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PubMed2005

Cortical demyelination and diffuse white matter injury in multiple sclerosis.

Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

Acute Disease↗
PubMed2000

Autologous stem cell transplantation in progressive multiple sclerosis--an interim analysis of efficacy.

Based on the good results of experimental transplantation in animal models of multiple sclerosis and of other autoimmune diseases, we have treated 24 patients suffering from chronic progressive multiple sclerosis with high-dose chemotherapy (BEAM regimen) followed by autologous blood stem cell rescue and antithymocyte globulin. Blood stem cells were mobilised with cyclophosphamide at 4g/m2 and G- (or GM-) CSF. In 9 cases, additional CD34+ cell-selection of the graft was performed. Here we update previously published results of this novel treatment, mainly with regard to clinical efficacy, as the median follow-up time has reached 40 months (range, 21-51). Infections were the principal toxicity early after the procedure, with death of a patient from aspergillosis 65 days post stem cell infusion. No serious late events occurred apart from a case of autoimmune thyroiditis that developed 11 months after transplant in a patient who had received a CD34+ cell-depleted graft. Mild and transient neurotoxicity was observed in 10 patients (42%), most probably associated with fever and infections. Eighteen patients (18/23; 78%) responded to the treatment, i.e., they were improved or stabilized, while five patients progressed, of which 4 had primary progressive disease. Of those improved or stabilised (18), 9 patients have maintained stable condition whereas 9 developed relapses or they slowly resumed progression, although their disability scores have not gotten worse than they were before transplantation. The probability of progression-free survival (compared to entry status) at 3 years is 92% for patients with secondary progressive disease and 39% for the primary progressive type. CD34+ cell-selection did not seem to yield better results except for a delay in progression or in relapse after transplantation. These results appear better than those achieved by any other treatment of progressive multiple sclerosis, including beta-interferon, but they need to be confirmed by other open or controlled studies in view of the well-known difficulty of judging objectively the effect of a treatment in patients with this disease.

Adult↗
PubMed1992

A prospective study of depression and immune dysregulation in multiple sclerosis.

This study examined psychologic distress and immune function in patients with chronic-progressive multiple sclerosis participating in a placebo-control trial of cyclosporine. Immune measures included percentages and absolute numbers of CD2+, CD4+, CD8+, Leu-11-b+, HLA-DR (IA+), and transferrin-receptor-positive cells, which were evaluated by immunofluorescence using monoclonal antibodies. Distress was measured with self-report scales. The Expanded Disability Status Scale assessed neurologic disability. Subjects were followed up for 2 years, and their high-depressed and low-depressed times were compared. Times of greater depression were associated with lower CD8+ cell numbers and CD8+%, and a higher CD4/CD8 ratio. CD4+ cell numbers and percent were also higher when subjects were depressed, but only in the placebo group. There were no differences in Expanded Disability Status Scale when subjects were more depressed. Evaluation of a single subject revealed that Ia+ and transferrin-receptor-positive lymphocytes increased 3 months before distress increased. It was concluded that distress is associated with immune dysregulation in multiple sclerosis, although the mechanisms of this association have yet to be delineated.

Adult↗
PubMed1988

Serial immune evaluation of cyclosporine- and placebo-treated multiple sclerosis patients.

