofeedback could be used to induce a putatively adaptive alteration in these EEG parameters, toward a pattern indicative of improved processing speed. METHODS: N = 58 MS patients (RRMS/SPMS/PPMS N: 18/35/3, 2 cases excluded) participated in a neuropsychological examination and a resting-state EEG recording. Subsequently, N = 10 patients received neurofeedback training for two weeks in a hospitalized setting. The purpose was to reduce the frontal theta/beta ratio through operant conditioning. RESULTS: In the cross-sectional examination, patients with slow SDMT speed displayed an increased theta/beta ratio, relative to those with normal speed. This involved increased frontal theta power, whereas beta power was equal across groups. The theta/beta ratio remained stable during neurofeedback across sessions of the two-week training period. In an exploratory secondary analysis, within sessions a reduction in the theta/beta ratio during active training blocks relative pre/post session resting-states was observed, driven by reduced theta power. CONCLUSIONS: These findings provide support for utilizing frontal EEG theta activity as an inverse marker of processing speed in MS. Across sessions, there was no support for successful operant conditioning of the theta/beta ratio during the two-week training period. The observed state-specific shift within sessions, involving a transient reduction in theta activity, nevertheless may provide a rationale for a further investigation of neurofeedback as a treatment approach in MS.

Reasons to switch: a noninterventional study evaluating immunotherapy switches in a large German multicentre cohort of patients with relapsing-remitting multiple sclerosis.

BACKGROUND: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies. METHODS: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014-2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman's wish to become pregnant. Expectations of the new DMT and patients' assessment of the decision maker were also recorded. RESULTS: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients. CONCLUSIONS: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden.

Exploring resting-state EEG brain oscillatory activity in relation to cognitive functioning in multiple sclerosis.

OBJECTIVE: Neurophysiologic monitoring parameters related to cognition in Multiple Sclerosis (MS) are sparse. Previous work reported an association between magnetoencephalographic (MEG) alpha-1 activity and information processing speed. While this remains to be replicated by more available electroencephalographic (EEG) methods, also other established EEG markers, e.g. the slow-wave/fast-wave ratio (theta/beta ratio), remain to be explored in this context. METHODS: Performance on standard tests addressing information processing speed and attention (Symbol-Digit Modalities Test, SDMT; Test of Attention Performance, TAP) was examined in relation to resting-state EEG alpha-1 and alpha-2 activity and the theta/beta ratio in 25MS patients. RESULTS: Increased global alpha-1 and alpha-2 activity and an increased frontal theta/beta ratio (pronounced slow-wave relative to fast-wave activity) were associated with lower SDMT processing speed. In an exploratory analysis, clinically impaired attention was associated with a significantly increased frontal theta/beta ratio whereas alpha power did not show sensitivity to clinical impairment. CONCLUSIONS: EEG global alpha power and the frontal theta/beta ratio were both associated with attention. The theta/beta ratio involved potential clinical sensitivity. SIGNIFICANCE: Resting-state EEG recordings can be obtained during the routine clinical process. The examined resting-state measures may represent feasible monitoring parameters in MS. This notion should be explored in future intervention studies.

Measuring standing balance in multiple sclerosis: Further progress towards an automatic and reliable method in clinical practice.

BACKGROUND: Balance deficits in multiple sclerosis (MS) are often monitored by means of observer-rated tests. These may provide reliable data, but may also be time-consuming, subject to inter-rater variability, and potentially insensitive to mild fluctuations throughout the clinical course. On the other hand, laboratory assessments are often not available. The Nintendo Wii Balance Board (WBB) may represent a low-cost solution. The purpose of the current study was to examine the methodological quality of WBB data in MS (internal consistency, test-retest reliability), convergent validity with observer-rated tests (Berg Balance Scale, BBS; Timed-Up and Go Test, TUG), and discriminative validity concerning clinical status (Expanded Disability Status Scale, EDSS). METHODS: Standing balance was assessed with the WBB for 4min in 63 MS patients at two assessment points, four months apart. Additionally, patients were examined with the BBS, TUG and the EDSS. RESULTS: A period of 4min on the WBB provided data characterized by excellent internal consistency and test-retest reliability. Significant correlations between WBB data and results of the BBS and TUG were obtained after merely 2min on the board. An EDSS median-split revealed that higher EDSS values (>3) were associated with significantly increased postural sway on the WBB. CONCLUSIONS: WBB measures reflecting postural sway are methodologically robust in MS, involving excellent internal consistency and test-retest reliability. They are also characterized by convergent validity with other considerably lengthier observer-rated balance measures (BBS) and sensitive to broader clinical characteristics (EDSS). The WBB may hence represent an effective, easy-to-use monitoring tool for MS patients in clinical practice.

Cognitive screening in Multiple Sclerosis: the Five-Point Test as a substitute for the PASAT in measuring executive function.

