Abstract: OBJECTIVE: To describe the effect of natalizumab in the treatment of subjects with active multiple sclerosis (MS) treated before the age of 18 years. METHODS: Nineteen pediatric subjects with MS (mean age 14.6 +/- 2.2 years, mean number of attacks 5.2 +/- 1.9 during the pretreatment phase of 27.7 +/- 19.7 months, median pretreatment Expanded Disability Status Scale score [EDSS] 2.5, range 1.0-5.0) were treated with natalizumab at the dose of 300 mg every 28 days. After treatment initiation, patients were reassessed clinically every month; brain MRI was performed at baseline and every 6 months. RESULTS: Patients received a median number of 15 infusions (range 6-26). A transient reversible worsening of preexisting symptoms occurred in 1 subject during and following the first infusion. All the patients remained relapse-free during the whole follow-up. The median EDSS decreased from 2.5 to 2.0 at the last visit (p < 0.001). EDSS remained stable in 5 cases, decreased by at least 0.5 point in 6 cases, and decreased by at least 1 point in 8 cases. At baseline, the mean number of gadolinium-enhancing lesions was 4.1 (range 1-20). During the follow-up, no gadolinium-enhancing lesions were detected (p = 0.008); 3 patients developed new T2-visible lesions at month 6 scan but the overall number of T2 lesions remained stable during the subsequent follow-up. Transient and mild side effects occurred in 8 patients. CONCLUSIONS: Natalizumab was well-tolerated in all subjects. A strong suppression of disease activity was observed in all subjects during the follow-up. Classification of evidence: This study provides Class IV evidence that natalizumab, 300 mg IV once every 28 days, decreased EDSS scores in pediatric patients with MS over a mean treatment period of 15.2 months.
Abstract: BACKGROUND: Diffusion tensor (DT) MRI enables quantification of the severity of brain and cervical cord pathology in multiple sclerosis (MS). OBJECTIVE: To investigate DT MRI patterns of cervical cord damage in patients with benign MS (BMS) and secondary progressive MS (SPMS), in order to achieve a better understanding of the mechanisms underlying the development of irreversible disability in MS. METHODS: Conventional and DT MRI scans of the cervical cord and brain were acquired from 40 BMS patients, 28 SPMS patients and 18 healthy individuals. Cervical cord and brain mean diffusivity (MD) and fractional anisotropy (FA) maps were created and average MD and FA were calculated. Cross sectional cord area (CSA) was also computed. RESULTS: 37 (92%) BMS patients and all (100%) SPMS patients had macroscopic cervical cord lesions. Compared with healthy individuals, BMS patients had higher average cord MD while SPMS patients had higher average cord MD, lower average cord FA and lower average CSA. Compared with BMS patients, SPMS patients had lower cord average FA and lower average CSA. In MS patients, Expanded Disability Status Scale (EDSS) was correlated with CSA (r = -0.47, p<0.0001), average cord FA (r = -0.37, p = 0.002) and brain T2 lesion volume (LV) (r = 0.34, p = 0.005). A multivariate regression model identified CSA, average cord FA and brain T2 LV as variables independently influencing the EDSS score (r = 0.58, p<0.0001). CONCLUSIONS: Cervical cord damage outside focal macroscopic lesions is limited in patients with BMS. The assessment of cord and brain pathology provides complementary information to improve the understanding of disability accumulation in MS.
Abstract: The immunomodulating activity of glatiramer acetate on T-cells of multiple sclerosis patients has only been partially clarified. The objective of this work was to investigate whether glatiramer acetate modifies thymic release of newly produced T-cells and the peripheral composition of the T-cell repertoire. T-cell receptor excision circles, (thymic) naive (CD4(+)CD45RA(+)CCR7(+)CD31(+)) T helper cells, and central (CD4(+)CD45RA(-)CCR7(+)) and effector (CD4(+)CD45RA(-)CCR7(-)) memory T-cells were evaluated in 89 untreated patients, 84 patients treated for at least 1 year, and 31 patients beginning treatment at the time of inclusion in the study and then followed-up for 12 months; controls were 81 healthy donors. The T-cell repertoire was analysed in selected samples. The percentage of (thymic)naive T helper cells was diminished in untreated patients, but rose to control values in treated subjects; a decrease in central memory T-cells was also observed in treated patients. Follow-up patients could be divided into two subgroups, one showing unmodified (thymic)naive T helper cells and T-cell diversity, the other in which the increased release of new T-cells was accompanied by modifications of the T-cell repertoire. Glatiramer acetate modifies the peripheral T-cell pool by activating a thymopoietic pathway of T-cell release that leads to a different setting of T-cell diversity and, likely, to a dilution of autoreactive T-cells.
Abstract: The main objective of this study is to evaluate the effect of immunomodulatory agents (IMAs) (Interferon-Beta, Glatiramer Acetate) in a large cohort of multiple sclerosis (MS) patients with disease onset in childhood or adolescence, treated before 16 years of age, after a long-term follow-up. A total of 130 patients were identified, 77 were treated with Avonex, 39 with Rebif/Betaferon, 14 with Copaxone. After a mean (SD) treatment duration of 53.6 +/- 27.0, 59.9 +/- 39.5 and 74.6 +/- 35.5 months, respectively, the relapse rate decreased significantly. The final EDSS score was unchanged with respect to the initial score. Similar results were also observed in subjects who continued a long-term follow-up after they were included in an observational study in 2004, and in subjects who were treated before 12 years of age. The frequency of clinical and laboratory adverse events was similar to that observed in adult patients. To conclude, IMAs were effective and well tolerated in paediatric patients with MS.
Abstract: OBJECTIVE: The term benign multiple sclerosis (BMS) is referred to patients who have a mild or absent disability several years after disease clinical onset. Axonal damage can be measured in vivo using proton MR spectroscopy ((1)H-MRS). In this study, we quantified the severity of "global" axonal damage in BMS and early relapsing-remitting (RR) MS patients, using whole brain N-acetylaspartate (WBNAA) (1)H-MRS, to better elucidate the structural correlates of a non-disabling disease evolution. METHODS: WBNAA concentration was measured in 37 patients with BMS (mean disease duration 22.3 years) and 17 patients with early RRMS (mean disease duration 4.0 years), using an unlocalized (1)H-MRS sequence. Dual echo and T1-weighted scans were also obtained to measure T2-hyperintense lesion volume (TLV) and normalized brain volume (NBV). RESULTS: TLV was higher in BMS (mean TLV = 13.1 mL) than in early RRMS patients (mean TLV = 7.2 mL) (P = 0.018), whereas neither NBV (mean NBV: 1491.0 mL in BMS vs 1520.3 mL in RRMS) nor WBNAA concentration (mean WBNAA: 10.5 mmol in BMS vs 11.4 mmol in RRMS) significantly differed between the two groups. In MS patients, no correlation was found between WBNAA concentration and Expanded Disability Status Scale (EDSS), TLV and NBV. CONCLUSIONS: The similar WBNAA concentrations seen in BMS and early RRMS patients fit with the notion that a non-disabling long-term evolution of MS may be due, at least in part, to non-progression of pathology. Such a condition seems to be independent from MRI-visible lesions burden.
Abstract: A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.
Abstract: OBJECTIVE: To investigate the endogenous dopaminergic/adrenergic system of lymphocytes in multiple sclerosis (MS) patients during treatment with interferon (IFN)-beta. METHODS: Patients with relapsing-remitting MS undergoing IFN-beta treatment were prospectively studied during the first year of treatment. Circulating lymphocytes were obtained at baseline and after 1, 3, 6 and 12 months of treatment and assayed for catecholamine (CA) production and mRNA expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in the synthesis of CA), beta(2)-adrenoceptors (AR) and D2, D3 and D5 dopaminergic receptors (DR). RESULTS: In cells from patients treated with IFN-beta for 12 months the production of CA hugely increased and was less sensitive to IFN-gamma-induced inhibition. Expression of mRNA for TH, beta(2)-AR and DRD5 was already enhanced after 1 month and further increased up to 6-12 months of treatment. On the contrary, DRD2 mRNA progressively decreased and DRD3 mRNA did not significantly change over the whole study period. CONCLUSIONS: In MS patients IFN-beta treatment enhances the ability of lymphocytes to produce CA, and induces extensive modifications of both beta(2)-AR and DR-operated pathways. The clinical relevance of these effects deserves consideration.
