Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration.

BACKGROUND: Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if initiated before lymphocyte recovery has occurred. OBJECTIVE: To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent in relation to washout duration using data from the Italian MS Register. METHODS: The risk of relapses was assessed in relation to different washout durations (< 6, 6-11, 12-17 and > / = 18 weeks) in patients starting alemtuzumab, rituximab, ocrelizumab or cladribine following FTY discontinuation. RESULTS: We included 329 patients in the analysis (226F, 103 M; mean age 41 ± 10 years). During the cell-depleting treatment, the incidence rate ratio for a relapse was significantly greater in patients with a washout period of 12-17 and > / = 18 weeks compared to the reference period (< 6 weeks). The risk of a relapse was significantly influenced by the occurrence of relapses during FTY treatment and by washout length, with hazard ratios markedly increasing with the washout duration. CONCLUSION: The risk of relapses increases with the washout duration when switching from FTY to lymphocyte-depleting agents.

Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Dimethyl fumarate (DMF) causes a mean lymphocyte count drop of approximately 30% in relapsing-remitting multiple sclerosis (RRMS) patients. The relationship between this reduction and DMF effectiveness is controversial. The objective was to investigate if the decrease in absolute lymphocyte count (ALC) from baseline during DMF treatment is associated with clinical and magnetic resonance imaging (MRI) disease activity. A secondary aim was to evaluate ALC variations over time in a real-life cohort of DMF-treated patients. METHODS: Demographic, laboratory, clinical and MRI data were collected in this observational multicentre study, conducted on RRMS patients treated with DMF for at least 6 months. Multivariate Cox models were performed to evaluate the impact of 6-month ALC drop on time to no evidence of disease activity (NEDA-3) status loss. NEDA-3 is defined as absence of clinical relapses, MRI disease activity and confirmed disability progression. RESULTS: In all, 476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed up to 5-year follow-up. A greater lymphocyte decrease was associated with a lower risk of NEDA-3 status loss (hazard ratio 0.87, P = 0.01). A worse outcome in patients with lower ALC drop (<11.5%), compared with higher tertiles (11.5%-40.5% and >40.5%), was observed (P = 0.008). The nadir of ALC drop (-33.6%) and 35% of grade III lymphopaenia cases occurred after 12 months of treatment. CONCLUSION: A higher lymphocyte count drop at 6 months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.

Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band-negative patients with suspected multiple sclerosis.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) kappa free light chains (FLCs) may be a more sensitive marker of intrathecal immunoglobulin (Ig)G synthesis compared with oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a multiple sclerosis (MS) diagnosis in a group of OCB-negative patients with suspected MS. METHODS: The CSF and serum kappa and lambda FLCs were tested using the Freelite kit (serum) and Freelite Mx (CSF) assay (The Binding Site Group, Bimingham, UK) in 391 OCB-negative patients with suspected/possible MS and in 54 OCB-positive patients with MS. RESULTS: The CSF kappa FLC levels were below the detection limit (0.27 mg/L) in 61% of patients. Using quantitative data, we found the best kappa index cut-off value for the prediction of MS to be 5.8. A kappa index ≥5.8 was present in 25% of OCB-negative MS (23/92) and in 98% of OCB-positive patients with MS. Using a qualitative approach and a kappa index cut-off of 5.9, based on literature data, we likewise found that 24% of OCB-negative patients with MS had a kappa index ≥5.9, compared with 5.4% of OCB-negative patients without MS (P < 0.001). No reliable data could be obtained for the lambda index; lambda FLCs were below the detection limit (0.68 mg/L) in 90% of CSF samples. CONCLUSIONS: The kappa index could contribute to the identification of OCB-negative patients with a high probability of an MS diagnosis. Using more sensitive techniques might even improve the diagnostic performance of the kappa index and better define the role of the lambda index.

Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study.

BACKGROUND AND PURPOSE: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. METHODS: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. RESULTS: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7-1.6, P = 0.69). CONCLUSION: Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.

Use of herbal remedies by multiple sclerosis patients: a nation-wide survey in Italy.

