Is the walk ratio a window to the cerebellum in multiple sclerosis? A structural magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Existing research studies have demonstrated a relationship between magnetic resonance imaging (MRI) neuroimaging measures and walking speed in people with multiple sclerosis (PwMS). However, to date there are no data as to the brain structures involved in gait coordination and control in PwMS. Therefore, the aim of our study was to investigate the association between walk ratio, an indicator of gait coordination, and related brain structures in PwMS. METHODS: A brain MRI was performed by a 3.0-T MR scanner in conjunction with a volumetric analysis based on three-dimensional T1-weighted images. Regions of interest were volumes of the hippocampus, amygdala, putamen, caudate, pallidum, thalamus, cerebellum and the corpus callosum regions. Walking speed and walk ratio, defined as step length divided by step rate, was measured whilst walking on an electronic walkway. RESULTS: In all, 343 PwMS (41.1 ± 13.4 years, 69.1% female, median Expanded Disability Status Scale 2.5) were included in the study. A significant association was found between the left cerebellum volume and walk ratio after controlling for age, gender, total cranial volume and disability; R2  = 0.379, P = 0.002. A similar association was found between the right cerebellum volume and walk ratio, R2  = 0.364, P = 0.002. No correlations were observed between walk ratio and the thalamus, basal ganglia, hippocampus, amygdala and the corpus callosum volumes. No association was found between walking speed and all brain measures. CONCLUSIONS: The walk ratio should be considered when evaluating and assessing PwMS presenting with ataxia. Furthermore, it is also hypothesized that a low walk ratio indicates a lower cerebellum volume in the MS population.

Neural correlates of gait variability in people with multiple sclerosis with fall history.

BACKGROUND AND PURPOSE: The aim was to investigate the association between step time variability and related brain structures in accordance with fall status in people with multiple sclerosis (PwMS). METHODS: The study included 225 PwMS. Whole-brain magnetic resonance imaging was performed with a high-resolution 3.0 T magnetic resonance scanner in addition to volumetric analysis based on 3D T1-weighted images using the FreeSurfer image analysis suite. Step time variability was measured with an electronic walkway. Participants were defined as 'fallers' (at least two falls during the previous year) and 'non-fallers'. RESULTS: In all, 105 PwMS were defined as fallers and had a greater step time variability compared to non-fallers [5.6% (SD = 3.4) vs. 3.4% (SD = 1.5); P = 0.001]. MS fallers exhibited a reduced volume in the left caudate and both cerebellum hemispheres compared to non-fallers. On using a linear regression analysis no association was found between gait variability and related brain structures in the total cohort and the non-fallers group. However, the analysis found an association between the left hippocampus and left putamen volumes with step time variability in the faller group: P = 0.031, 0.048, respectively, controlling for total cranial volume, walking speed, disability, age and gender. Nevertheless, according to the hierarchical regression model, the contribution of these brain measures to predict gait variability was relatively small compared to walking speed. CONCLUSIONS: An association between low left hippocampal, putamen volumes and step time variability was found in PwMS with a history of falls, suggesting that brain structural characteristics may be related to falls and increased gait variability in PwMS.

Psoriasis comorbidity affects multiple sclerosis neurological progression: a retrospective case - control analysis.

BACKGROUND: Multiple sclerosis (MS) and psoriasis are inflammatory disorders, with epidemiological and biological associations. The impact of one disease on the course of the other has not been studied. OBJECTIVE: To characterize patients with psoriasis and MS, and to assess whether psoriasis comorbidity affected the progression of MS. METHODS: A retrospective case-control study. Patients with psoriasis comorbidity were identified from 3456 patients included in the Sheba Hospital Multiple Sclerosis Center database. Clinical and demographical characteristics and MS progression-related outcomes in patients whose follow-up exceeded 5 years were analysed and compared to those of a matched control cohort of MS-only (MSO) patients. RESULTS: Forty-five (1.3%) MS patients had psoriasis comorbidity. Psoriasis preceded MS in 35 (78%) cases. The psoriasis was defined as mild, moderate and severe in 24 (53%), twelve (27%) and nine (20%) cases respectively. MS progression-related outcomes were evaluated in 35 patients that had follow-up over 5 years. Patients with psoriasis onset preceding relapsing-remitting MS (RRMS) had slower progression of disease compared to MSO patients, as manifested by a longer time to second relapse (P < 0.01) and a longer time to significant neurological disability scores (P < 0.03). CONCLUSION: Psoriasis comorbidity preceding the onset of MS is associated with slower progression of disability.

