Introduction of the Watzmann Severity Scale: A sensorimotor approach to estimate the course of inpatient rehabilitation in multiple sclerosis.

Multiple sclerosis is an autoimmune disease with a plethora of potentially arising impairments and a coarse standard clinical estimation of severity, the expanded disability status scale (EDSS). In this study, we introduced the Watzmann Severity Scale (WSS), a sensorimotor function based statistical model of the EDSS of 113 patients. Using the WSS, we examined the rehabilitation course of 87 patients. The WSS revealed to be a reliable estimate of the EDSS with an R²adjusted of 0.81, although lower EDSS grades were systematically overestimated. Further, patients slightly improved during their inpatient stay of in average 17d by 0.21 on the WSS, with changes in gait performance being the driving factor (|ß|-weight of 0.84). We were not able to reliably predict changes in the WSS and found no association with the duration of hospitalization. We conclude and advise that rehabilitation should start earlier, if lower EDSS grades were not overestimated, to emphasize gait less in rehabilitation, and to change from a perspective of impairment and disability to performance in order to maximize patient rehabilitation.

Lethal outcome after pelvic salvage radiotherapy in a patient with prostate cancer due to increased radiosensitivity : Case report and literature review.

BACKGROUND: In general, late side effects after salvage radiotherapy (RT) for prostate cancer are below 10%. Patients with impaired DNA repair ability and genetic instability can have significantly increased reactions after RT. CASE, CLINICAL FOLLOW-UP, AND EXAMINATION: We present a patient who experienced severe side effects after additive RT for prostate cancer and died from the complications 25 months after RT. Imaging (MR) is shown as well as three-color fluorescence in situ hybridization. The blood sample testing revealed that radiosensitivity was increased by 35-55%. We undertook a review of the literature to give an overview over the tests established that are currently considered useful. CONCLUSION: This case highlights that the identification of patients with increased radiosensitivity is an important task in radiation protection. Groups of patients who should be screened have to be found and corresponding research facilities have to be set up.

Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.

BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.

["Time is brain" in relapsing remitting multiple sclerosis. Current treatment concepts in immunotherapy]. / "Time is brain" bei der schubförmigen Multiplen Sklerose. Aktuelle Behandlungskonzepte in der Immuntherapie.

BACKGROUND: Despite highly divergent time scales of disease evolution in multiple sclerosis (MS) and ischemic stroke, clear analogies are apparent that may point the way to optimization of MS treatment. Inflammatory disease activity and neurodegeneration may induce potentially irreversible damage to central nervous system structures and thus lead to permanent disability. For the treatment of MS early detection of disease activity and early immunotherapy or treatment optimization are pivotal determinants of long-term outcomes. Such therapeutic concepts may be described with the catchy phrase "time is brain" as coined for the acute thrombolytic treatment of ischemic stroke. RESULTS AND DISCUSSION: For MS a "time is brain" concept would comprise an early initiation of first line therapy as well as sensitive and structured monitoring of disease activity under therapy in conjunction with a low threshold for timely treatment optimization to achieve sustained freedom from measurable disease activity. This approach may substantially improve the long-term outcome in patients who show insufficient response to platform therapies. The intersectorial collaboration in regional MS care networks involving office-based neurologists and specialized MS centers may facilitate the timely use of highly active therapies with their specific benefit-risk profiles thus supporting sustained stabilization of patient quality of life.

MS susceptibility is not affected by single nucleotide polymorphisms in the MMP9 gene.

Matrix metalloproteinase 9 (MMP9) plays an important role in the pathogenesis of multiple sclerosis (MS). However, the impact of genetic variants affecting MMP9 on MS susceptibility is still in debate. We could not detect an association of MMP9 SNPs with MS on a genome-wide significance level by SNP genotyping, followed by imputation of SNPs within a region stretching 2Mbp up- and down-stream of MMP9. Rs6073751, located within WFDC2, was found associated with MS most strongly. Rs3918242, associated with MS according to previous reports, showed nominal significance only. Meta-analysis of our own and published data did not confirm this effect.

A proposed methodology to estimate the cumulative life-time UVB exposure using geographic information systems: An application to multiple sclerosis.