During an ongoing clinical trial of cyclosporine (CsA) immunosuppression therapy for chronic progressive multiple sclerosis (MS), a comparison was made of the immune responses of 18 CsA- and 18 placebo (P)-treated MS patients. Patients randomized to receive either CsA or P had identical entry immune profiles. However, these MS patients displayed significantly increased T-helper:T-suppressor (TH:TS) ratios (P less than 0.01), percentage (%) active-T (P less than 0.01), % Ia+-T (P less than 0.05) and % Ta1+-T (P less than 0.01) cell phenotypes when compared to age-matched normal controls. Further, the MS-P-treated patients displayed significant increases (all P less than 0.01) in % pan-T, % helper-T, % active-T and % Ta1+-T cell phenotypes as well as panel mixed lymphocyte culture (panel MLC) functional responsiveness from entry to cumulative 12-month study data. In contrast, the MS-CsA-treated patients only displayed an increased % pan-T cell phenotype. The cumulative 12-month follow-up data showed that the MS-P-treated patients displayed significantly higher immune parameters than the MS-CsA-treated patients for % pan-T (P less than 0.05), % helper-T (P less than 0.01), TH:TS ratio (P less than 0.05), % active-T (P less than 0.01), % Ta1+-T cells (P less than 0.01) and panel MLC stimulation index (P less than 0.01). Thus, MS-CsA-treated patients did not display the progressive immune activation seen on serial evaluation during the follow-up time period that characterized the placebo-treated MS group.

Acute Disease↗
PubMed2003

Working memory deficits in multiple sclerosis: a controlled study with auditory P600 correlates.

BACKGROUND: Recently, the P600 component of event related potentials, a waveform that is conceived to be generated and/or modulated by basal ganglia and cingulate area has been considered an index of the completion of any synchronised operation after target detection, having much in common with working memory operation. Moreover, dysfunction of these brain structures as well as working memory deficits have been implicated in the pathophysiology of multiple sclerosis. The aim of this study was to investigate the patterns of P600 elicited during a working memory test in multiple sclerosis patients compared with healthy controls. METHODS: Twenty two definite, chronic progressive multiple sclerosis patients, with recent exacerbation of their illness, and 20 normal subjects matched for age, sex, and educational level, were studied with a computerised version of the digit span test of Wechsler batteries. Auditory P600 were measured during the anticipatory period of this test. RESULTS: The patient group, as compared with healthy controls, showed significantly reduced latencies of P600 at left frontal areas and reduced P600 amplitudes at left temporoparietal region. Moreover, memory performance of patients was significantly more impaired when compared with healthy controls. CONCLUSIONS: These findings may indicate that multiple sclerosis is associated with abnormal features of the completion of synchronised operation after target detection, as they are reflected by P600 amplitudes and latencies. Dysfunction of this mechanism may contribute to the identification of basic cognitive processes that could account for the cognitive deficits in multiple sclerosis.

Adult↗
PubMedDate not supplied

Hyperbaric oxygen therapy in the treatment of multiple sclerosis. A clinical and electrophysiological study in a 2 year follow-up.

15 patients with chronic progressive Multiple Sclerosis were treated with Hyperbaric Oxygen Therapy at 2.0 atmospheres absolute for a total of 20 daily exposures followed by 2 exposures every month. The treatment was carried out for a 24 months follow-up. No objective benefit resulted from Hyperbaric Oxygen Therapy at the completion of the study while a subjective improvement in bladder control was reported in the short and in the long-term follow-up by 8 and by 5 patients respectively. No significant variations in the electrophysiological results were observed after the first 20 consecutive exposures. It is concluded from this trial that a long-term Hyperbaric Oxygen Treatment cannot moderate the progression of Multiple Sclerosis. However, an improvement in the quality of life can be obtained in some patients resulting from a better control of bladder function.

Adult↗
PubMed1987

Administration of monthly-pulse cyclophosphamide in multiple sclerosis patients. Effects of long-term treatment on immunologic parameters.

Eleven patients with chronic progressive multiple sclerosis received monthly pulses of cyclophosphamide (CY) for approximately one year. During the final 9 months the monthly dose ranged between 1000 mg/m2 and 2000 mg/m2. This resulted in a marked (47% or greater) reduction in CD4 (T helper/inducer) cells a less striking (22%) decrease in CD8 (T suppressor/cytotoxic) cells and a decline in the CD4/CD8 ratio. The magnitude of the decrease in CD4 cells correlated with the total dose received (r = 0.88, P less than 0.05). B cells were reduced 50% and FcR+ lymphocytes were reduced 48% without comparable reduction in natural killer cells or antibody-dependent cellular cytotoxicity. Proliferative responses to PHA were suppressed. Two patients improved, seven stabilized and two continued to worsen. Monthly pulses of CY can achieve substantial and differential reduction in immune parameters and appear to slow the disease progression in some MS patients.