Abstract: Complex neuroendocrine mechanisms regulating the immune response can be recognized in all autoimmune diseases. Such mechanisms develop through endocrine loops and feedback processes along the hypothalamus-pituitary-gonads axis and the hypothalamus-pituitary- adrenal gland axis. Females are not only more susceptible to autoimmune diseases, but are also more exposed to relevant variations of hormonal levels that physiologically go along with women's life. This paper reviews female-specific issues in multiple sclerosis and how treatments must be considered accordingly. In particular, aspects related to puberty, menses, fertility, pregnancy, lactation and menopause are considered in addition to epidemiological and clinical issues.
Abstract: We retrospectively analyzed data from 70 multiple sclerosis (MS) patients treated with mitoxantrone (MX) before Interferon-beta (IFN-beta) because of clinically and MRI very active isolated syndrome (CIS) or relapsing-remitting MS (induction therapy) or due to breakthrough/persistently active disease in spite of IFN-beta (add-on/combination therapy), or for increased disability suggesting a secondary progression (rescue therapy). After almost 2-year follow-up, relapse rate and disability decreased very significantly in the two former groups while MX was essentially ineffective as rescue therapy. Induction therapy is a valid option for very aggressive/active CIS and MS at onset.
Abstract: Neutralising antibodies develop in 15% of interferon-beta (IFNbeta)-treated patients, causing the reduction of the clinical effects of the treatment. This is the first study that shows that switching patients from IFNbeta to glatiramer acetate (GA) in case of neutralising antibodies (NAb) positivity is effective in reducing relapse rate and in delaying the time to first relapse. In conclusion, our data suggest the use of GA in NAb-positive patients.
Abstract: Sixty, relapsing remitting (RR) multiple sclerosis (MS) patients, who underwent treatment with glatiramer acetate (GA), interferon (IFN)-beta 1a, and immunoglobulins (Igs) (20 per treatment group), were assessed for levels of brain-derived neurotrophic factor (BDNF) in the supernatants of unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) in the first year of treatment. Phytohemagglutinin (PHA), anti-OKT3 antibody, myelin basic protein (MPB) and GA were used as stimuli. Cytokine responses by ELISPOT and lymphoproliferative responses were also assessed. The GA-treated MS patient group showed a progressive increase in BDNF levels, from baseline to month three; thereafter, the levels remained stable and significantly greater compared with baseline and controls (ANOVA=P<0.001). IFN-beta 1a had no effect on BDNF production, whereas Igs induced a slight decrease (ANOVA=P<0.04). ELISPOT analysis revealed a significant decrease of IFN-gamma, an increase of interleukin (IL)-4 and IL-5 in GA-treated MS patients, and an increase of IL-10 in patients treated with IFN-beta 1a and GA. No significant correlation was found between BDNF secretion in the supernatants of PBMCs and cytokine response, lesional load, and measures of atrophy. Increased BDNF production related to GA treatment can have implications for understanding the mechanism of action of this immunomodulatory agent, in light of evidence suggesting its effects in promoting neuroprotective immunity in MS patients; however, a clinically measurable effect, especially in terms of an impact on actual disease progression, remains to be established.
Abstract: The objective was to evaluate the safety, tolerability and effectiveness of intramuscular (IM) interferon beta-1a (IFNbeta-1a; Avonex, Biogen) 30 mg once a week in patients with onset of symptoms of multiple sclerosis (MS) in childhood or adolescence. Patients with a diagnosis of definite MS according to McDonald's criteria, relapsing course according to Lublin's criteria, onset of symptoms of MS before 16 years of age, and who had received IM IFNbeta-1a therapy before 16 years of age were eligible for the study if they had a pretreatment and treatment duration of at least 6 months. Clinical and laboratory evaluations were performed every 3 months. A total of 52 patients were identified as receiving treatment with IM IFNbeta-1a 30 mg once a week before 16 years of age. Mean age at onset of symptoms of MS was 11.7+/-2.7 years, mean disease duration was 25.9+/-30.3 months, mean annualised relapse rate was 1.9+/-1.1 and mean Expanded Disability Status Scale (EDSS) score was 1.5+/-1.1. After a mean (+/-SD) treatment duration of 42.9+/-19.9 months, annualised relapse rate decreased to 0.4+/-0.5. Final EDSS score was 1.3+/-1.1. Adverse events were recorded for 35 (67%) patients (flulike syndrome, 33%; headache, 29%; myalgia, 21%; fever, 11%; fatigue, 6%; nausea and vomiting, 6%; and skin reaction, 4%); most were transient. IM IFNbeta-1a was effective and well tolerated in these paediatric patients with MS.
Abstract: Immunosuppressive drugs have been used out of label in multiple sclerosis (MS) for over 30 years and around 10% of patients are actually under immunosuppressive treatment. The rationale for immunosuppression in MS lies in the hypothesis that MS is an inflammatory immune-mediated disease that can take advantage of strong anti-inflammatory activity. Azathioprine, methotrexate, cyclophosphamide and mitoxantrone are the most utilised agents, but only the latter has been approved for clinically active MS. Many of them are safe in combination with interferon-beta and are under investigation in controlled trials. Plasma exchange is limited to catastrophic attacks in refractory MS whilst bone marrow transplantation is considered in patients with an extremely severe, active disease as the final option in escalation therapy. Although immunosuppressants are best effective in induction therapy, their use is limited by toxicity and potential long-term risk.
Abstract: Interferon (IFN)-gamma plays a pivotal role in the pathogenesis of multiple sclerosis (MS), while IFN-beta may be able to modify the clinical course of the disease, eventually also by counterbalancing IFN-gamma-mediated effects. Catecholamines (CA) exert important effects on the immune response, both as transmitters between the nervous and the immune system, as well as autocrine/paracrine mediators in immune cells, and several lines of evidence support their involvement in MS. In particular, dysregulated production of CA seems to occur in peripheral blood mononuclear cells (PBMCs) of MS patients. We assessed the effects of IFN-beta and IFN-gamma on endogenous CA in PBMCs. In cultured PBMCs stimulated with phytohaemagglutinin (PHA), IFN-beta increased CA production and induced CA release in the culture medium, while IFN-gamma decreased both CA production and the expression of mRNA for the CA-synthesizing enzyme tyrosine hydroxylase. Coincubation with both IFNs prevented the inhibitory effect of IFN-gamma, as well as the stimulatory effect of IFN-beta. IFNs are the first physiological compounds shown to affect endogenous CA in PBMCs: in view of the role of CA-dependent mechanisms in the immune response, these findings may help to better understand the mechanisms of action of IFN-beta as an immunomodulatory drug in MS.
Abstract: Reliable, and easy to measure, immunological markers able to denote disease characteristics in multiple sclerosis (MS) patients are still lacking. We applied a multivariate statistical analysis on results obtained by measuring-by real-time RT-PCR-mRNA levels of 25 immunological relevant molecules in PBMCs from 198 MS patients. The combined measurement of mRNA levels of IL-1beta, TNF-alpha, TGF-beta, CCL20 and CCR3 was able to distinguish MS patients from healthy individuals. CXCR5, CCL5, and CCR3 combined mRNA levels identify primary progressive MS patients while TNF-alpha, IL-10, CXCL10 and CCR3 differentiate relapsing MS patients. Our results indicate that multi-parametric analysis of mRNA levels of immunological relevant molecules in PBMCs may represent a successful strategy for the identification of putative peripheral markers of disease state and disease activity in MS patients.
Abstract: Not all patients with multiple sclerosis (MS) respond equally to available disease modifying agents (DMA). Rational and reliable criteria are needed to identify responders and non responders in order to optimize the treatment. Natural history of the disease, clinical evolution and magnetic resonance imaging are the putative indicators to be considered with this respect, but neutralizing antibodies, possible immunological markers and pathological or genetic diversity may also represent future additional indicators. Clinical recommendations and consensus criteria for defining a suboptimal response to DMA have been proposed by different international panels of experts, but all need validation in experimental settings to provide solid guidelines for establishing when and how to take action on MS treatment with DMA.