OBJECTIVE: The Paced Auditory Serial Addition Test (PASAT) is frequently employed to measure executive functions in patients with Multiple Sclerosis (MS). In the past, the PASAT has often been criticized because of its stressful and demanding requirements. Continuous utilization might also reduce its validity. The Five-Point Test (FPT) by Regard, Strauss, and Knapp ((1982) Children's production on verbal and non-verbal fluency tasks. Perceptual and Motor Skills, 55, 839-844.) is a short test of figural fluency which might serve as a substitute. METHOD: 116 patients diagnosed with MS were tested with a short version of the Brief Repeatable Battery (BRB) by Rao and the Cognitive Function Study Group of the National Multiple Sclerosis Society including the PASAT, as well as the FPT. A factor analysis was computed and the frequency of cognitive impairment was calculated for both the original short version of the BRB and the alternative version (involving the FPT). RESULTS: In the factor analysis, PASAT and FPT loaded highest on the same factor (two factors were extracted). The estimation of the frequency of cognitive impairment showed that replacing the PASAT with the FPT did not considerably alter the proportion of patients identified as cognitively impaired. CONCLUSIONS: The FPT proved to be a viable alternative to the PASAT in this study. It may be recommended as a possible replacement in neuropsychological screening of MS-patients with the advantage of avoiding the indicated limitations of the PASAT.

Cognitive screening tools in multiple sclerosis revisited: sensitivity and specificity of a short version of Rao's Brief Repeatable Battery.

BACKGROUND: Cognitive deficits are common in multiple sclerosis (MS) and require continuous monitoring. In routine examinations, screening instruments such as the Brief Repeatable Battery (BRB) may serve this purpose. It was suggested that even a shortened version of the BRB, comprising the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT) and Selective Reminding Test (SRT), may be feasible. However, an evaluation of sensitivity and specificity of the short BRB in comparison to an independent battery of established tests has not yet occurred. Therefore in the current study, this short version of the BRB was matched against the gold standard of an extensive test battery comprehensively assessing neuropsychological functions. METHODS: 127 MS-patients were tested with a short version of the BRB and an extensive procedure. The latter served as the gold standard for defining sensitivity and specificity. RESULTS: For subtests of the short BRB, estimates of sensitivity (38-44 %) and specificity (81-94 %) were obtained. Combining subtests into a single indicator of cognitive deficits yielded increased sensitivity (78 %), while reducing specificity (65 %). CONCLUSION: The short BRB is reasonably sensitive and specific in detecting cognitive deficits. However, these qualities only emerge, if the short BRB is administered as a whole, whereas sensitivity is considerably lower than suggested by previous work, when relying on subtests separately (SDMT, PASAT, SRT). While the short BRB may not be regarded as conclusive as an extensive test battery, it represents a valid and economic screening instrument.

Dynamic walking features and improved walking performance in multiple sclerosis patients treated with fampridine (4-aminopyridine).

BACKGROUND: Impaired walking capacity is a frequent confinement in Multiple Sclerosis (MS). Patients are affected by limitations in coordination, walking speed and the distance they may cover. Also abnormal dynamic walking patterns have been reported, involving continuous deceleration over time. Fampridine (4-aminopyridine), a potassium channel blocker, may improve walking in MS. The objective of the current study was to comprehensively examine dynamic walking characteristics and improved walking capacity in MS patients treated with fampridine. METHODS: A sample of N = 35 MS patients (EDSS median: 4) underwent an electronic walking examination prior to (Time 1), and during treatment with fampridine (Time 2). Patients walked back and forth a distance of 25 ft for a maximum period of 6 min (6-minute 25-foot-walk). Besides the total distance covered, average speed on the 25-foot distance and on turns was determined separately for each test minute, at Time 1 and Time 2. RESULTS: Prior to fampridine administration, 27/35 patients (77 %) were able to complete the entire 6 min of walking, while following the administration, 34/35 patients (97 %) managed to walk for 6 min. In this context, walking distance considerably increased and treatment was associated with faster walking and turning across all six test minutes (range of effect sizes: partial eta squared = .34-.72). Importantly, previously reported deceleration across test minutes was consistently observable at Time 1 and Time 2. DISCUSSION: Fampridine administration is associated with improved walking speed and endurance. Regardless of a treatment effect of fampridine, the previously identified, abnormal dynamic walking feature, i.e. the linear decline in walking speed, may represent a robust feature. CONCLUSIONS: The dynamic walking feature might hence be considered as a candidate for a new outcome measure in clinical studies involving interventions other than symptomatic treatment, such as immune-modulating medication. TRIAL REGISTRATION: DRKS00009228 (German Clinical Trials Register). Date obtained: 25.08.2015.

Use of a telestroke service for evaluation of non-stroke neurological cases.