Prevalence of overweight, obesity and metabolic syndrome components in multiple sclerosis patients with significant disability.

BACKGROUND AND PURPOSE: Information about metabolic comorbidities in patients with multiple sclerosis (MS) is scarce. Our aim was to examine the prevalence of the metabolic syndrome (MetS) and its components in patients with long duration of MS and significant disability. METHODS: Demographic and clinical data, weight, height, waist circumference, blood pressure, and levels of fasting glucose, triglycerides and high density lipoprotein cholesterol (HDL-C) were obtained from 130 MS patients with Extended Disability Status Scale (EDSS) score ≥3.0. RESULTS: Seventy-two percent were female, mean ± SD age 55.8 ± 6.0, range 45-65 years, disease duration 18.2 ± 10.1 years, EDSS 5.5 ± 1.0. Obesity [body mass index (BMI) ≥ 30 kg/m(2) ] was present in 18.5% and overweight (BMI 25.0-29.9 kg/m(2) ) in 34.6%. The prevalence of the MetS was 30% with no gender difference. Fifty-six percent had central obesity by waist circumference, 28% treated hypertension, 45.8% elevated blood pressure, 11% type 2 diabetes mellitus, 31.4% treated dyslipidemia, 28.8% elevated triglyceride levels and 31.4% had low HDL-C. MS patients with MetS were significantly older (59.0 ± 5.5 vs. 53.8 ± 5.5, P < 0.0001) and heavier (BMI 29.0 ± 6.9 vs. 25.1 ± 4.7, P = 0.0009). There were no differences between the groups in neurological disability by the EDSS (5.7 ± 1.0 vs. 5.4 ± 1.0), disease duration (18.4 ± 9.9 vs. 18.2 ± 10.2 years) and number of steroid courses received (6.6 ± 9.5 vs. 6.3 ± 8.4). CONCLUSIONS: Compared to the general population, adult disabled MS patients had lower rates of obesity and overweight, as assessed by BMI. Despite these reduced rates, the prevalence of the MetS was similar to the general population. Specifically higher rates of increased waist circumference were found, suggesting that the lower BMI may be misleading in terms of health risk.

Common and specific signatures of gene expression and protein-protein interactions in autoimmune diseases.

The aim of this study is to understand intracellular regulatory mechanisms in peripheral blood mononuclear cells (PBMCs), which are either common to many autoimmune diseases or specific to some of them. We incorporated large-scale data such as protein-protein interactions, gene expression and demographical information of hundreds of patients and healthy subjects, related to six autoimmune diseases with available large-scale gene expression measurements: multiple sclerosis (MS), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), Crohn's disease (CD), ulcerative colitis (UC) and type 1 diabetes (T1D). These data were analyzed concurrently by statistical and systems biology approaches tailored for this purpose. We found that chemokines such as CXCL1-3, 5, 6 and the interleukin (IL) IL8 tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In addition, the anti-apoptotic gene BCL3, interferon-γ (IFNG), and the vitamin D receptor (VDR) gene physically interact with significantly many genes that tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In general, similar cellular processes tend to be differentially expressed in PBMC in the analyzed autoimmune diseases. Specifically, the cellular processes related to cell proliferation (for example, epidermal growth factor, platelet-derived growth factor, nuclear factor-κB, Wnt/ß-catenin signaling, stress-activated protein kinase c-Jun NH2-terminal kinase), inflammatory response (for example, interleukins IL2 and IL6, the cytokine granulocyte-macrophage colony-stimulating factor and the B-cell receptor), general signaling cascades (for example, mitogen-activated protein kinase, extracellular signal-regulated kinase, p38 and TRK) and apoptosis are activated in most of the analyzed autoimmune diseases. However, our results suggest that in each of the analyzed diseases, apoptosis and chemotaxis are activated via different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the Fcɛ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the diagnoses and understanding of autoimmunity and/or specific autoimmune diseases.