Abstract: OBJECTIVE: Immunomodulatory drugs (IDs) (interferon beta (IFNgamma) and glatiramer acetate (GA)) reduce relapse rate and disease progression in relapsing remitting multiple sclerosis (RRMS) but extensive data are not available on the effectiveness and tolerability of these drugs in childhood or adolescence. The aim of this study was to evaluate the impact of IFNbeta and GA in MS patients treated before 16 years of age. METHODS: A research group (Immunomodulatory Treatment of Early onset MS (ITEMS)) was promoted in Italy to collect a large series of patients affected by clinically definite and RRMS and treated with IDs before 16 years of age. Fifteen centres recognized subjects suitable for inclusion: 76 patients (52 females) were collected with a mean age at onset of 12.4 (SD 2.5) years, a mean disease duration of 18.6 (SD 14.7) and a relapse rate of 3.1 (SD 2.9). RESULTS: Results were evaluated in 65 (45 females) subjects with a pretreatment and a treatment duration >3 months: 38 were treated with IFNbeta-1a once weekly (Avonex), 18 with IFNbeta three times weekly (16 with Rebif, 2 with Betaferon) and nine with GA (Copaxone). The mean pretreatment period was respectively 20, 18 and 9.2 months. The treatment duration lasted respectively 23.3, 40.7 and 33.3 months. The mean annualized relapse rate decreased dramatically during the treatment: from 2.4 to 0.4 in the Avonex group, from 3.2 to 0.8 in the Rebif-Betaferon group and from 2.8 to 0.25 in the GA group. The mean final EDSS scores were respectively (in brackets the initial scores): 1.3 (1.4), 1.6 (1.8) and 0.6 (1.1). In the whole group, the final score was unchanged or reduced in all subjects except eight. Clinical side effects were recorded in 41/65 subjects (mainly in subjects treated with IFNbeta), abnormal laboratory findings were observed in 13/65 subjects: they were transient in most cases. IFNgamma was stopped in six cases: in four because of inefficacy and in two cases because of side effects. CONCLUSIONS: Sixty-five clinically definite MS subjects were treated during childhood or adolescence with IDs. The treatment reduced the relapse rate and the progression of the disease in most cases. Side effects were common in subjects treated with IFNbeta but were well tolerated in most cases.
Abstract: OBJECTIVES: To evaluate the clinical characteristics, course and prognosis of Devic's neuromyelitis optica (DNO), to evaluate the prognostic role of demographic and clinical features, to evaluate the current DNO diagnostic criteria. METHODS: Demographic, clinical, CSF and MRI data of patients affected by DNO were collected from fifteen Italian MS centres. Inclusion criteria were: 1) two or more acute episodes of neurological dysfunction indicating involvement of the optic nerve and spinal cord, in a simultaneous or subsequent temporal relationship; 2) no evidence of lesions beyond the optic nerve or the spinal cord; 3) brain MRI at onset negative or non-specific for multiple sclerosis (MS) (white matter lesions < or = 2). Disability was scored by means of Kurtzke's Expanded Disability Status Scale (EDSS). RESULTS: 46 patients with relapsing DNO were included, 37 females and 9 males, with mean age at onset of 40.1 +/- 16.3 years (range 12-77 years). The follow up duration was 8.8 +/- 3.5 years, the mean annualised relapse rate was 1.3 +/- 1.2. After 5, 10 and 15 years EDSS 3.0 was reached respectively by 65%, 82 % and 86% of cases, EDSS 6.0 respectively by 42%, 53 % and 69% of cases, EDSS 10 respectively by 8%, 12% and 23% of cases. The probability of reaching EDSS 3 was statistically correlated with age at onset, interval between the first and 2(nd) attack, and relapse rate. The probability of reaching EDSS 6.0 was correlated with the residual EDSS at onset and to relapse rate. During the follow up, brain white matter lesions appeared in 8 subjects. Spinal cord MRI showed lesions extending across 3 or more segments in 39 subjects, only 1 lesion involving 1 segment in 4 subjects, and was normal in 3 subjects. One or more CSF abnormalities were found at least once in 29/44 patients (65.9 %), the most frequent findings being pleocytosis (38.6 %), oligoclonal bands (34.1 %), high protein level (25 %), and high albumin ratio (20.5 %). CONCLUSIONS: DNO has a poor prognosis in most cases. Compared with MS, DNO patients have a higher age at onset, females are more frequently affected, the course is more severe. Brain and spinal cord MRI permit the differentiation of DNO from MS. CSF supports the probability of DNO if it shows increased cells and proteins.
Abstract: Relapsing Devic's neuromyelitis optica (DNO) may be clinically undistinguishable from multiple sclerosis (MS), thus the differential diagnosis relies mainly on neuroimaging and cerebrospinal fluid (CSF) findings. We studied CSF samples from 44 patients with DNO submitted to at least one lumbar puncture. Pleocytosis, IgG synthesis and blood brain barrier damage were the most frequent abnormalities, pleocytosis being very suggestive of DNO in patients fulfilling clinical and MRI diagnostic criteria. Pleocytosis > or =50 cells/mm3 is more frequent in the active phases of the disease. Oligoclonal bands (OBs) should be re-considered within the diagnostic criteria of DNO for possible variations in time: at variance with MS they may also disappear. Thus, more than one CSF examination should be done in the presence of suspected DNO, preferably in different disease phases. Although uncommon, OBs do not exclude DNO if optic nerve and spinal cord are the only sites of white matter damage, provided that cerebral MRI is normal at onset and during follow up.
Abstract: Cases are described with Leber's optic atrophy and neurological symptoms and/or MRI lesions suggestive of multiple sclerosis. We describe a case of a young woman with Devic's neuromyelitis optica and 3460 homoplasmic mitochondrial DNA mutation.
Abstract: Recent functional magnetic resonance imaging (fMRI) work has suggested that cortical reorganisation might have an adaptive role in limiting the clinical impact of multiple sclerosis (MS) structural damage. In this study, we investigated whether, in patients with MS, the presence and extent of structural damage of the normal-appearing brain tissue are associated with the extent of the movement-associated pattern of cortical activations. Using fMRI and a general search method, we assessed the patterns of brain activations associated with simple motor tasks in 12 right-handed patients with clinically definite MS and nonspecific T2-weighted abnormalities on conventional MRI scans of the brain and compared them with those from 12 sex- and age-matched right- handed healthy controls. Also investigated were the extent to which the fMRI changes correlated with normal-appearing white matter and grey matter (GM) pathology, measured using diffusion tensor MRI. When performing the simple motor task with the dominant hand, MS patients had more significant activations of the ipsilateral supplementary motor area (SMA), the ipsilateral superior frontal sulcus, the contralateral superior temporal gyrus, and the thalamus than controls. On the contrary, healthy subjects showed more significant activations of the medial part of the contralateral parieto-occipital fissure and the ipsilateral primary sensorimotor cortex (SMC) than patients with MS. In patients with MS, the relative activation of the ipsilateral SMA was correlated with the peak height (r = -0.88, P < 0.001) and position (r = 0.87, P < 0.001) of the GM mean diffusivity histogram. This study shows that cortical reorganisation occurs over a rather distributed sensorimotor network even in patients with MS and nonspecific abnormalities on conventional brain MRI scans. This suggests that, in patients with MS, an increased recruitment of movement-associated cortical network can be elicited by the presence of normal-appearing tissue pathology, which is independent of macroscopic T2-weighted abnormalities.