BACKGROUND: The cause of multiple sclerosis (MS) is unknown; multiple risk factors have been implicated, including environmental exposures, such as sunlight. Many studies have relied on latitude alone as a crude proxy for sunlight exposure. We aimed to develop a protocol allowing a more detailed estimate of cumulative ambient ultra-violet B (UVB) exposure at critical time-periods over a patient's life-course. METHODS: 4010 definite MS patients with a 'movement history' from birth to the study end (2005) were selected from the University of British Columbia, Canada's MS Genetic database. Patient's place of resident from birth were tracked, each place being geocoded (latitude and longitude) and assigned a UVB value using the NASA Total Ozone Mapping Spectrometer (TOMS) dataset. Combined, these data allowed an estimated UVB value for each patient based on year and location. RESULTS: Using this protocol, we provide a potentially more detailed cumulative UVB exposure for critical periods in a patients' life history based on their individual spatial migration through time. CONCLUSIONS: This protocol is intended to provide a framework for researchers to more accurately estimate UVB exposures for individuals over the course of their life history and may be useful for understanding etiology of MS and other chronic disease.

[Central pain processing and Parkinson's disease. Epidemiology, physiology, and experimental results issuing pain processing]. / Zentrale Schmerzverarbeitung bei Morbus Parkinson. Epidemiologie, Physiologie und experimentelle Befunde zur Schmerzverarbeitung.

Parkinson's disease (PD) is caused by degeneration of the dopaminergic neurons in the substantia nigra (SN) and a resulting dysfunction of the nigrostriatal pathways including the basal ganglia. Beside motor symptoms, different types of pain (e.g., dystonic musculoskeletal pain or central pain) occur in a considerable number of patients. In addition, abnormalities in pain processing have been observed in PD patients, which may present as increased pain sensitivity. The pathophysiological mechanisms involved in disturbed pain processing of PD, however, are still poorly understood. The present article gives an overview of the relevant experimental studies, investigating the abnormalities of pain processing in PD by means of electrophysiological [electroencephalography (EEG), sympathetic skin response (SSR)] and psychophysical methods [quantitative sensory testing (QST), RIII reflex threshold]. Based on a review of the literature, it is postulated that dysfunction in endogenous pain inhibition caused by dopaminergic deficiency in the basal ganglia, especially in the striatum, but also in mesolimbic areas is a main pathophysiological mechanism involved in nociceptive abnormalities in PD.

[MusiQol: international questionnaire investigating quality of life in multiple sclerosis: validation results for the German subpopulation in an international comparison]. / MusiQol: Internationaler Fragebogen zur Erfassung der Lebensqualität bei Multipler Sklerose : Validierungsergebnisse der deutschen Subpopulation im internationalen Vergleich.

BACKGROUND: The existing health-related quality of life questionnaires on multiple sclerosis (MS) only partially reflect the patient's point of view on the reduction of activities of daily living. Their development and validation was not performed in different languages. That is what prompted the development of the Multiple Sclerosis International Quality of Life (MusiQoL) Questionnaire as an international multidimensional measurement instrument. This paper presents this new development and the results of the German subgroup versus the total international sample. PATIENTS AND METHODS: A total of 1,992 MS patients from 15 countries, including 209 German patients, took part in the study between January 2004 and February 2005. The patients took the MusiQoL survey at baseline and at 21±7 days as well as completing a symptom-related checklist and the SF-36 short form survey. Demographics, history and MS classification data were also generated. Reproducibility, sensitivity, convergent and discriminant validity were analysed. RESULTS: Convergent and discriminant validity and reproducibility were satisfactory for all dimensions of the MusiQoL. The dimensional scores correlated moderately but significantly with the SF-36 scores, but showed a discriminant validity in terms of gender, socioeconomic status and health status that was more pronounced in the overall population than in the German subpopulation. The highest correlations were observed between the MusiQoL dimension of activities of daily living and the Expanded Disability Status Scale (EDSS). CONCLUSION: The results of this study confirm the validity and reliability of MusiQoL as an instrument for measuring the quality of life of German and international MS patients.

Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.

BACKGROUND: Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. OBJECTIVE: To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing-remitting MS. METHODS: A total of 1,326 patients were randomized 1:1:1 to two short-course regimens of cladribine tablets (3.5 or 5.25 mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. RESULTS: Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribine-treated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. CONCLUSION: The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.

More CLEC16A gene variants associated with multiple sclerosis.

