Gianluca Moscato

Absence of cerebrospinal fluid oligoclonal bands is associated with delayed disability progression in relapsing-remitting MS patients treated with interferon-β

To assess the role of CSF oligoclonal bands (OB) in determining the clinical outcome in patients with relapsing-remitting multiple sclerosis (RRMS) treated with IFN-beta, we carried out a retrospective, multicentre, observational study recruiting 209 RRMS patients from six MS centres from northern, central and southern areas of Italy under treatment with IFN-beta-1a i.m., IFN-beta-1a s.c. and IFN-beta-1b s.c. Twenty-two of 209 patients (10.6%) showed no OB in CSF. The patients without had, at disease onset, significantly higher frequency of visual disturbances (p=0.02) and less sensory involvement (p=0.04) than those with OB. A statistical trend (p=0.056) towards a longer time to reach sustained disability progression during treatment was found in patients without compared to those with OB. Thirty-six of 187 (19%) patients with OB worsened by at least 1 EDSS point compared to none of 22 (0%) OB-negative patients (p=0.017). The delaying of disability progression in OB-negative patients during treatment was significantly dependent only on the number of baseline MRI T2-weighted lesions (p=0.012) that was found to be significantly lower in OB-negative than in OB-positive patients (p=0.04). The absence of OB and low number of baseline T2-weighted lesions in this cohort of MS patients are favourable prognostic factors influencing the clinical response to IFN-beta treatment in RRMS patients.

Motor unit number estimation (mune) as a quantitative measure of disease progression and motor unit reorganization in amyotrophic lateral sclerosis.

Motor Unit Number Estimation (MUNE), a technique allowing to estimate the number of functioning Motor Units (MU) in single muscles, was used to score the diseases severity and progression rate in a group of 58 patients with Amyotrophic Lateral Sclerosis (ALS). All patients underwent MUNE in the abductor digiti minimi (ADM) muscle during the diagnostic work-up (T0), after three (T1) and six (T2) months. A significant loss [p < .001] of MU and a decrease [p < .001] of the maximal M wave area at T0 was found, whereas mean step area was increased [p < .001]. During the follow-up (T1 and T2), MU loss continued, maximal M wave decreased, and mean step area increased significantly. The results confirm that MUNE is a suitable tool to quantify the pathological changes in MU in patients with ALS.

Discordant effect of IFN-β1a therapy on anti-IFN antibodies and thyroid disease development in patients with multiple sclerosis

Interferon-beta1b (IFN-beta1b) therapy is associated with a relatively high risk of developing thyroid disease. IFN-beta1a is regarded as less immunogenic than IFN-beta1b because of its structural homology to natural IFN-beta. We assessed the effect of 1 year of IFN-beta1a treatment on thyroid function and autoimmunity in 14 multiple sclerosis (MS) patients. The results were compared with those obtained in a series of 31 MS patients treated with IFN-beta1b. The prevalence of positive binding antibody (BAb) titer and neutralizing (NAb) anti-IFN antibody titer in the two groups was also assessed. The BAb and NAb positivity rate in IFN-beta1a-treated patients was significantly lower than in the group submitted to IFN-beta1b therapy (7% vs. 84% and 0% vs. 30%, respectively). Although the incidence of thyroid dysfunction was slightly higher in IFN-beta1b-treated patients than in those undergoing IFN-beta1a treatment (33% vs. 23%, respectively), it did not reach statistical significance. Thyroid disease was unrelated to the presence of positive serum BAb or NAb titer in both the group undergoing IFN-beta1a therapy and in that treated with IFN-beta1b. In both groups, thyroid disease developed mostly in women (71%) against a background of preexisting thyroiditis and a diffuse hypoechoic ultrasound thyroid pattern (80%). IFN-beta1a treatment was associated with a significantly lower prevalence of both BAb and NAb-positive titers than was IFN-beta1b. Conversely, thyroid disease was similar and unrelated to the presence of positive anti-IFN-beta antibody titer. Therefore, routine thyroid assessment may be advised during IFN-beta1a treatment, especially in patients with preexisting thyroiditis.

Increased T-lymphocyte interleukin-6 binding in patients with multiple sclerosis.

Multiple sclerosis (MS) represents a T‐cell‐mediated autoimmune demyelinating disease of the central nervous system associated with altered immunoregulation. Interleukin (IL)‐6 is a cytokine that has several effects on the neuroimmune system. Specific IL‐6 receptors have been found in human lymphocytes and neuroglial cells. The aim of the present study was to assay IL‐6 binding on peripheral blood T lymphocytes in MS patients. We found that T cells from MS patients had significantly more IL‐6 receptors [Bmax: 279 ± 7 vs. 246 ± 8 (mean ± SEM) receptors/cell, in patients and controls, respectively], whereas Kd values were similar to those of healthy subjects [26.8 ± 0.7 vs. 25.4 ± 0.6 (mean ± SEM) pM, in patients and controls, respectively]. Significant (P < 0.05) differences in IL‐6 binding values were observed between stable patients and those relapsing (272 ± 9 vs. 300 ± 12 (mean ± SEM) receptors/cell, respectively). We found significantly (P < 0.001) higher amounts of IL‐6 receptors on CD4+ T cells from MS patients than on CD4+ lymphocytes from controls (434 ± 11 vs. 363 ± 9 (mean ± SEM) receptors/cell, respectively); CD8+ T cells showed very few IL‐6 receptors in both patients and controls. These data are discussed in terms of MS immune pathogenesis and pathophysiology, because T‐cell activation seems to be linked to increased IL‐6 binding. The upregulated IL‐6 system might be involved in antibody‐mediated demyelinating pathways, because IL‐6 is well known to enhance humoral immune response.

