Anat Achiron

Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses.

We conducted a double-blind, placebo-controlled study of 40 patients (aged 19 to 60 years) with clinical definite relapsing remitting (RR) MS and brain MRI confirmed. Patients were randomly assigned to receive a loading dose of immunoglobulin IgG (0.4 g/kg/body weight per day for 5 consecutive days), followed by single booster doses (0.4 g/kg/body weight) or placebo once every 2 months for 2 years. The primary outcome measures were change in the yearly exacerbation rate (YER), proportion of exacerbation-free patients, and time until first exacerbation. Neurologic disability, exacerbation severity, and changes in brain MRI lesion score were the secondary outcome measures, all determined at baseline, 1 year, and on completion. Treated patients showed a reduction in YER from 1.85 to 0.75 after 1 year and 0.42 after 2 years versus 1.55 to 1.8 after 1 year and to 1.4 after 2 years in the placebo group (p = 0.0006, overall), reflecting a 38.6% reduction in relapse rate. Six patients in the IVIg group were exacerbation free throughout the 2—year period of the study, whereas none were exacerbation free in the placebo group. The median time to first exacerbation was 233 days in the IVIg group versus 82 days in the placebo group (p = 0.003). Neurologic disability as measured by the Expanded Disability Status Scale (EDSS score) decreased by 0.3 in the IVIg group and increased by 0.15 in the placebo group. Total lesion score evaluated by brain MRI did not show a significant difference between groups. Side effects were minor and occurred in only 19 of 630 (3.0%) infusions administered in both groups. Our results suggest that IVIg may be safe and effective in reducing the frequency of exacerbations in RR-MS.

Dopamine induces apoptosis-like cell death in cultured chick sympathetic neurons — A possible novel pathogenetic mechanism in Parkinson's disease

We report that exposure of cultured, postmitotic chick-embryo sympathetic neurons, to physiological concentrations of dopamine (0.1-1 mM) for 24 h initiates a cellular death process characteristic of apoptosis (= programmed-cell-death, PCD). Dopamine caused marked morphological alterations, mainly axonal disintegration and severe shrinkage and condensation of cell bodies. Flow-cytometric analysis of propidium-iodide-stained cell nuclei revealed the characteristic apoptotic nuclear fragmentation: increase in nuclear granularity and emergence of a large, distinct population of nuclei with reduced DNA content (subdiploid, apoptotic peak). These alterations were similar to changes induced by nerve growth factor (NGF) deprivation, a model of sympathetic neuronal PCD. Alterations were inhibited by the anti-oxidative agent DTT. Inappropriate, dopamine-induced activation of PCD might have a role in nigral neuronal degeneration in Parkinsons disease.

Cognitive impairment in probable multiple sclerosis

Objectives: To evaluate and characterise cognitive impairment in the very early stage of multiple sclerosis (MS), in which patients are still diagnosed as suffering from probable MS. Methods: The Brief Repeatable Battery-Neuropsychological (BRB-N) that has been validated for MS patients was used. Abnormal performance was defined as one standard deviation below the mean reported for healthy age matched subjects. Neurological disability and brain magnetic resonance imaging (MRI) were performed for all patients. Correlation coefficients were calculated between disease burden variables and performance on the BRB-N. Results: Sixty seven patients with probable MS were evaluated within a mean of one month of the onset of new neurological symptoms. Evidence for the presence of cognitive impairment was shown in 53.7% of patients. Verbal abilities and attention span were most frequently affected. Impairment was not correlated with neurological disability or MRI disease burden. Conclusion: Prevalent cognitive impairment already exists at onset of MS.

Gait analysis in multiple sclerosis: Characterization of temporal–spatial parameters using GAITRite functional ambulation system

BACKGROUND Gait impairment is a significant problem in multiple sclerosis (MS), leading to decreased activity and limitations in function. However, specific characterization of abnormal gait in MS patients has only been described in small groups of patients, mainly using observational tools. OBJECTIVE The aim of the current study was to characterize the spatio-temporal gait parameters in MS patients and ascribe them to clinical variables, in order to enable target-oriented management. METHODS Eighty-one MS patients with relatively short disease duration (5.3; S.E.=0.3) able of independent walking and 25 age-matched healthy subjects were evaluated using the GAITRite Functional Ambulation System. Subjects also underwent a thorough neurological examination to assess their disability using the Expanded Disability Status Scale (EDSS). Gait parameters were compared between patients and able-bodied controls to characterize the gait impairments in MS. Within the group of patients the correlation of gait parameters with clinical neurological variables was investigated. RESULTS MS patients demonstrated significant impairments in all spatio-temporal gait parameters compared to able-bodied healthy subjects. MS patients had a mean Functional Ambulation Profile (FAP) score of 83.0 and a mean velocity of 85.5m/s while the controls had a FAP score of 95.0 (p<0.001) and a velocity of 138.6m/s (p<0.001). Cadence was 94.4 steps/min in MS patients and 115.2 in controls (p<0.001). Step length was 45.3 cm in MS patients and 72.1 cm in controls (p<0.001). FAP score negatively correlated with disease duration (p<0.001) and EDSS (p<0.001). The most significant correlations of the FAP were found with the pyramidal (p<0.002), and the cerebellar (p<0.05) functional scores. Specifically, gait velocity, single support time and swing time negatively correlated with the pyramidal functional score, while double support time positively correlated with the pyramidal score. The base support width positively correlated with cerebellar functional score. CONCLUSIONS Gait parameters were impaired in MS, even in patients with relatively short disease duration. The impaired gait patterns correlated with the associated neurological disability. Specific and accurate assessment of gait can be a useful tool to monitor MS evolution and can be used to advise target-oriented rehabilitative management of MS patients.

Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis

Abstract.Acute exacerbations may complicate the course of pregnancy and the postpartum period in patients with relapsing-remitting multiple sclerosis (RRMS). To evaluate relapse rate and the effect of immunomodulatory treatment with intravenous immunoglobulin (IVIg) during pregnancy and the postpartum period we retrospectively analysed the data of 108 pregnant RRMS patients. Group I patients were not treated, Group II patients were treated with IVIg 0.4 g/kg body weight/day for 5 consecutive days within the first week after delivery with additional booster doses of 0.4 g/kg body weight/day at 6 and 12 weeks postpartum (defined as 12 weeks after labor), and Group III patients were treated continuously with IVIg during gestation and the postpartum period (0.4 g/kg body weight/day for 5 consecutive days within the 6–8 weeks of gestation with additional booster doses of 0.4 g/kg body weight/day once every 6 weeks until 12 weeks postpartum). All patients underwent antenatal care and fetal ultrasonographic surveillance examinations. Relapse rate per woman per year during the pregnancy and the postpartum period as well as neonatal outcome data and IVIg related adverse events were analysed.Relapse rate per woman per year for patients treated with IVIg for the whole pregnancy and postpartum period (Group III, N = 28) compared with the untreated Group I patients (N = 39) were as follows: first trimester 0.43 vs. 0.72, second trimester 0.15 vs. 0.61, third trimester 0.0 vs. 0.41, and postpartum period 0.28 vs.1.33 (p < 0.05). Patients treated with IVIg only during the postpartum period (Group II, N = 41) also showed a decrease in relapse rate compared with untreated Group I patients, 0.58 vs. 1.33 (p = 0.012). The mean maternal age, disease duration, gestational age at delivery and fetal delivery weight did not significantly differ between the three groups. Mode of delivery, obstetrical complications, the use of epidural analgesia and breast-feeding, did not affect postpartum relapse rate. No severe adverse events were associated with IVIg treatment either during the pregnancy or postpartum period for the patients and newborns.We conclude that in RRMS patients IVIg treatment could be considered as an optional treatment to reduce the incidence of pregnancy and postpartum-related relapses. Further randomized double-blind studies are needed to confirm our findings.

Blood transcriptional signatures of multiple sclerosis: Unique gene expression of disease activity

Multiple sclerosis (MS) is a central nervous system disease with an unpredictable course and outcome. Peripheral blood mononuclear cells (PBMCs) are involved in the disease pathogenesis and induce active demyelination. Using oligonucleotide microarrays, we identified a statistically significant transcriptional signature of 1,109 genes in PBMCs from 26 MS patients, irrespective of disease activation state or immunomodulatory treatment. This signature contains genes that implicate underlying processes involved in MS pathogenesis including T‐cell activation and expansion, inflammation, and apoptosis. Another transcriptional signature of 721 genes involved in cellular recruitment, epitope spreading, and escape from regulatory immune surveillance identified MS patients in acute relapse compared with remission. Our results offer new opportunity for understanding the mechanisms involved in MS and indicate that gene expression patterns in PBMCs contain information about a remote‐target disease process that may be useful for diagnosis and future tailoring of therapeutic strategies for MS.

Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis†

To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12‐week period in multiple sclerosis patients.

Low-back pain of pregnancy

Background. Low‐back pain (LBP) is a commonly observed symptom during pregnancy. Despite its high frequency the extent of the problem is less well documented and detailed studies concerning related risk factors are scarce. Furthermore, efforts to address the problem are hampered by the inability to predict accurately which pregnancies are at risk. This study was conducted in order to assess the frequency, manifestations and the contribution of various factors to the development of LBP during pregnancy.

Effect of Interferon-beta-1b on Cognitive Functions in Multiple Sclerosis

Introduction: Multiple sclerosis (MS) is recognised as a central nervous system disease also affecting cognition. The rate of cognitive dysfunction in MS is in the range of 45–65% and adversely affect the quality of life. Objective: To evaluate the effect of 1 year of treatment with interferon-beta-1b (IFNβ-1b) on cognitive functions in patients suffering from relapsing-remitting MS. Methods: A battery of cognitive tests was used to assess verbal learning, delayed recall, visual learning and recall, complex attention, concentration and verbal fluency at baseline and after 1 year of treatment with IFNβ-1b. A group of 23 relapsing-remitting MS patients matched for neurological disability served as controls. Results: Eighteen of 23 patients treated with IFNβ-1b (74%) completed the study. In the IFNβ-1b-treated group, complex attention, concentration as well as visual learning and recall improved significantly (p = 0.024, p = 0.006 and p = 0.005, respectively), while no deterioration was observed in the other dimensions. In the control group, complex attention, verbal fluency, as well as visual learning and recall deteriorated significantly (p = 0.02, p = 0.004 and p = 0.01, respectively), while no deterioration was observed in the other dimensions. Conclusion: Immunomodulating drugs that reduce the relapse rate and slow the disease progression also inhibit cognitive deterioration in patients with MS.

Reduced cancer incidence among patients with schizophrenia

The incidence of cancer in patients with schizophrenia has been conversely reported to be higher, lower, or similar to that in the general population. The effects of lifestyle factors such as excess smoking, exposure to neuroleptic medications, and genetic factors that may influence the incidence of cancer in this group are not clear. The current study was performed to evaluate the frequency of cancer in a large cohort of patients with schizophrenia and to determine the standardized incidence ratios (SIRs) of any malignancy in this group.