Abstract: BACKGROUND: Interferon beta 1b (Betaferon) and 1a (Avonex) were licensed in Italy for treating relapsing-remitting multiple sclerosis in February 1996 and August 1997, respectively. OBJECTIVES: To evaluate the effectiveness of these agents on the basis of clinical experience in northern Italian multiple sclerosis centres. DESIGN: Clinical data on patients with relapsing-remitting multiple sclerosis were collected on an appropriate form from 65 centres in northern Italy. Intention to treat analysis was not possible, so patients who discontinued treatment (drop-outs) and who continued treatment (treated) were analysed separately. The main outcome measures were annual relapse frequency, number of relapse-free patients, mean change in extended disability status scale score (EDSS), and number of patients who worsened. RESULTS: 1481 patients were included; 834 were treated with Betaferon and 647 with Avonex for mean periods of 21.4 and 12.0 months, respectively. Basal EDSS was 2.37 and 2.17, respectively, and relapse frequency was 1.62 and 1.45. The annual relapse rate decreased by more than 60% with Betaferon and 55% with Avonex. The proportions of relapse-free, improved, and worsened patients were similar in the two groups. More patients interrupted treatment with Betaferon (41.1%) than with Avonex (15.3%); such patients showed more active disease at baseline and during treatment. The incidence of side effects was higher in Betaferon treated patients. CONCLUSIONS: The effectiveness of Betaferon and Avonex is confirmed. There was a more marked effect than expected from the experimental trial results. This might reflect differences in inclusion criteria, or, more likely, loss of drop-outs, favouring selective retention of responders.
Abstract: The recent re-discovery of axonal damage in multiple sclerosis has led to a renewed interest in neurodegenerative mechanisms of the disease. Transected or injured axons release several molecules from their proximal extremity into the intercellular space. Although these molecules can be measured, however, a biological marker of axonal and neuronal degeneration is still lacking. Cytoskeleton structural proteins like actin, tubulin, L-neurofilaments and tau protein, axon-specific antibodies, other neuronal or glial proteins like S-100, 14-3-3 and glial fibrillary acid protein, neuronal specific enolase, and nitric oxide and its metabolites are some of the putative markers that deserve further investigation and validation. At present, none of them fulfils the criteria of applicability in clinical practice, and the levels of N-acetylaspartate determined by magnetic resonance spectroscopy remain the most reliable measure of axonal damage.
Abstract: BACKGROUND: The three interferon beta preparations approved for treatment of relapsing-remitting multiple sclerosis (MS) differ in dose and frequency of administration. Interferon beta-1a 30 microg is administered once a week, interferon beta-1a 22 microg or 44 microg is given three times a week, and interferon beta-1b 250 microg is administered on alternate days. No clinical study directly comparing the different regimens has been published. The INCOMIN study was designed to compare the clinical and magnetic resonance imaging (MRI) benefits of on-alternate-day interferon beta-1b 250 microg with once-weekly interferon beta-1a 30 microg. METHODS: INCOMIN was a 2-year, prospective, randomised, multicentre study. 188 patients with relapsing-remitting MS were assigned to interferon beta-1b (n=96) or interferon beta-1a (n=92). Primary outcome measures were the proportion of patients free from relapses and that of patients free from new proton density/T2 lesions at MRI assessment. Several secondary outcome measures were also assessed. Analysis was by intention to treat. FINDINGS: Over 2 years, 49 (51%) individuals administered interferon beta-1b remained relapse-free compared with 33 (36%) given interferon beta-1a relative risk of relapse 0.76; 95% CI 0.59-0.9; p=0.03); and 42 (55%) compared with 19 (26%), respectively, remained free from new T2 lesions at MRI (relative risk of new T2 lesion 0.6; 0.45-0.8; p<0.0003). In both groups, the differences between the two treatments increased during the second year. There were also significant differences in favour of interferon beta-1b in most of the secondary outcome measures, including delay of confirmed disease progression. INTERPRETATION: High-dose interferon beta-1b administered every other day is more effective than interferon beta-1a given once a week.
Abstract: Fifty-four subjects (36 females and 18 males) affected by clinically definite multiple sclerosis (MS) and with onset of the disease at 15 years of age or before were prospectively studied in five Italian MS centres. Female/male ratio was 4.7 in subjects with age > or = 12 years, suggesting a role of hormonal changes in triggering MS onset The mean follow-up duration was 10.9+/-5.6 years. The functional systems more frequently involved at onset were the pyramidal and brainstem (both in 28% of cases). The onset was monosymptomatic in 31 subjects (57%). The course was relapsing-remitting in 39 subjects (72%) and relapsing-progressive in 15 (28%). Disability was assessed by the Expanded Disability Status Scale (EDSS): the mean score after 8 years of follow up was 3.5 (+/-2.5). The score was <4 in 68% of cases, between 4 and 6 in 8% of cases, >6 in 24% of cases. Disability after 8 years was highly predicted by disability in the first year (p=0.008). There was a tendency to a worse prognosis in relation to the number of relapses in the first 2 years (p=0.08). The outcome was not influenced by the characteristics of symptoms at onset age and gender.
Abstract: Autoimmune side effects, namely autoantibody (autoAb) occurrence and thyroid function alteration, have been described during interferon-beta (IFN-beta) treatment for multiple sclerosis (MS). AutoAb occurrence and autoimmune thyroid diseases are also frequently detected in MS patients free of any treatment. The aim of this study was to evaluate the relationship between IFN-beta 1b treatment, autoAb occurrence, and autoimmune diseases in MS. Thyroid and liver function and serum autoAb (antithyroid, antinuclear, anti-liver, anti-kidney microsomes, anti-smooth muscle and parietal cell antigens) occurrence were evaluated in 156 relapsing-remitting MS (RRMS) patients before and every 3 months after starting IFN-beta 1b treatment (8 MIU subcutaneously [s.c.] on alternate days). The probability of having liver or thyroid function alteration or autoAb occurrence was analyzed longitudinally with the generalized estimating equations (GEE) approach. At baseline, 16.1% of patients had autoAb. During treatment, autoAb occurred de novo in 7.2% of patients. GEE analysis showed that the probability of having autoAb at any time during IFN-beta 1b treatment did not change significantly compared with baseline. AutoAb occurring de novo rarely persisted during treatment and significantly less than those already present at baseline. Positivity for autoAb at baseline or during treatment was not correlated with the development of thyroid or liver function alteration during IFN-beta 1b treatment. Our study indicates that IFN-beta treatment is a safe treatment for MS patients, free of risk of autoimmunity and of associated liver or thyroid function alteration.
Abstract: This baseline-vs-treatment study of 20 patients with relapsing-remitting MS investigated whether glatiramer acetate (GA) has a graduated effect on MS inflammatory activity, which was measured using monthly, standard, and triple dose gadolinium (Gd)-enhanced MRI. GA significantly reduced the mean numbers of enhancing lesions/patient/month on both standard dose and triple dose scans, without interactions with the Gd dose. GA is effective in reducing MS activity, independent of the severity of the MRI-detectable inflammatory process.
Abstract: Sympathoadrenergic mechanisms may play a role in multiple sclerosis (MS). We examined catecholamine (CA) levels and production and tyrosine hydroxylase (TH) expression in peripheral blood mononuclear cells (PBMCs) from MS patients, and the correlation between CA production and apoptosis in PBMCs. PBMCs from MS patients had increased norepinephrine (NE) levels. However, phytohaemagglutinin (PHA)-stimulated PBMCs from MS patients with active disease synthesized less dopamine (DA) than cells from both healthy controls and patients with inactive disease. PBMCs from patients with inactive disease showed lower expression of TH. Pharmacological inhibition of TH in cultured PBMCs stimulated with PHA reduced the percentage of apoptotic cells. Since a failure of activation-induced apoptosis in immune cells may be involved in MS, it is suggested that altered CA production by PBMCs may be implicated in such dysregulation.