Though recent progress in multiple sclerosis (MS) treatment is remarkable, numerous unmet needs remain to be addressed often inducing patients to look for complementary and alternative medicines (CAM), especially herbal remedies (HR). HR use, scarcely investigated in MS, may cause adverse reactions (AR) and interfere with conventional treatment. We performed a survey aimed at evaluating use and attitudes towards HR and factor associated to HR use. Other CAM use and attitudes have been investigated as well. Multiple-choice questionnaires were distributed to MS out patients attending 14 Italian referral Centers. Multivariable logistic regression was used to identify HR use determinants. Present/past HR use for either MS or other diseases was reported in 35.6 % of 2419 cases (95 % CI 36.0-40.0 %). CAM use was reported in 42.5 % of cases. Independent predictors of HR use were represented by higher education, geographic area, dissatisfaction with conventional treatment of diseases other than MS and benefit perception from CAM use. Both HR and CAM use were not always disclosed to the healthcare professional. In conclusion, HR and other CAM appear to be popular among MS patients. The involvement of the healthcare professionals appears to be scarce with potential risk of AR or interference with conventional treatments.

Biological markers in cerebrospinal fluid for axonal impairment in multiple sclerosis: acetylcholinesterase activity cannot be considered a useful biomarker.

An impairment of the cholinergic system activity has been demonstrated in multiple sclerosis (MS). The correlation between the cholinergic system and the cognitive dysfunction in MS has led to studies on the use of acetylcholinesterase inhibitors (AChEI). The acetylcholinesterase (AChE), essential enzyme for the regulation of turnover of acetylcholine, can be considered the most important biochemical indicator of cholinergic signaling in the nervous system. Besides its catalytic properties, AChE has a crucial role in the regulation of the immune function. Based on the role of the AChe in the regulation of cholinergic signaling in the nervous system, the aim of the present study is to evaluate the activity of AChE in different pathological conditions: MS, other inflammatory neurological disorders (OIND) and non-inflammatory neurological disorders (NIND). We measured AChE activity in CSF samples obtained from 34 relapsing-remitting MS patients and, as controls, 40 patients with other inflammatory neurological disorders (OIND) and 40 subjects with other non-inflammatory neurological disorders (NIND). Fluorimetric detection of the AChE in MS patients and in the controls showed no statistically significant differences: 1.507 ± 0.403 nmol/ml/min in MS patients, 1.484 ± 0.496 nmol/ml/min in OIND and 1.305 ± 0.504 nmol/ml/min in NIND. Similar results were obtained in another recent study, using a different method. Further studies must be conducted on a larger number of patients, with different degrees of cognitive impairment. However, AChE measured in CSF can probably not be considered a useful biomarker for the assessment of the functional alterations of cholinergic system in pathological conditions.

Técnicas neuroquirúrgicas de neuromodulación del dolor / Neurosurgical techniques for the neuromodulation of pain

Resumen. La neuromodulación para el tratamiento del dolor se remonta a los tiempos de los antiguos egipcios, quienes aplicaban corrientes eléctricas producidas en la naturaleza para modular la sensación dolorosa. Desde entonces, este concepto ha evolucionado de forma paralela al desarrollo científico y tecnológico, y se han originado diversas modalidades de neuromodulación con indicaciones y características diferentes. Los pacientes con dolor crónico pueden estar en situaciones de incapacidad significativa, con importantes repercusiones físicas, laborales y sociales. La estimulación de nervios periféricos, medular crónica analgésica, cerebral profunda y motora cortical son técnicas eficaces en pacientes seleccionados, que ofrecen control del dolor con escasos efectos secundarios

Summary. Neuromodulation for treating pain goes back to the times of the ancient Egyptians, who applied natural electric currents to modulate the painful sensation. Since then, this concept has been developed in parallel with the scientific and technological development, and various forms of neuromodulation with different indications and characteristics have originated. Chronic pain may produce significant disability, which leads to important physical, social and psychological consequences. Peripheral nerve, spinal cord, deep brain and motor cortex stimulation are safe and effective techniquesthat control pain and improve quality of life in selected patients

Serum and CSF N-acetyl aspartate levels differ in multiple sclerosis and neuromyelitis optica.