Retinal layers thickness changes following epiretinal membrane surgery.

PurposeTo evaluate the time course of changes in the thickness of retinal layers after epiretinal membrane (ERM) removal surgery.MethodsA retrospective cohort study of patients following surgery for idiopathic ERM. We used new specialized image analysis software to create a thickness map of each retinal layer and analyzed changes during one year follow-up. Healthy fellow eyes were used as negative controls and the retina prior to surgery as positive control.ResultsTwenty-one patients were included with a mean age of 68±13 years. Central macular thickness decreased steadily until 6 months after surgery (25% decrease, 516±76 to 386±73 µm, P<0.001) with no further decrease between 6 and 12 months (386±73 to 390±73 µm, P=0.291). The retinal nerve fiber layer (RNFL), and the ganglion cell and inner plexiform layer (GCIPL) were most affected (57%, P<0.001 and 27%, P=0.010, respectively). The thickest region showed a more abrupt decrease of 21% at first follow-up (504±61 to 399±58 µm, P=0.001) with subsequent decrements of about 3%. Prior to surgery all retinal layers were thicker in study eyes compared with healthy control eyes (6-63%, all P<0.05).ConclusionsFollowing ERM surgery, in the course of 6 months, the macula gradually becomes thinner after which a stable state is reached. All layers appear to be affected, with the RNFL and GCIPL impacted the most. Our results provide a unique view on how the thickness of different retinal layers changes following ERM surgery.

Intravenous immunoglobulin treatment of experimental T cell-mediated autoimmune disease. Upregulation of T cell proliferation and downregulation of tumor necrosis factor alpha secretion.

It has been reported previously that intravenous administration of normal human immunoglobulins (IVIg) to human patients can suppress the clinical signs of certain autoimmune diseases. However, the mechanism(s) by which normal Ig interferes with the various disorders and the scheduling of treatment have been poorly delineated. To study these questions, we examined IVIg treatment of two experimentally induced T cell autoimmune diseases in rats: experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA). We now report that IVIg treatment (0.4 g/kg) inhibited the active induction of both EAE and AA, and that this treatment did not affect the acquisition of resistance to reinduction of EAE. The importance of the site of administration and schedule of treatment were studied in the AA model. Ig was effective when given intravenously, but not when administrated subcutaneously or intraperitoneally. IVIg treatment was effective when given daily from immunization to outbreak of disease; but it was also effective when given once at the time of immunization or once 2 wk after induction of AA, just at the clinical outbreak of disease. Administration of IVIg between immunization and outbreak of AA was less effective. Prevention of disease by IVIg occurred despite the presence of T cell reactivity to the specific antigens in the disease. In fact, IVIg administrated to naive rats activated T cell reactivity to some self-antigens. Nevertheless, IVIg treatment led to decreased production of the inflammatory cytokine TNF alpha. Thus, IVIg treatment may exert its therapeutic power not by inhibiting T cell recognition of self-antigens, but by inhibiting the biological consequences of T cell recognition.

Prolonged response times characterize cognitive performance in multiple sclerosis.

Cognitive impairment is amongst the main symptoms affecting multiple sclerosis (MS) and should be comprehensively and accurately assessed. To study the added value of a computerized neuropsychological battery enabling the measurement of response times in the cognitive domains, 58 randomly selected MS patients and 71 age-, gender- and education-matched healthy subjects were evaluated. Construct and discriminant validity were assessed for the standard Neuropsychological Screening Battery for Multiple Sclerosis (NSBMS) and the Mindstreams Computerized Cognitive Battery (MCCB). The MCCB demonstrated good construct validity in comparison with the NSBMS in memory (P < 0.001), executive function (P < 0.001), attention (P < 0.05) and information processing (P < 0.05) domains. In addition, it showed high discriminant validity most prominently for executive function, attention and motor skills (P < 0.001). Response times measured by the computerized battery were longer in all cognitive domains and varied with cognitive load, demonstrating that response time deficits in MS are associated with particular task demands. We conclude that in MS prolonged response times on a range of cognitive tasks signify abnormal conduction within demyelinative tracts.