Abstract: BACKGROUND: The occurrence or recurrence of autoimmune diseases or of autoantibodies (autoAb) has been reported during type I interferon (IFN) treatment. OBJECTIVE: To define the frequency of thyroid and liver dysfunction and of autoimmunity during IFN-beta 1b (IFNB) treatment of MS. METHODS: Prospective 1-year multicenter follow-up of 156 patients with MS recruited by 18 centers was conducted. Thyroid-stimulating hormone and anti-thyroid autoAb were measured by an immunoradiometric method, thyroid hormones by chromatographic assay, and non-organ-specific autoAb by indirect immunofluorescence. Tests were repeated every 3 months. The probability of having liver, thyroid, or autoAb alterations was analyzed longitudinally with the generalized estimating equations (GEE) method. RESULTS: Thyroid dysfunction was observed in 5.3% of cases at baseline and 8.3% de novo during IFNB treatment. GEE analysis showed that the probability of having thyroid alteration did not change significantly during treatment compared with baseline. Liver alteration was observed in 4.6% of cases at baseline and 37.5% de novo during IFNB treatment (p < 0.0001). GEE analysis showed that the probability of having liver alteration was higher (p < 0.002) at months 3 and 6 compared with baseline, returning to values similar to baseline by month 9. AutoAb were detected in 16.1% of patients at baseline and in 20% during IFNB. GEE analysis showed that the probability of having autoAb did not change significantly during treatment compared with baseline. Thyroid or liver alteration or autoAb occurring de novo during IFNB were usually transient. CONCLUSIONS: Differently from the frequency of liver function alteration (which significantly increased during the first months of IFNB treatment, suggesting a probable causal relationship with IFNB), the frequency of thyroid dysfunction or of autoimmunity showed random and insignificant changes over time, probably not related to IFNB treatment.
Abstract: Thyroid dysfunction and autoimmunity have been reported during type I interferon therapy, namely interferon-alpha for chronic hepatitis or interferon-beta for multiple sclerosis. To define the frequency of thyroid dysfunction and autoimmunity during interferon-beta treatment, 156 multiple sclerosis patients were prospectively followed up by 18 centers for 1 yr after starting interferon-beta-1b treatment. Serial clinical assessments and tests of thyroid and liver function and antithyroid autoantibodies (all performed by the same centralized laboratory) were conducted every 3 months. TSH and antithyroid autoantibodies against human TG or thyroid microsomal antigens were measured by immunoradiometric methods; free T3 and T4 were measured by chromatographic assays. Longitudinal occurrence of thyroid or liver alterations or of autoantibodies was analyzed with the generalized estimating equations method, correcting for the correlation of repeated measurements of the same subject over time. Pretreatment comparison with a control group of 437 healthy blood donors did not show significant differences in the frequency of thyroid dysfunction or antithyroid autoantibody positivity. During interferon-beta treatment, the de novo frequency of thyroid alteration was 8.3%, that of liver alteration was 37.5%, and that of antithyroid autoantibody was 4.5%. Generalized estimating equations analysis demonstrated that the frequency of liver alteration significantly increased during treatment compared with the baseline value (odds ratio, 7.03; confidence interval, 2.49-19.9), whereas that of thyroid alteration or of antithyroid autoantibodies did not. The frequency of thyroid dysfunction during interferon-beta treatment showed random, nonsignificant changes over time and, in addition, was not correlated to antithyroid autoantibody positivity.
Abstract: To evaluate the effects of in vivo beta-IFN-1b treatment on transmigration of mononuclear cells, we monitored for one year in vitro mononuclear cells trafficking through HUVECs monolayers stratified over a collagen gel during beta-IFN-1b treatment of 7 RR MS patients. The number of transmigrated cells was analysed before treatment (T0) and after 3 (T3), 6 (T6) and 12 months (T12); at the same time, levels of serum MMP-9 were quantified. The number of transmigrated cells decreased during treatment compared to pre-treatment values: the lowest number of transmigrated cells was detected at T3, and, although transmigration was still lower at T12, there was a trend to a return to pre-treatment levels over time. The amount of MMP-9 also decreased during therapy, although we could not find an absolute correlation between transmigration and levels of MMP-9, nor between either parameter and the clinical course of patients.
Abstract: Diagnosis of acute myelopathy applies to subjects with acute motor involvement, segmental sensory loss and sphincter dysfunction, reaching a maximum no later than 4 weeks after onset. Among the different causes of acute myelopathy (e.g. compressive, vascular, traumatic or toxic lesions, paraneoplastic involvement and electrical injury), acute myelitis due to infective agents or to an autoimmune-inflammatory process frequently causes problems relating to the differential diagnosis of multiple sclerosis (MS) and its potential risk of developing MS.
Abstract: In this retrospective study we evaluated the efficacy and functional benefits of chronic intrathecal baclofen infusion in severe spinal spasticity. Twenty patients with a diagnosis of severe intractable spinal spasticity were evaluated prior to implantation of a programmable pump for chronic intrathecal baclofen therapy and at follow up, which ranged from 12 to 36 months (mean 22.4 months). The mean age of the patients was 39.1 years. The prevailing pathology was multiple sclerosis. All were unable to walk. Patient assessment was based on the Ashworth Scale, the Spasms Frequency Scale, self-reported pain and Functional Independence Measure (FIM) scores. The Wilcoxon test was used for statistical analysis. A statistically significant decrease in muscle tone, spasms and pain was observed in all the patients. The Ashworth score decreased from 4.4 to 1.8, the spasms frequency score from 2.5 to 0.5 and the self-reported pain score from 5.5 to 2.3. The FIM score also showed a statistically significant change (increasing from a mean of 33.8 to 58.7). Two patients in employment were able to return to work. No severe side effects were observed. Chronic intrathecal baclofen infusion was seen to produce a functional improvement in patients with severe spinal spasticity, particularly as regards bathing, comfortable wheelchair sitting and mobility.
Abstract: A clinically isolated syndrome indicating a pathological process involving the cranial nerves or the posterior fossa may constitute a hard diagnostic challenge for the clinician. Whereas internuclear ophthalmoplegia, for example, is almost pathognomonic of multiple sclerosis (MS), other clinical presentations are often puzzling. The main alternative causes of symptoms that may suggest a clinical onset of MS are reviewed here, grouped in principal clinical syndromes, with particular attention to some rare, recently recognised conditions.
Abstract: Neurological manifestations of gastrointestinal disorders are described, with particular reference to those resembling multiple sclerosis (MS) on clinical or MRI grounds. Patients with celiac disease can present cerebellar ataxia, progressive myoclonic ataxia, myelopathy, or cerebral, brainstem and peripheral nerve involvement. Antigliadin antibodies can be found in subjects with neurological dysfunction of unknown cause, particularly in sporadic cerebellar ataxia ("gluten ataxia"). Patients with Whipple's disease can develop mental and psychiatric changes, supranuclear gaze palsy, upper motoneuron signs, hypothalamic dysfunction, cranial nerve abnormalities, seizures, ataxia, myorhythmia and sensory deficits. Neurological manifestations can complicate inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease) due to vascular or vasculitic mechanisms. Cases with both Crohn's disease and MS or cerebral vasculitis are described. Epilepsy, chronic inflammatory polyneuropathy, muscle involvement and myasthenia gravis are also reported. The central nervous system can be affected in patients with hepatitis C virus (HCV) infection because of vasculitis associated with HCV-related cryoglobulinemia. Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a disease caused by multiple deletions of mitochondrial DNA. It is characterized by peripheral neuropathy, ophthalmoplegia, deafness, leukoencephalopathy, and gastrointestinal symptoms due to visceral neuropathy. Neurological manifestations can be the consequence of vitamin B1, nicotinamide, vitamin B12, vitamin D, or vitamin E deficiency and from nutritional deficiency states following gastric surgery.
Abstract: The evolution of multiple sclerosis at the time of diagnosis remains unpredictable since a reliable prognostic marker is not yet available. Nevertheless, a series of useful prognostic indicators have been singled out from epidemiological studies. Young age at onset, female gender, relapsing/remitting course, and sensitive or visual disturbances as initial symptoms are considered favourable prognostic factors. Conversely, late age at onset, male gender, progressive course, and pyramidal or cerebellar symptoms at the first episode predict an unfavourable evolution. Another prognostic indicator has been recognized in pregnancy: although the overall effect of pregnancy on short-term MS course is neutral, in the long-term it seems to protect from disease progression. Most prognostic indicators seem to act through the neuro-endocrine-immune network, modulating the immune response in the context of the Th1/Th2 paradigm.