Telemedicine is a growing field in many medical specialties. Within clinical neurosciences one of its largest applications is in acute stroke care. However, little is known about its value and effect in general neurology, despite stroke. In a retrospective survey of 1500 teleconsultations over a time period of 12 months from October 2008 to September 2009, from a large telestroke network in Germany, we evaluated 352 cases with a non-stroke diagnosis. Duration and methods of teleconsultation as well as neurological consultations at bedside and discharge diagnosis were analyzed and compared to stroke cases. Discharge diagnosis was not identical to teleconsultation diagnosis in 48.9% of all non-stroke cases compared to 12.5% of all stroke cases. Duration of teleconsultation was 26.5 min in non-stroke cases compared to 14.3 min for stroke cases. In non-stroke cases other parts of the neurological examination were added to the pure administration of a stroke scale. There were no significant differences between non-stroke cases with correct and incorrect consultation diagnoses concerning in-hospital mortality (4.6 vs. 5.0%) and length of hospital stay (8.3 vs. 7.6 days). We conclude that diagnostic accuracy and protocol routine is not as exact in non-stroke cases compared to acute stroke cases. Other neurologic conditions may need different algorithms for a telemedicine service. Thus experience from a telestroke service cannot be transferred to other neurologic conditions on a routine basis.

Feasibility of certified quality management in a comprehensive stroke care network using telemedicine: STENO project.

BACKGROUND: Stroke care networks with and without telemedicine have been established in several countries over the last decade to provide specialized stroke expertise to patients in rural areas. Acute consultation is a first step in the management of stroke, but not the only one. Methods of standardization of care and treatment are much needed. So far, quality management systems have only been used for single stroke units. To the best of our knowledge, we are the first stroke network worldwide to aim for certification of a network-wide quality management system. METHODS: The Stroke Network Using Telemedicine in Northern Bavaria (STENO), currently with 20 associated medical institutions, is one of the world's largest stroke networks, caring for over 5000 stroke patients each year. In 2010, we initiated the implementation of a network-wide 'total' quality management system according to ISO standard 9001:2008 in cooperation with the German Stroke Society and a third-party certification organization (LGA InterCert). RESULTS: Certification according to ISO 9001:2008 was awarded in March 2011 and maintained over a complete certification cycle of 3 years without major deviation from the norm in three external third-party audits. Thrombolysis rate significantly increased from 8·2% (2009) to 12·8% (2012). CONCLUSIONS: Certified quality management within a large stroke network using telemedicine is possible and might improve stroke care procedures and thrombolysis rates. Outcome studies comparing conventional stroke care and telestroke care are inevitable.

Mindfulness-based interventions in multiple sclerosis: beneficial effects of Tai Chi on balance, coordination, fatigue and depression.

BACKGROUND: Patients suffering from Multiple Sclerosis (MS) experience a wide array of symptoms, including balance problems, mobility impairment, fatigue and depression. Physical exercise has recently been acknowledged as a treatment option complementary to medication. However, information regarding putative effects of structured exercise programs on neurological symptoms is sparse. Tai Chi, a Chinese martial art incorporating physical exercise and mindfulness training, has been shown to yield health benefits in various neurological groups. It seems particularly suitable for patients with motoric deficits as it challenges coordination and balance. The purpose of the current study was to explore the therapeutic value of structured Tai Chi training for coordination, balance, fatigue and depression in mildly disabled MS patients. METHODS: A sample of 32 MS patients (Expanded Disability Status Scale, EDSS < 5) was examined. A structured Tai Chi course was devised and a Tai Chi group participated in two weekly sessions of 90 minutes duration for six months, while a comparison group received treatment as usual (TAU). Both groups were examined prior to and following the six-months interval with regards to balance and coordination performance as well as measures of fatigue, depression and life satisfaction. RESULTS: Following the intervention, the Tai Chi group showed significant, consistent improvements in balance, coordination, and depression, relative to the TAU group (range of effect-sizes: partial η2 = 0.16 - 0.20). Additionally, life satisfaction improved (partial η2 = 0.31). Fatigue deteriorated in the comparison group, whereas it remained relatively stable in the Tai Chi group (partial η2 = 0.24). CONCLUSIONS: The consistent pattern of results confirms that Tai Chi holds therapeutic potential for MS patients. Further research is needed to determine underlying working mechanisms, and to verify the results in a larger sample and different MS subgroups.

FADD is upregulated in relapsing remitting multiple sclerosis.

OBJECTIVE: To elucidate the role of tumor necrosis factor (TNF) receptor signal transduction in multiple sclerosis (MS). METHODS: We performed a cross-sectional analysis of the gene expression of TNF receptor-associated death domain protein (TRADD) and Fas-associated death domain protein (FADD) in peripheral blood leukocytes of 23 relapsing remitting (RR), 19 secondary progressive (SP) and 12 primary progressive (PP) MS patients, as well as of 29 healthy controls by quantitative RT-PCR. Additionally, we monitored a subgroup of 15 RR MS patients longitudinally every 3 months over the time period of 9 months. RESULTS: FADD expression was significantly elevated in RR MS patients compared to the other disease courses (p < 0.048). The median of FADD expression was elevated in the RR MS patient groups compared to the healthy group, but this was not significant (p < 0.053). The median of TRADD expression was elevated in the patient groups compared to the healthy group, but this was not significant (p < 0.14). Neither variable changed significantly over the time course of 9 months. CONCLUSION: FADD elevation in leukocytes might be interpreted as the molecular equivalent of an elevated general inflammatory activity in RR MS patients compared to other disease courses. FADD elevation in RR MS reinforces the concept that different pathophysiological and immunological processes sustain RR MS and SP or PP MS.