Experimental Autoimmune Encephalomyelitis Ameliorated by Passive Transfer of Polymerase 1-Silenced MOG35-55 Lymphatic Node Cells: Verification of a Novel Therapeutic Approach in Multiple Sclerosis.

In the current study, we present an innovative concept based on the knowledge that enhancing naturally occurring biological mechanisms is effective in preventing neuronal damage and maintaining low disease activity in about 15% of multiple sclerosis (MS) patients presenting the benign type of MS. Recently, we have demonstrated that low disease activity in benign MS is associated with suppression of RNA polymerase 1 (POL1) pathway; therefore, targeting POL1 transcription machinery as a strategy for suppressing active forms of MS is suggested. To further establish our approach, we aimed to suppress POL1 pathway by silencing of the POL1-related RRN3, POLR1D and LRPPRC genes in specific MOG35-55-activated lymphocytes and assess their capacity to induce experimental autoimmune encephalomyelitis (EAE) by passive transfer. We have demonstrated that silencing of specific POL1 pathway-related genes significantly decreased viability and increased the proportion of CD4+/AnnexinV+/PI+ apoptotic cells in MOG35-55-primed lymphocytes. POL1-gene silencing significantly decreased the proportion of CD4+IL17+ and increased proportion of CD4+IL10+ and CD4+TNFa+ lymphocytes that occurred simultaneously with over-presentation of Treg CD4+CD25+FoxP3+ cells. Passive transfer of MOG35-55-primed lymphocytes after POL1-gene silencing suppressed EAE development in mice as demonstrated by delayed onset and peak of disease accompanied by significantly lower maximal and cumulative EAE scores. Our study supports a basis for direct targeting of POL1 transcription pathway as a strategy for selective induction of apoptosis and suppression of inflammation in EAE and consequently paves the way for innovative and targeted MS therapeutic strategy that is based on naturally existing biological mechanism.

RAM-589.555 a new Polymerase-1 inhibitor as innovative targeted-treatment for multiple sclerosis.

Targeting Polymerase-1 (POL1) transcription machinery is a new strategy for suppression of multiple sclerosis (MS) disease activity that is based on suppression of ribosomal biogenesis and subsequent activation of apoptosis. We developed an oral POL1 inhibiting compound RAM-589.555, that suppress ribosomal biogenesis as an innovative therapeutic approach to ameliorate MS. RAM-589.555 shows high permeability, specificity to POL1 pathway, ability to induce apoptosis and to inhibit proliferation and viability of activated lymphocytes both in-vitro and in-vivo. Moreover, oral administration of RAM-589.555 blocks ribosomal RNA transcription and significantly suppresses and ameliorates experimental autoimmune encephalomyelitis (EAE).

Peripheral blood gene expression signature mirrors central nervous system disease: the model of multiple sclerosis.

Global gene expression analysis using cDNA microarrays has proven to be a sensitive method to gain insight into molecular pathways mediating multiple sclerosis (MS) activity and to develop and refine the molecular taxonomy of the disease. This method was applied as a tool to investigate molecular heterogeneity of MS related gene transcripts in the aim of distinguishing between transcripts that trigger disease activity and account for direct genotype-phenotype correlation, and those whose expression is altered as a downstream effect of other genes. This review summarizes the current state of gene expression microarray applications for the study of MS, and specifically emphasizes the results of gene expression studies using peripheral blood mononuclear cells (PBMC) that were shown to be useful for better understanding of disease related pathways, monitoring of therapeutic responses to various drugs and prediction of clinical outcome. In the long run it is expected that the information provided by cDNA microarrays experiments will allow the determination of key molecular players involved in MS pathogenesis, and lead to better management of the disease using targeted treatments that will prevent its progression.

Cognitive changes in early MS: a call for a common framework.

Cognitive dysfunction is among the main symptoms of multiple sclerosis (MS) and adversely affects patients' quality of life. The occurrence of cognitive impairment early in the disease process raises crucial issues related to definition of the impairment and its magnitude as well as to the tools applied to the assessment. To date there is little evidence concerning the reliability and validity of cognitive measures in early MS and their predictive long-term role. As MS is a complex disease, multidimensional approaches should be further developed and validated to study the cognitive sphere in the early stages of the disease. Considering that none of the available tests performed in isolation is able to provide a complete picture of the cognitive impairment in early MS, this calls for the definition of phase duration, impairment and tools appropriate for use by clinicians and researches. The present review proposes a framework aimed to help neurologists in approaching cognitive impairment in early MS and stimulate discussions and evaluations of the suggested recommendations.