BACKGROUND: The identification of biomarkers able to improve the differential diagnosis between multiple sclerosis (MS) and neuromyelitis optica (NMO) is challenging because of a different prognosis and response to treatment. Growing evidence indicates that brain and CSF N-acetyl aspartate (NAA) concentration is a useful marker for characterising different phases of axonal pathology in demyelinating diseases, and preliminary studies suggest that increased serum NAA levels may be a telltale sign of acute neuronal damage or defective NAA metabolism in oligodendrocytes. OBJECTIVE: To evaluate whether serum and CSF NAA concentration differs in patients with MS and NMO. DESIGN: Observational, multicentre, prospective, cross sectional study. METHODS: Serum samples were collected from 48 relapsing-remitting MS, 32 NMO and 76 age matched healthy controls. Coeval CSF samples were available for all MS and for 8/32 NMO patients. NAA was measured in serum and CSF by liquid chromatography-mass spectrometry. RESULTS: MS patients showed higher serum and CSF NAA levels than NMO patients, and higher serum NAA levels than healthy controls (p<0.001). High serum NAA values, exceeding the 95th percentile of serum NAA values in healthy controls, were found in 100% of patients with MS and in no patient with NMO. No differences in serum NAA levels were found between NMO and healthy controls. In MS, serum and CSF NAA levels correlated with disability score. CONCLUSIONS: Determination of serum and CSF NAA levels may represent a suitable tool in the diagnostic laboratory workup to differentiate MS and NMO.

Primary progressive multiple sclerosis and generalized myasthenia gravis: an uncommon association.

The co-occurrence of myasthenia gravis (MG) and multiple sclerosis (MS) is rare, and in all the described cases MS had a relapsing-remitting course and the diseases had a benign clinical evolution. We describe herewith a patient with primary progressive MS (PPMS) and generalized MG with severe clinical course. This is the first report on a case of PPMS associated to MG. Studies on the histology and pathogenesis show that neurodegeneration is predominant over inflammation in PPMS, even if cellular and humoral immune-mediated mechanisms are thought to maintain a crucial importance in the development and progression of this form of disease. In the present case, the detection of cerebrospinal fluid IgM oligoclonal bands support the hypothesis of a possible role of antibody-mediated immunity in PPMS and suggest that humoral immunity may take part in the concomitant development of both MS and MG.

Is serum neopterin level a marker of responsiveness to interferon beta-1a therapy in multiple sclerosis?

BACKGROUND: Interferon beta (INFbeta) may induce the expression of several proteins, including neopterin, considered a biological marker of INFbeta activity. OBJECTIVES: The aim of this study was to determine the serum neopterin concentration at the beginning of, and during, IFNbeta-1a therapy in relapsing-remitting multiple sclerosis (r-r MS) patients, and to look for a possible correlation between protein synthesis and the clinical course of the disease. METHODS: Thirteen r-r MS patients were treated with INFbeta-1a (i.m. 6 MIU/week) for 2 years. Blood samples for neopterin determinations were taken daily over a period of 1 week at the end of each 6 months of therapy, and tested for neutralizing antibodies (NABs). RESULTS: Neopterin levels peaked 24-48 h post-injection and returned to baseline after 120 h. After 1 year of therapy, four patients dropped out of the study because of progression of the disease: in these subjects a significant decrement of neopterin was observed. CONCLUSION: Neopterin baseline values were not found to decrease over the 2 years of therapy, and neopterin may be considered to be a useful marker of responsiveness to IFNbeta.

Monofocal acute large demyelinating lesion mimicking brain glioma.