Abstract: We evaluated the risk of developing clinically definite multiple sclerosis (CDMS) after acute isolated optic neuritis in 102 patients in a follow-up study (duration 6.5 +/- 2.0 years). The probability of CDMS was 13% after 2 years, 30% after 4 years, 38% after 6 years, and 49% after 8 and 10 years. CDMS occurred in 42 (59%) of 71 patients with brain lesions detected with magnetic resonance imaging (MRI). No patient with normal MRI exam developed the disease. Patients with 3 or more MRI-detected lesions presented a shorter first interattack interval and a higher relapse rate compared to subjects with only 1 or 2 lesions. The predictive value of CSF examination and of evoked potentials was poor.
Abstract: The A1/A1 genotype of the anti-inflammatory cytokine interleukin 1 receptor antagonist (IL-1Ra) polymorphism was more frequent in 339 Italian MS patients than in healthy controls (HCs) (odds ratio = 1.83). A more aggressive disease course was also associated with A1+ genotypes and might reflect the reduced ability of mononuclear cell cultures of A1+ HCs to produce IL-1Ra. We conclude that an IL-1Ra gene polymorphism is associated with occurrence of disease and clinical course variability in Italian MS patients.
Abstract: Leukocyte extravasation across the blood-brain barrier is a critical event in the pathogenesis of multiple sclerosis (MS). This complex multistep process includes the adhesion of leukocytes to the endothelial cells of the central nervous system microvasculature. To investigate this phenomenon in MS, we developed a modified version of the frozen-section assay. Peripheral blood mononuclear cells (PBM) from 26 MS patients, 26 healthy controls and 10 patients with other inflammatory non- neurological diseases (OIND) were co-incubated with cryostat sections of normal brain white matter, immunohistochemically labelled with anti-CD45 antibody and counterstained with Giemsa stain. CD45-positive PBM adherent to transected microvasculature were counted with an automated image analyzer. MS patients showed an increased number of vessel-bound PBM (48.8 +/- 36.4) with respect to healthy controls (27.4 +/- 20.7, P = 0.01) and OIND patients (22.6 +/- 7.8, P = 0.01). Significant differences were also obtained counting the number of vessel-bound PBM as a percent of total vascular cells between MS patients (12.7 +/- 7.2%) and healthy controls (6.9 +/- 5.4%, P = 0.002) or OIND patients (7.4 +/- 4.4%, P = 0.03). We confirm that PBM from MS patients show an increased potential of binding to cerebral vessels. The frozen-section assay provides a unique tool to study in situ the molecular interactions of leukocytes with brain vascular structures.
Abstract: We evaluated the risk of developing clinically definite multiple sclerosis (CDMS) after an acute attack of isolated optic neuritis (ON) in 112 patients, in relation to demographic and paraclinical findings. Patients were examined by brain MRI, CSF analysis, and multiple evoked potentials (EPs); 10 were lost to follow-up, and the other 102 were enrolled in a prospective study (follow-up duration 6. 3 +/- 2.2 years). Of these, 37 (36.3%) developed CDMS after a mean interval of 2.3 +/- 1.6 years. The risk of developing CDMS was 13% after 2 years, 30% after 4, 37% after 6, and 42% after 8 and 10 years. Gender, age, and season of ON onset did not affect the risk. MS occurred in 37 of 71 patients (52.1%) with one MRI lesion or more; no patient with a normal MRI developed the disease. MS developed more frequently in patients with intrathecal IgG synthesis than in those without (43% vs. 28%), but the difference was not statistically significant. Multiple EPs showed a slight predictive value only including somatosensory EPs of the lower limb. Multiple sclerosis was mild in most cases (EDSS 2.2 +/- 1.9). The EDSS was less than 4 in 32 cases (86%), between 4 and 6 in 2 (5%), higher than 6.5 in 3 (8%).
Abstract: The in vitro effects of dexamethasone (Dx) and low and high-dose 6-methylprednisolone (MP) on the expression of adhesion molecules ICAM-1,VCAM-1 and class II antigen HLA-DR on human brain endothelial cells (HBECs) was studied. HBECs were obtained from the surgical specimen of a multiple sclerosis patient undergoing brain surgery for vascular aneurysm. HBECs obtained from apparently normal brain capillaries of surgical specimens of two patients undergoing brain surgery for a meningioma and a low-grade glioma, respectively, were used as controls. The effect of steroids was studied both in the basal condition and after stimulation with proinflammatory cytokines (gamma-IFN and TNF-alpha). In order to detect possible endothelium local tissue specific differences, the experiment was repeated using human umbilical vein endothelial cells (HUVECs). Only high-dose MP was able to down-regulate TNF-alpha-induced VCAM-1 expression on endothelial cells.
Abstract: An epistatic gene interaction has been advocated to explain disease susceptibility in multiple sclerosis (MS). Cytokine genes are possible candidates due to the central role played by cytokines in the regulation of the immune-mediated pathogenetic process leading to central nervous system demyelination in these patients. Since interleukin (IL)-4 gene polymorphisms have been associated with immune-mediated diseases, we have analysed the relationship between a variable number of tandem repeat polymorphism of the IL-4 gene and clinical and physiological features of 256 sporadic MS patients and 146 healthy controls. Genotype frequencies were similar between the MS group and healthy controls. However, in MS patients a positive and significant correlation (r = 0.91; p < 0.001) was found between the carriage rate of the IL-4 B1 allele (from 0.21 to 0.36) and age of disease onset. No association was found between IL-4 alleles and disease progression, sex or ethnic background of the patients. Our results show that the IL-4 B1 allele is associated with late onset of MS and therefore might represent a modifier of age of onset rather than a susceptibility factor for patients with MS.
Abstract: From the retrospective study of 3375 patients affected by clinically definite or probable multiple sclerosis (MS), 149 patients were collected with onset of the disease before the age of 16 years (4.4%). Female/male ratio was higher than that of the adult onset MS (AOMS) population (2.2 vs 1.6) particularly at ages of onset after 12 years (3.0, P = 0.007 vs AOMS). Among initial symptoms, those suggesting brainstem dysfunction (25%) were more frequent compared to other systems and compared to AOMs symptoms; motor and sensory disturbances were slightly less frequent (respectively 17.5% and 18.3%). Optic neuritis appeared in 16.5% of cases with onset in childhood and in 16.2% of cases with AOMS, cerebellar disturbances respectively in 9.1% and 7.7%. The first interattack-interval and the clinical course of early onset MS did not differ significantly from AOMS. In early onset MS patients with disease duration < 8 years, cases with EDSS > 6 were slightly more frequent than in the AOMS group (P = 0.04). The frequency of cases for different levels of disability was similar for disease duration > 8 years.
Abstract: Our study evaluated the frequency of developing multiple sclerosis (MS) after acute isolated optic neuritis (ON), the possible association with risk factors (gender, age), and the diagnostic and prognosis role of paraclinical tests. We studied 100 ON patients (mean age 28.9 years: SD 8.9): 85 patients were regularly followed up. Sixty-six patients underwent multimodality evoked potential (EP) test, examination and brain MRI within six months of the onset of ON. Over a mean follow-up of 5.2 years, MS occurred in 28/85 cases. The risk of developing MS after four years was 0.35 at life-table analysis, regardless of gender or age at the onset of ON. Visual EPs in unaffected eyes were abnormal in 25.4%, brainstem auditory EPs in 6.5% somatosensory EPs in 8.1%, upper limb motor EPs in 6.8% of the tested patients; intrathecal IgG synthesis was revealed in 51.7% and MRI lesions in 73.8%. Fifty-one of the patients who underwent paraclinical tests were followed up for more than one year, and MS occurred in 13 cases. All of these presented MRI lesions, nine intrathecal IgG synthesis, and two abnormal extraocular EPs. The risk of developing MS after four years was 0.33 in patients with MRI lesions; the simultaneous presence of intrathecal IgG synthesis increased the risk to 0.46.