Intraocular pressure measurement after DSAEK by iCare, Goldmann applanation and dynamic contour tonometry: A comparative study.

PURPOSE: Corneal thickness inevitably increases following Descemet's stripping automated endothelial keratoplasty (DSAEK), owing to the addition of a donor graft. The current study compares different devices in assessing post-DSAEK intraocular pressure (IOP). METHODS: We compared IOP values measured by the Goldmann tonometry (GAT), iCare rebound tonometry (iCare) and Pascal dynamic contour tonometry (PDCT) in eyes following DSAEK. Agreement between measurements was calculated with correlation analysis and Bland-Altman plots. Effects of keratometry, central, thickness (CCT), endothelial cell density (ECD) and axial length on IOP measurements were assessed with Pearson's correlation. RESULTS: Twenty eyes of 20 patients (mean age 74.3±14.4, 14 females) post-DSAEK were included in this study. There was a high concordance between the IOP readings obtained by the three devices: a strong and significant correlation was found between GAT and PDCT (r=0.94, P<0.001) GAT and iCare (r=0.86, P<0.001) and iCare with PDCT (r=0.81, P<0.001). However, the iCare measurements were significantly and consistently lower than that obtained with GAT (ΔIOP=1.68±2.0, P=0.002, 95% CI: 0.7-2.6) and with PDCT (ΔIOP=1.61±2.5, P=0.01, 95% CI: 0.4-2.8). CCT, ECD, CCT, AXL, corneal curvature or astigmatism did not influence IOP measurement by any instrument. CONCLUSIONS: IOP measurement with three different techniques (applanation, rebound and dynamic contour) showed good correlations, despite an increased corneal thickness following DSAEK. However, the iCare, which is based on a rebound tonometry showed significant lower IOP then the two other methods. This should be taken into account when evaluating patients post DSAEK.

Circulatory neurosteroid levels in underweight female adolescent anorexia nervosa inpatients and following weight restoration.

Nineteen female adolescent inpatients diagnosed with anorexia nervosa, restricting type (AN-R) and 16 non-eating disordered (ED) controls were assessed for plasma dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulphate (DHEA-S), and cortisol levels, and for eating-related and non-eating-related psychopathology. AN-R patients were assessed at admission, 1 month and 4 months following hospitalization. The non-ED controls were assessed once. No baseline between-group differences were found in plasma cortisol, DHEA, and DHEA-S levels, whereas the patient group had a significantly lower Cortisol/DHEA-S ratio and elevated scores on most psychopathological parameters. A significant increase was found in the body mass index of the AN-R patients at 4 months post-hospitalization, accompanied by a decrease in plasma cortisol levels and a trend towards decreased Cortisol/DHEA and Cortisol/DHEA-S ratios, whereas no change occurred in psychopathology. The difference in Cortisol/DHEA-S ratio between AN-R patients and non-ED controls, and the different patterns of change in cortisol vs. DHEA(-S) levels following weight restoration, may in part account for the feeding difficulties in AN, particularly during refeeding.

The role of laquinimod in modulation of the immune response in relapsing-remitting multiple sclerosis: Lessons from gene expression signatures.

Laquinimod, is a potential oral immunomodulatory drug, for relapsing-remitting multiple sclerosis (RRMS). We analyzed the blood-transcriptional changes in RRMS patients (who participated in the ALLEGRO clinical trial) at one and six months after laquinimod treatment using gene expression microarrays. The molecular effects of laquinimod were enhanced by duration of treatment and showed down-regulation of inflammatory responses mainly via TGFb signaling, and of pro-inflammatory cytokines as well as of cellular movement, including adhesion, migration and leukocyte extravasation signaling. Our results demonstrate that laquinimod suppresses inflammation through down-regulation of inflammatory cytokines and arrest of leukocyte extravasation and thereby could attenuate disease activity in RRMS patients.

T-cell subsets in acute psychotic schizophrenic patients.