We report the case of a 34-year-old woman with clinical, neuroradiological and intraoperative histological findings, suggesting a low-grade astrocytic tumour. The demyelinating nature of the lesion was established through biopsy only after neurosurgery. The lesion size, in fact, greatly exceeded that of the perivenous demyelination seen in typical multiple sclerosis (MS) and tended to present as a space-occupying mass. This case underlines the importance of considering demyelinating isolated lesions in the differential diagnosis of a brain mass. Since misdiagnosis can result in unwarranted and aggressive therapy, it is critical for the neurologist to be aware of this serious diagnostic pitfall.

Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7.

We examined the association between risk of sporadic amyotrophic lateral sclerosis (ALS) and seroprevalence of antibodies to echovirus-7 (echo-7) and herpesviruses 6, 7, and 8 through a population-based case-control study. We enrolled in a northern Italy area 20 newly diagnosed ALS cases and 20 referents. Risk of ALS was higher in subjects seropositive for echo-7 when we used the immunofluorescent assay, while little increase was noted with the neutralization test. Considering the different characteristics of these two serological assays, these results suggest an association between disease risk and infection with enterovirus (EV) family members (not specifically echo-7). ALS risk was slightly associated with seropositivity of human herpesvirus-6 (odds ratio: 3.2; p = 0.102) and more strongly with human herpesvirus-8 seropositivity (odds ratio: 8.4; p = 0.064), though these point estimates were statistically unstable due to the limited number of observed cases. The findings of this study warrant further investigation in larger studies of the possible etiologic role of EV or herpesvirus infection in sporadic ALS.

[The short-term effects of air pollution on mortality: the results of the EMECAM project in the city of Pamplona, 1991-95. Estudio Multicéntrico Español sobre la Relación entre la Contaminación Atmosférica y la Mortalidad]. / Efectos a corto plazo de la contaminación atmosférica sobre la mortalidad: resultados del proyecto EMECAM en la ciudad de Pamplona, 1991-95.

BACKGROUND: To assess the short-term impact of air pollution on the daily death rate in the city of Pamplona. METHOD: Ecological study with a population of 212,000 inhabitants. A time series data analysis is conducted by means of multiple linear regression and Poisson regression, with the daily death rate data, air pollution levels for Particles and SO2, weather parameters of average relative humidity and temperature daily and number of cases weekly of flu for the 1991-1995 period. RESULTS: The average number of deaths daily for non-external causes is that of 4.15 deaths, with a range from zero to 13 deaths. The city of Pamplona has a mean annual temperature of 12.7 degrees C (-2.3 degrees C to 31.6 degrees C) and a relative humidity of 68.5%. In the model, the temperature (with a one-day time lag and a six-day time lag temperature squared) and the humidity (with a one-day time lag) is related to the death rate for all causes. But the death rate for non-external causes is only related in the model with the temperature (one-day time lag, P: 0.035) and five-day time lag with temperature squared (p: 0.028). The timely estimates of the relative particle-related risk show that the highest risk of dying stems from respiratory causes with a relative risk of 1.13. However, none of these relationships is statistically significant. In the case of Sulfur Dioxide, the estimates closely near the zero figure, and none of them is significant. CONCLUSIONS: The Temperature has an impact of the death rate for all causes, both external and non-external, and the relative humidity solely has an impact on the death rate for non-external causes. It has not been possible to prove any influence of the daily environmental pollution levels on the daily death rate.

Indications for a home standing program for individuals with spinal cord injury.

Additional analyses were conducted on a recently published survey of persons with spinal cord injury (SCI) who used standing mobility devices. Frequency and duration of standing were examined in relation to outcomes using chi square analyses. Respondents (n = 99) who stood 30 minutes or more per day had significantly improved quality of life, fewer bed sores, fewer bladder infections, improved bowel regularity, and improved ability to straighten their legs compared with those who stood less time. Compliance with regular home standing (at least once per week) was high (74%). The data also suggest that individuals with SCI could benefit from standing even if they were to begin several years after injury. The observation of patient benefits and high compliance rates suggest that mobile standing devices should be more strongly considered as a major intervention for relief from secondary medical complications and improvement in overall quality of life of individuals with SCI.

Human herpes virus 6 and human herpes virus 8 DNA sequences in brains of multiple sclerosis patients, normal adults and children.