Abstract: To verify whether multiallelic polymorphisms belonging to HLA class II genes are linked to multiple sclerosis (MS) in the Italian population, we studied 28 multiplex MS families originating from different areas of Italy. Allelic characterization was carried out by analysis of RFLPs and oligonucleotide typing. Evidence supporting the existence of linkage between MS susceptibility and the HLA class II loci DRB1, DQA1 and DQB1 was provided using two non-parametric tests, affected sib-pair analysis, and affected-pedigree-member (APM) analysis. The APM analysis also suggested the existence of genetic heterogeneity for the HLA class II loci and MS susceptibility in our series. Linkage disequilibrium between MS susceptibility and the haplotype DRB1*1501,DQA1*0102,DQB1*0602 was demonstrated by applying the transmission linkage disequilibrium test to our families. Finally, lod score analysis suggests that in our Italian families, MS susceptibility is conferred by HLA class II alleles according to a low-penetrance autosomal recessive mode of inheritance.
Abstract: Synthesis of IgG by peripheral blood mononuclear cells from patients with multiple sclerosis (MS) and with other neurological diseases and from healthy controls was induced by Pokeweed mitogen (PWM) in short-term cultures. As expected, MS patients produced more immunoglobulin (Ig) G and had a higher percentage of 'high responders' to PWM stimulation as compared to controls. Interleukin (IL)-4 was undetectable in all samples. IL-6 and tumor necrosis factor (TNF)-alpha synthesis was induced by PWM stimulation in all groups, but MS patients showed the most significant increase of both cytokines. Interestingly, only MS patients showed a significant increase of the soluble form of CD23 receptor (sCD23). Moreover, only sCD23 levels correlated with in vitro IgG production in MS patients. The levels of IL-6, TNF-alpha, sCD23 were greater in high responders compared to low responders in all groups. The mean value of each molecule, however, did not differ significantly among overall groups. A highly significant difference was reported for sCD23 in MS patients. We suggest that sCD23, also known as B cell growth factor, may play a role in the well-documented phenomenon of in vitro IgG hypersynthesis in MS patients, adding support to the concept of B cell up-regulation in the peripheral blood of these patients.
Abstract: Pudendal evoked potentials, motor evoked potentials of the bulbocavernosus muscle to magnetic stimulation and bulbocavernosus reflex were recorded in 34 patients with multiple sclerosis (MS). Responses were delayed in 26, 20 and 3 cases respectively. No relationship was found between neurophysiological abnormalities and the presence or severity of erectile dysfunction, showing that these tests have little diagnostic usefulness in MS patients with impotence. Nocturnal penile tumescence was assessed in 14 cases: the test result was normal in 10 patients, including 3 severely paraplegic subjects.
Abstract: We studied the expression of class II MHC product (HLA DR) and IL-2 receptor on circulating monocytes (M phi) in MS patients, neurological and healthy controls, by double color flow cytometry. In all groups most M phi were DR+ without significant differences. More interesting, low percentages of IL-2+ M phi were detectable in healthy and neurological controls, whilst a few MS patients with active disease showed higher levels. This finding is in agreement with similar studies in other T-cell mediated diseases and with the report of rare IL-2+ macrophages in MS plaques. Although the actual role of IL-2+ M phi in the immune response still needs elucidation, our findings suggest their relevance to the pathological process of demyelinating disease.
Abstract: Motor potentials of the bulbocavernosus muscle were recorded in 17 healthy subjects after transcranial and lumbar magnetic stimulation. The latencies (SD) were respectively: 22.9 (1.8) and 5.9 (0.4) ms. The central conduction time was 17.0 (2.5) ms. The bulbocavernosus reflex presented an onset at 34.5 (3.3) ms and a negative peak at 43.1 (3.9) ms. The cortical pudendal evoked potential was W shaped: the first peak had a latency of 35.4 (2.8) ms. The concurrent recording of motor potentials, bulbocavernosus reflex, pudendal evoked potentials gives a measure of peripheral and central, afferent and efferent neurological pathways related to pudendal nerve function.
Abstract: We studied paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples from 18 inactive multiple sclerosis (MS) patients and 10 with non-inflammatory neurological diseases. By means of a dual-colour cytofluorimetric micromethod we were able to count 1500 cells on average in each CSF sample. We found a significant reduction of CD45RA+ and CD4+CD45RA+ cells in the CSF of MS patients. Similarly, CD45RA+ and CD4+CD45RA+ CSF/PB ratios were lower compared with controls. The reduction of suppressor-inducer T-cells did not correlate with CD8+ cell levels in the CSF. The CD4+ subset ratio (CD4+CD45RA-/CD4+CD45RA+) was significantly increased in the CSF of MS patients. Our data suggest that the reduction of CD4+CD45RA+ cells in the PB is not due to a segregation of such cells in the CSF. Conversely, CSF changes reflect changes in the PB similar to these found for other T-cell subsets.
Abstract: Motor potentials to transcranial and cervical magnetic stimulation and F-wave were recorded in 37 arms of 25 normal subjects. Clockwise and anticlockwise cervical stimulation were performed over C5, C7 and T2 spinous processes. A significant correlation was found between height and measurements of central and peripheral motor conduction. Peripheral motor conduction measured by F-wave derived techniques (Kimura formula) was 0.5 msec higher as compared with responses to cervical magnetic stimulation. The site and current flow direction of cervical magnetic stimulation influenced the amplitude of responses but not their latency: responses were larger in the right arm when the centre of the coil was placed over the C5 spinous process and clockwise stimuli were used. The same results were obtained in the left arm when the coil was reversed.
Abstract: In a series of 2,353 multiple sclerosis (MS) patients, 40 subjects presented seizures, with an overall prevalence of 1.70%. The prevalence was 2.33% (34/1,459) in definite MS cases, 0.58 in probable cases (3/518), 0.79 in possible cases (3/376). Twenty-six patients were females, 14 were males. In 13 cases, epilepsy had begun before MS onset; in 4 patients, the two diseases started contemporarily; in 23 patients, epilepsy followed MS onset. No relationship was found between frequency of seizures and course of MS nor between frequency of seizures and MS severity. In 12 patients, magnetic resonance imaging was performed: plaques adjacent to the cerebral cortex were found in 3 cases. The electroencephalogram showed paroxysmal discharges in 11 patients (focal in 2, diffuse in 9). Slow theta and/or delta activity was found in 15 patients (focal in 7, diffuse in 6, both focal and diffuse in 2). The EEG was normal in 14 patients. Possible etiological factors other than MS were recognized in 4 patients only: cranial trauma in 3, meningitis in 1. Our study on a large MS population confirms that MS is associated to a risk for epilepsy higher than that of the general population.
Abstract: Circulating lymphocyte subpopulations defined by anti-CD45 and other more common T-cell-specific monoclonal antibodies were analysed in 77 patients with multiple sclerosis and 38 healthy controls. A selective decrease of CD4+CD45+ cell percentages and absolute numbers in chronic-progressive patients was found; in 13 out of 26 patients this subpopulation was less than 11% CD4+CD45+ cells. Similarly, the whole CD45+ cell subset, as well as CD45+ cells expressed as percentages of CD4+ cells, were significantly reduced in chronic-progressive multiple sclerosis. CD4+CD45+ cells, commonly termed "inducer of suppression" T-lymphocytes, did not correlate with percentages or numbers of CD8+ cells. It is concluded that suppressor inducer T-cells act on the CD8+ subset function rather than reducing CD8+ cell numbers. Since CD4+CD45+ cells represent an early stage of lymphocyte maturation (naive T-cells), an under-representation of this subpopulation in active multiple sclerosis might reflect an increased conversion of naive cells into memory cells. This concept may be relevant for a better understanding of the disease pathogenesis.
Abstract: Visual, brainstem auditory and somatosensory evoked potentials to medial nerve stimulation were recorded in 27 patients affected by amyotrophic lateral sclerosis. VEP N75, P100, N140, N75-P100 latencies and P100 amplitude, BAEP I-III, III-V and I-V interpeak-latencies were within normal limits in all ALS patients. Somatosensory evoked potentials were abnormally delayed in 8 patients: in 3 arms because of a delayed N9-N13 latency, in 9 arms because of a delayed N13-N19 latency.