Two-color flow cytometric analysis was performed on peripheral blood lymphocytes of 16 untreated schizophrenic patients during an acute psychotic attack and 16 healthy control subjects to evaluate differences in T-cell subpopulations. In schizophrenic patients, we observed decrease in CD4+ 2H4+ (suppressor-inducer) and CD8+ 2H4+ (suppressor-effector) T-cell subsets. The selective loss of 2H4+ cell markers both on helper and suppressor T cells was not correlated to the severity of the acute psychosis. Our results may indicate a mechanism of an immune disequilibrium in schizophrenic patients during an acute psychotic attack.

Multiple sclerosis-from probable to definite diagnosis: a 7-year prospective study.

OBJECTIVES: To investigate the rate of progression from probable to clinically definite multiple sclerosis (MS) and to define patients who had rapidly (within 1 year) progressed to a definite diagnosis. DESIGN: A 7-year prospective study. PATIENTS: A group of 163 patients experiencing their first episode of neurologic symptoms suggestive of MS. All patients had brain magnetic resonance imaging that demonstrated at least 3 demyelinating lesions at onset. RESULTS: Within the follow-up period (mean, 42 months; range, 13-84 months), 136 patients (83.4%) had an additional relapse and were thus defined as having clinically definite MS, whereas 27 patients (16.6%) were defined as having clinically probable MS. Most of the 136 patients with clinically definite MS (57.6%, 94 patients) experienced the additional relapse within 1 year. Demographic and clinical parameters at presentation were analyzed to identify variables predictive of rapid progression (within 1 year) to clinical definite MS. Motor involvement at onset was the only clinical parameter associated with rapid progression to a definite diagnosis. Survival curves demonstrated that polysymptomatic involvement and higher Extended Disability Status Scale score at presentation correlated with rapid progression to definite diagnosis. CONCLUSION: Most patients with a diagnosis of probable MS and positive brain magnetic resonance imaging will progress rapidly to clinically definite MS.

Open controlled therapeutic trial of intravenous immune globulin in relapsing-remitting multiple sclerosis.

Ten patients with relapsing-remitting multiple sclerosis were treated with intravenous immune globulin, 0.4 g/kg per day for 5 consecutive days, and then with additional booster doses of immune globulin of 0.4 g/kg, once every 2 months, for the next 12 months. Ten untreated patients with relapsing-remitting multiple sclerosis who were matched with the study patients for age, disease duration, and number of attacks per year served as controls. Immune globulin treatment was well tolerated, with no side effects. The exacerbation rate decreased from 3.7 +/- 1.2 exacerbations per year before treatment to 1.0 +/- 0.7 exacerbations per year during the treatment in the immune globulin-treated patients, while it remained unaltered in the controls. The posttreatment Kurtzke Expanded Disability Status Scale score decreased from a mean of 4.45 to 4.15, whereas in controls it increased from 3.55 to 3.75. The results suggest that immune globulin suppresses the ongoing pathologic process in multiple sclerosis and may be a promising treatment to prevent disease exacerbations.

Fatigue in multiple sclerosis compared with chronic fatigue syndrome: A quantitative assessment.

Fatigue, a common complaint among patients with multiple sclerosis (MS), is poorly characterized. We developed a computerized method that quantitatively measures fatigue, and defined a fatigue index (FI), which is the ratio between the integral of muscle strength decay over time and maximal voluntary contraction. Thirty patients (mean age, 37.4 +/- 10.3 years) were examined - 20 patients with pyramidal tract involvement and 10 patients with involvement of other neurological systems. We evaluated 10 patients during relapse and 3 months afterwards, and compared their results with those of four patients with chronic fatigue syndrome (CFS) and 13 age-matched health subjects. The FI was significantly higher in the MS patients as compared with the CFS patients and normal controls: 34.2 +/- 6.4% versus 27.5 +/- 1.0% and 23.6 +/- 6.8%, p < 0.05. Within the MS group, the FI correlated with the presence of pyramidal signs- 43.5% compared with 33% in patients without pyramidal signs, p < 0.01. In MS patients, fatigue worsened during a relapse affecting the pyramidal tract, but not during a relapse in other systems. These results demonstrate that fatigue can be quantitatively measured in MS patients, and that pyramidal dysfunction leads to increased fatigability.