In order to determine whether the newly discovered human herpesviruses (HHVs) are involved in multiple sclerosis (MS), we investigated by polymerase chain reaction the presence of specific deoxyribonucleic acid (DNA) sequences belonging to human herpesvirus 6 (HHV-6) and to human herpesvirus 8 (HHV-8), in the peripheral blood mononuclear cells (PBMCs), and in the brain and spinal cord plaques from MS patients. Normal adult and stillborn children's brains were investigated as controls. PBMCs from 56 MS patients contained HHV-6 DNA in only 3 cases and in none were there HHV-8 sequences. The cerebral DNA from 5 MS patients was positive for HHV-8 and not for HHV-6 sequences, while the nervous tissue of one patient who died with neuromyelitis optica was positive for HHV-6 and negative for HHV-8. The brains of 4/8 adult controls were positive for HHV-6, as were 3/8 for HHV-8; none of the 7 stillborn children's cerebral tissue contained HHV-6 sequences, while 2 contained HHV-8 DNA. Although these data do not support a hypothesis that there is a role for these two HHVs in the pathogenesis of MS, nevertheless it may be suggested that (1) the two viruses possess strong neurotropism and the central nervous system seems to be a reservoir for them (2) HHV-6 infection is probably not transmitted maternally, but is acquired later in infancy.

Pain in the first stage of labor: relationship with the patient's position.

This study was designed to evaluate the relationship between the parturient's position and her abdominal and lumbar (continuous and contraction) pain during the first stage of labor. A homogeneous group of 100 parturients was randomly assigned to alternately assume the horizontal or the vertical position for 15-min periods. Their pain was measured at 2-3, 4-5, 6-7, and 8-9 centimeters dilatation. To avoid "carry over" effect, these positions were preceded by a self-elected posture. Thus, the patient adopted (a) a self-elected position, (b) recumbent (or erect), (c) a self-elected position, (d) erect (or recumbent), and so on. Pain intensity was measured by the Argentine Pain Questionnaire's Present Pain Intensity and the Huskisson's visual analogue scale. Only the patients with at least one pain evaluation in both positions using both instruments were included in the study. The setting for the study was the obstetric department of a general hospital for people connected with public education (professors, teachers, or members of school administrative staffs). The analysis revealed that a majority of patients felt less abdominal and lumbar pain, either continuous or due to contractions, during recumbency. The effect was more remarkable when dilation exceeded 5 centimeters and less intense during the first half of the first stage of labor.

Encephalomyeloradiculopathy associated with Epstein-Barr virus: primary infection or reactivation?

INTRODUCTION: Encephalomyeloradiculopathy (EMR) is a new syndrome, characterized by extensive involvement of the nervous system at different levels, including brain, medulla and spinal roots. We describe a patient presenting with prodromal febrile illness, followed by a wide infection of the nervous system with transverse myelitis and less severe meningitis, encephalitis and polyradiculopathy. The patient was treated with high-dose corticosteroids, antibiotics and acyclovir; in spite of therapy his condition improved very slowly, with severe neurological sequelae. MATERIAL AND METHODS: Antiviral antibodies were searched for in serum and cerebrospinal fluid (CSF) by commercially available ELISA kits. Viral investigations were performed by cell culture isolation and search for viral antigens, and genomic nucleic acids were investigated by polymerase chain reaction (PCR). RESULTS: Virological and serological studies evidenced a primary infection by cytomegalovirus (CMV), possibly responsible for the prodromal illness, persisting in the course of the disease. PCR performed in the peripheral blood mononuclear cells (PBMCs), DNA collected early and in the CSF drawn 30 days after the onset of the disease showed Epstein-Barr virus (EBV) DNA. The serum panel of EBV antibodies was typical of an intercurrent virus reactivation, more than of a primary infection. CONCLUSION: EBV is known to be highly infectious for the nervous system, in this case of EMR the presence of DNA sequences in the PBMCs and CSF suggests that EBV plays a role in the development of this newly described syndrome.