Abstract: We followed-up 30 patients with definite multiple sclerosis (MS) for one year recording monthly: clinical evolution, neurological examination and T-lymphocyte subsets in peripheral blood recognized by monoclonal antibodies. Although clinical relapses could not be strictly associated with lymphocyte abnormalities in all cases, the parallel clinical-immunological survey permitted to correlate significantly the type of clinical course (chronic-progressive, relapsing, stable) with a correspondent immunological pattern (steadily high, transiently high, steadily normal CD4/CD8 ratios respectively). Our results suggest a possible role of serial lymphocyte subsets analysis in defining evolution of MS.
Abstract: Thirty patients with definite multiple sclerosis (MS) were examined monthly for one year. Each time, neurological examination, clinical history and monoclonal-antibody-defined T cell subsets were evaluated. Particularly, the helper/suppressor ratio (T4/T8) and the T4/T8 test-to-test variability (delta T4/T8) were considered in relation to the occurrence of clinical exacerbations. Statistically significant correlations were found between clinical course and laboratory parameters, suggesting a possible role of T cell subset analysis in defining the clinical evolution of MS.
Abstract: Intrathecal IgG synthesis and CSF oligoclonal bands were reexamined after 18-24 months in 66 patients with multiple sclerosis; 40 of them received azathioprine (AZA) 2.5 mg/Kg/die; all received a course of dexamethasone (DEXA) during clinical relapses. The IgG Index was significantly reduced in the group treated with AZA, especially in patients with short disease duration, low disability and high IgG index. Changes observed in CSF banding pattern were not significant. These results suggest an effect of AZA on IgG synthesis, as reported by in vitro studies.
Abstract: Our study focused on the relationship between lymphocyte H/S ratios and antiviral antibodies. We have concluded a longitudinal survey of 29 clinically definite MS patients for 8 months seeking a possible correlation among clinical modifications, fluctuations of T-cell subsets and antiviral antibody titers. For this purpose in each patient the following parameters were recorded monthly:--clinical history and neurological examination;--blood T-cell subpopulation as defined by monoclonal antibodies of the OKT series;--serum antibody titers against measles, herpes simplex type 1 and 2, HTLV-1 viruses. All these data were compared with the different MS subgroups as defined by clinical course: stable, relapsing, progressive. We found that constantly normal OKT4+/OKT8+ ratios correlate with a stable clinical course; that highly fluctuating ratios parallel clinical exacerbation; that constantly high ratios are associated with a chronic-progressive course. These results are discussed with special reference to the correlation between OKT8+ lymphocyte percentages and anti-HTLV-1 antibodies, since this last virus has recently been claimed to be of pathogenetic importance in MS.
Abstract: Serial visual, brainstem auditory and somatosensory evoked potentials have been recorded in 36 MS patients. The follow-up lasted 18 months. A correlation among neurophysiological modifications and clinical status of the tested pathways was inconstantly found. At the end of the study responses at the three modalities worsened in a higher percentage of progressive patients with respect to stable ones (in 41% instead of 11% of cases). Final latencies were more delayed in progressive that in stable cases.
Abstract: Evoked potentials and T-lymphocyte helper/suppressor ratio (H/S) were evaluated serially together with neurological status in 30 definite multiple sclerosis patients to evaluate their possible role in monitoring disease progression. Evoked potentials in many cases reflected the clinical status of the pathways tested, but some exceptions were observed, probably due to subclinical relapses or physical factors. In some instances the occurrence of subclinical relapses was suggested by increased H/S ratios. Serial H/S values increased in parallel with clinical and subclinical relapses, and seemed to show specific patterns in relation to the type of clinical course (relapsing, stable, chronic progressive). Our results suggest that evoked potentials and H/S ratio serial analysis can contribute to a better assessment of the progress of multiple sclerosis.
Abstract: We contemporarily studied cerebrospinal fluid (CSF) and peripheral blood (PB) T-cell subsets, defined by monoclonal antibodies, in 29 patients with multiple sclerosis (MS) and 10 patients with other neurological diseases (OND). All subjects showed a clear-cut prevalence of CSF T-cells. Similarly, T-helper and T-suppressor subsets tended to show higher percentages in CSF in almost all subjects except relapsing MS, who were characterized by low percentages of T-suppressors in PB and even much lower percentages in CSF. Helper/suppressor ratios were found to be almost similar in the two body compartments of OND patients, lower in CSF than in PB of chronic progressive MS, always higher in CSF than in PB of relapsing MS. MS patients in remission showed both patterns of progressive MS and OND patients. Our results demonstrate that the loss of PB T-suppressor in relapsing MS is not due to a migration of such cells into CSF. Furthermore, regarding T-lymphocyte subsets, a typical CSF/PB pattern characterizes relapsing MS from other patients.
Abstract: Short-term treatment with lymphocytoplasmapheresis was evaluated in 6 multiple sclerosis patients with special reference to the electrophysiological and immunological findings. Visual, somatosensory, brainstem auditory evoked potentials, flicker fusion test, helper/suppressor blood lymphocyte ratio, serum immunocomplexes and immunoglobulins and Kurtzke scores were evaluated in each patient before and after treatment. No statistically significant results were obtained.
Abstract: The present study deals with the characterization of peripheral blood T-cell subpopulations in multiple sclerosis (MS) patients during different stages of the disease. An indirect immunofluorescence assay was performed using monoclonal antibodies directed at lymphocyte surface antigens. Patients in exacerbation were found to have significantly (p less than 0.001) reduced OKT8+ (T-suppressor) cells and a high helper/suppressor ratio (p less than 0.001). Patients in remission showed a significant increase of suppressor T-cells compared to controls (p less than 0.02) and patients during relapse (p less than 0.001); H/S ratio was consequently low compared to acute MS (p less than 0.001) and controls (p less than 0.1). Patients with a progressive course showed an intermediate T-subset pattern. The results are discussed in the light of the most recent neuroimmunological approaches to MS.
Abstract: 49 patients with multiple sclerosis (MS) were evaluated on several lines of investigation: clinical examination with disability rating scale, disease activity staging, multimodal evoked potentials and cerebrospinal fluid analysis. 24 patients were monthly re-examined and T-cell subsets were analysed in the peripheral blood. Evoked potentials were re-evaluated every 3 months in 24 patients. All paramethers were correlated in transversally and longitudinally during a 3 to 18 months follow-up. The results are discussed in the view of a methodological approach to a laboratory evaluation of disease evolution in its natural course and during therapeutic trials.
Abstract: Cerebrospinal fluid (CSF) and serum samples from patients with multiple sclerosis and other neurological diseases were examined by capillary isotachophoresis (ITP). The percentage and the rate of synthesis of CSF IgG which migrated slowly with ITP were calculated. CSF specimens of most patients with multiple sclerosis contained increased percentages of slowly migrating IgG (slow IgG), corresponding to IgG oligoclonal bands in the "high-alkaline" region on isoelectric focusing. The patients with multiple sclerosis were found to have increased intrathecal synthesis of slow IgG, which correlated closely with the rate of intrathecal CNS IgG synthesis calculated by Tourtellotte's formula.
Abstract: Electrophysiological tests (visual and somatosensory evoked potentials, flicker fusion test) and electrophoretic examination of cerebrospinal fluid were performed in 17 patients who previously suffered from one or more attacks of optic neuritis. The association of the tests revealed the demyelinating inflammatory pathogenesis in eight cases. In the remaining nine cases the CSF oligoclonal pattern was absent. The evidence that a bilateral delayed VEP, suggesting a subclinical contralateral involvement of optic pathways, could be related to multiple sclerosis, is discussed. A case was finally ascertained as being affected by Leber's optic atrophy.
Abstract: Three different methods were compared to detect an intrathecal IgG synthesis in cerebrospinal fluid of patients with Multiple Sclerosis. A preliminary investigation was carried out on serum and cerebrospinal fluid proteins fractionated by means of analytical isotachophoresis. This technique shows many advantages but isoelectrofocusing is still the most available technique in diagnostic trials.