OBJECTIVES: Recently, associations of several single-nucleotide polymorphisms (SNPs) within the CLEC16A gene with multiple sclerosis (MS), type-I diabetes, and primary adrenal insufficiency were reported. METHODS: We performed linkage disequilibrium (LD) fine mapping with 31 SNPs from this gene, searching for the region of highest association with MS in a German sample consisting of 603 patients and 825 controls. RESULTS: Four SNPs located in intron 19 of the CLEC16A gene were found associated. We could replicate the finding for SNP rs725613 and were able to show for the first time the association of rs2041670, rs2080272 and rs998592 with MS. CONCLUSION: All described base polymorphisms are mapping to one LD block of approximately 50 kb within intron 19 of the CLEC16A gene, suggesting a pivotal role of this region for susceptibility of MS and possibly also for other autoimmune diseases.

Patient-reported quality of life in multiple sclerosis differs between cultures and countries: a cross-sectional Austrian-German-Polish study.

BACKGROUND: Patient-reported quality of life (QOL) is an outcome measure in clinical trials in multiple sclerosis (MS), but translated QOL instruments may affect the actual comparability of data. OBJECTIVES: We aimed to investigate possible differences in QOL in MS between cultures and countries. We employed the Functional Assessment of Multiple Sclerosis (FAMS) Version 4 questionnaire, which is a state-of-the-art QOL instrument. METHODS: Some 484 MS patients from Austria (145), Germany (144), and Poland (195) aged 20-60 years, and stratified for sex and disease severity as measured by the Expanded Disability Status Scale (EDSS) score completed the respective FAMS translation and a socio-demographic questionnaire. RESULTS: Analysis of variance and post-hoc Scheffé-test showed that 64% of the FAMS items were answered significantly differently (p < 0.001) between the three countries. A multivariate regression analysis including all the available disease-related and socio-demographic variables revealed the factors age, EDSS score, employment, social contacts, MS course, and country to be significant predictors of both the total FAMS score and the score for items answered differently between the three countries. CONCLUSIONS: Differences exist in the QOL of MS patients from Austria, Germany, and Poland which seem to lie beyond the impact of disease severity. They appear to be related to culture or other country-specific factors, as country was an independent predictor of differently answered items of the FAMS and thus also of the whole FAMS. QOL instruments should consider this aspect to faithfully reflect subjective information such as patient-reported benefit of treatment in multinational clinical trials.

Disease onset in familial and sporadic primary progressive multiple sclerosis.

The pathophysiology of primary progressive (PP) multiple sclerosis (MS) involves diffuse axonal degeneration which is believed to start early in the disease process, even before the onset of clinical symptoms. Symptomatic onset then occurs when this process reaches a threshold after which the axonal loss can no longer be compensated. A preliminary study showed that patients with familial PPMS had an earlier clinical onset than patients with sporadic disease, suggesting a hereditary component to the disease process of PPMS. In this study, we combined data from two large, population-based, longitudinal MS databases to investigate disease onset in familial and sporadic PPMS. We examined 411 patients with PPMS. There were no differences in gender distribution or onset symptoms between familial and sporadic PPMS. Patients with familial PPMS were significantly younger at disease onset (n = 84, median age: 37.6 years) than patients with sporadic disease (n = 327, median age: 42.7, p = 0.007). This difference was due to a greater proportion of familial cases with a disease onset before the age of 30 and a smaller proportion with disease onset between 40 and 50 years of age (p = 0.002). Gender had no significant effect on the age at disease onset. Further analyses showed that these findings were unlikely to be due to ascertainment bias towards an earlier diagnosis in familial cases. Our findings suggest a hereditary component to the disease process of PPMS. It would be worthwhile to identify patients with familial PPMS for future research on disease modifying genes in MS.

Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS.

BACKGROUND: Mitoxantrone is used for aggressive multiple sclerosis (MS), but concerns about safety, including cardiotoxicity and other laboratory measures, prevail. OBJECTIVE: To evaluate the incidence and potential predictors of adverse events associated with mitoxantrone at the MS Clinic, University of British Columbia, Canada. METHODS: Retrospective review of patients treated with mitoxantrone by standard protocol; maximum cumulative dose = 120 mg/m(2). Left ventricular ejection fraction (LVEF) was measured with regular multiple-gated acquisition (MUGA) scans; blood cell counts and biochemical liver tests were performed before infusions. Generalized estimating equations were used to examine potential predictors of adverse events (graded according to the Common Toxicity Criteria, version 4) in patients with normal baseline and > or =1 follow-up MUGA or laboratory assessment. RESULTS: All 163 patients (58% women) treated with mitoxantrone from 1999 to 2007 were reviewed. Mean baseline age was 41.9 (SD 10.8) years, cumulative dose was 59.7 (SD 26.0) mg/m(2), and median follow-up duration was 14 months (maximum 6.5 years). By study end, 14% developed de novo cardiotoxicity (grade > or =2) as measured by decreased LVEF, 27% neutropenia (grade > or =1), 15% anemia (grade > or =1), and 15% liver toxicity (grade > or =1). Possible predictors of adverse events included sex, age, disease duration, and cumulative dose; only women exposed to a higher cumulative dose were at a greater risk of anemia (adjusted odds ratio 1.26, 95% confidence interval 1.08-1.48 per 10 mg/m(2)). CONCLUSIONS: Based on cardiac and laboratory assessments, mitoxantrone was reasonably well tolerated. However, cardiotoxicity was evident after doses well below current maximum recommended levels. A dose-response effect was not apparent. Findings emphasize the importance of monitoring; the long-term effects of mitoxantrone in multiple sclerosis require investigation.