Macro-EMG and MUNE Changes in Patients with Amyotrophic Lateral Sclerosis: One-Year Follow Up

ABSTRACT Objective: We assessed changes in Motor Units (MU) and extent of MU loss using macro-electromyography (macro-EMG) and Motor Unit Number Estimation (MUNE). Methods: We applied these techniques to a sample of 61 Amyotrophic Lateral Sclerosis (ALS) patients basally (T0) and after 4 (T1), 8 (T2), and 12 (T3) months. Macro Motor Unit Potentials (macro-MUPs) were derived from Biceps Brachii (BB) muscle; MUNE was performed both in BB and Abductor Digiti Minimi (ADM) muscles of the same side. Results: Macro-MUPs area resulted in progressive increase at T1, T2, and T3 with respect to T0. Fiber density (FD) at T3 decreases a bit than at T2. Functioning MUS number decreased in both the muscles throughout the entire follow-up with respect to T0 and the rate of MU decrease was similar in both the muscles, but steeper distally. Conclusions and Significance: Macro-EMG increase and FD decrease suggest that a process of MU rearrangement begins to fall after 8 months of disease course. Combined use of macro-EMG and MUNE techniques in ALS patients allows to track over time changes in muscle MU features and number in face of progressive anterior horn cells death during diseases evolution.

ELECTROPHYSIOLOGICAL EVALUATION OF GENITO-SPHINCTERIC DYSFUNCTION IN MULTIPLE SYSTEM ATROPHY

Thirteen patients with multiple system atrophy underwent multimodality neurophysiological evaluation, including sphincteric needle electromyography (EMG), sacral reflexes, pudendal nerve terminal latency, pudendal (PSEPs) and tibialis posterior nerve somatosensory evoked potentials (TPSEPs), and perineal motor evoked potentials (PMEPs). EMG revealed denervation or neurogenic changes, with reduction in spontaneous tonic activity at rest and abnormal pudendal nerve terminal latency in 10 patients (76.9%); anal reflex was delayed in 7 patients (53.8%). TPSEPs scalp responses were clearly abnormal in 4 patients (30.7%), whereas PSEPs exhibited changes in 9 (69.2%): in 6 patients responses were delayed at lumbar level (46.2%), and in 5 over the scalp (38.4%). PMEPs showed an increase in latency with a mild prolongation of central motor conduction time (CMCT) in 2 cases (15.3%); 1 patient had prolonged latencies following both cortical and sacral stimulation, but a normal CMCT. Even if diagnostic yield is not improved using these investigations they provide evidence of multiple lesion sites other than Onufs nucleus.

T‐cell interleukin‐6 receptor binding in interferon‐β‐1b‐treated multiple sclerosis patients

Multiple sclerosis (MS) is a T‐cell‐mediated autoimmune demyelinating disease of the central nervous system, associated with an altered cytokine network. We previously assayed peripheral blood T‐lymphocyte binding for two prototypic cytokines, tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), and found that T cells from MS patients had significantly more TNF‐α and IL‐6 receptors than those from healthy controls. In the present work, paralleling a previous one on T‐cell TNF‐α binding, we studied the effect of interferon (IFN)‐β‐1b treatment on T‐lymphocyte IL‐6 binding in patients with relapsing–remitting MS. T cells from MS patients had significantly (P < 0.001) higher amounts of IL‐6 receptors than those from controls [292 ± 6 vs. 228 ± 8 (mean ± SEM) receptors per cell, respectively], whereas the ligand‐receptor affinity values were similar in the two groups [26.2 ± 0.7 and 25.7 ± 0.4 (mean ± SEM) pmoles/l, respectively]. After a 3‐month IFN‐β‐1b treatment, they showed a significant decrease in IL‐6 binding [266 ± 7 (mean ± SEM) receptors per cell]. After 6 and 9 months, T‐cell IL‐6 Bmax values were even lower [258 ± 8 and 251 ± 8 (mean ± SEM) receptors per cell]. Since an increased IL‐6 binding might be linked to a lymphocyte activation, our data give further support for an enhanced immune response in patients with MS. Our data seem to demonstrate that the major effects of IFN‐β‐1b treatment result in a decrease of T‐cell activation.