Rapid-onset central motor plasticity in multiple sclerosis.

OBJECTIVE: To study rapid-onset central motor plasticity, and its relationship to motor impairment and CNS injury in patients with multiple sclerosis (MS). METHODS: In this cross-sectional observational study, motor plasticity was examined neurophysiologically and behaviorally in 22 patients with moderately severe (median Expanded Disability Status Scale score 2.5 [0-6]) stable MS and matched healthy controls. First, plasticity was assessed using paired associative stimulation (PAS), a protocol modeling long-term synaptic potentiation in human cortex. PAS combines repetitive electric nerve stimulation with transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Second, motor learning was tested by a force production task. Motor impairment was assessed by functional tests. CNS injury was evaluated by obtaining normalized N-acetyl-aspartate (NAA/Cr) spectra using magnetic resonance spectroscopy and by the corticomuscular latency (CML) to the abductor pollicis brevis muscle as tested by TMS. RESULTS: Patients with MS performed worse than controls in functional motor tests, CMLs were prolonged, and NAA/Cr was decreased. PAS-induced enhancement of corticospinal excitability and training-induced increments of motor performance were comparable between patients with MS and controls. Neither PAS-induced plasticity nor motor learning performance correlated with motor impairment or measures of CNS injury. Patients with high CNS injury and good motor performance did not differ significantly from those with high CNS injury and poor motor performance with respect to PAS-induced plasticity and motor learning success. CONCLUSIONS: Despite motor impairment and CNS injury in patients with multiple sclerosis (MS), rapid-onset motor plasticity is comparable to that in healthy subjects. Compensation of MS-related CNS injury is unlikely to be constrained by insufficient rapid-onset neuroplasticity.

Impact of multiple sclerosis relapses on progression diminishes with time.

OBJECTIVE: The relationship between relapses and long-term disability in multiple sclerosis (MS) remains to be fully elucidated. Current literature is conflicting and focused on early relapses. We investigated the effects of relapses at different stages on disability progression. METHODS: We conducted a retrospective review of 2,477 patients with definite relapsing-onset MS followed until July 2003 in British Columbia, Canada. Time-dependent Cox proportional hazards models examined the effect of relapses at different time periods (0-5; >5-10; >10 years postonset) on time to cane (Expanded Disability Status Scale [EDSS]) and secondary progressive MS (SPMS). Findings were derived from hazard ratios with 95% confidence intervals (CIs), adjusted for sex, onset age, and symptoms. RESULTS: Mean follow-up was 20.6 years; 11,722 postonset relapses were recorded. An early relapse (within 5 years postonset) was associated with an increased hazard in disease progression over the short term, by 48%; 95% CI 37%-60% for EDSS 6 and 29%; 95% CI 20%-38% for SPMS. However, this substantially lessened to 10%; 95% CI 4%-16% (EDSS 6) and 2%; 95% CI -2%-7% (SPMS) after 10 years postonset. The impact of later relapses (>5-10 years postonset) also lessened over time. Effects were modulated by age, impact being greatest in younger (<25 years at onset) and least in older (>or=35 years) patients where relapses beyond 5-years postonset typically failed to reach significance. Relapses during SPMS had no measurable impact on time to EDSS 6 from SPMS. CONCLUSION: Relapses within the first 5 years of disease impacted on disease progression over the short term. However, the long-term impact was minimal, either for early or later relapses. Long-term disease progression was least affected by relapses in patients with an extended disease duration (>10 years) or already in the secondary progressive phase.

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS: In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS: All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION: Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING: Teva Pharmaceutical Industries, Israel.

The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis.

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.

Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations.

This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.