Cyclophosphamide↗
PubMed2000

Serial magnetic resonance imaging in multiple sclerosis: correlation with attacks, disability, and disease stage.

Serial MRI and clinical testing was performed on 45 well-defined untreated multiple sclerosis patients in different categories of disease (relapsing-remitting, progressive, stable). Up to 24 MRIs were scheduled over a 1-year period for each patient. Clinical evaluation was performed monthly and at times of attacks using the Expanded Disability Status Scale (EDSS) and the Ambulation Index (AI). MRI scans were performed both with and without gadolinium enhancement. MRI lesion volume was determined by computerized analysis and gadolinium-enhancing lesions were counted by radiologists. We observed an increase in lesion volume over 1 year in all patient groups except those classified clinically as stable. In relapsing-remitting patients there were correlations between increases in the number of gadolinium enhancing lesions and increases in EDSS and the occurrence of attacks. In chronic progressive patients, increases in lesion volume were correlated with both increases in EDSS and AI. These results demonstrate a linkage between MRI and clinical disease that depends both on the stage of MS and the MRI measures used and support the use of MRI as a surrogate marker of clinical disability in the study of multiple sclerosis.

Adult↗
PubMed1997

Clinical and magnetic resonance imaging changes correlate in a clinical trial monitoring cyclosporine therapy for multiple sclerosis. The MS Study Group.

Magnetic resonance imaging (MRI) was used to monitor cyclosporine therapy for chronic progressive multiple sclerosis in a multicenter clinical trial and an analysis was performed to determine whether there was a correlation between clinical changes and MRI changes. MRI was performed on 163 patients at the onset and completion of the 2-year study. Burden of disease (BOD, lesion load) was quantitated by a single observer using a computer program. Active lesions were also identified. The Expanded Disability Status Scale (EDSS) score was determined every 3 months MRI data did not show any effect of cyclosporine treatment on BOD progression (mean 24.5% increase/yr) or lesion activity. However, there was a statistically significant positive correlation between the baseline total BOD value and the baseline EDSS score (r = 0.221, p = 0.005) and a positive correlation between the percent changes in BOD from baseline to exit and EDSS score (r = 0.186, p = 0.018). The study supports the concepts that MRI is a useful technique in monitoring therapeutic trials and that MRI is a direct measure of pathology.

Brain↗
PubMed1993

Magnetic fields normalize visual evoked potentials and brainstem auditory evoked potentials in multiple sclerosis.

The present communication concerns a 46 year old woman with a 10 year history of chronic progressive multiple sclerosis (MS) in whom external application of magnetic fields (MF) (7.5 picoTesla; 5 Hz) during a period of remission resulted in a rapid and dramatic improvement in symptoms including vision, cerebellar symptomatology (ataxia and dysarthria), mood, sleep, bowel and bladder functions as well as fatigue. Improvement in the patient's symptoms was associated with normalization of the pretreatment latencies of the visual evoked potentials and brainstem auditory evoked potential responses within a week after initiation of magnetic treatment. This report demonstrates that treatment with picoTesla MF is an effective, nonpharmacological modality in the management of MS and for the first time documents reversal of abnormal evoked potential responses by this treatment. The pineal gland is a magnetosensor. As MF affect the release of the pineal gland's principal hormone, melatonin, it is hypothesized that the effects of picoTesla MF in MS are partly mediated by the pineal gland which has recently been implicated in the pathogenesis of MS (Sandyk, 1992 a; b).

Electromagnetic Fields↗
PubMed2006

Drug Insight: interferon treatment in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Between 1987 and 1997, clinical trials of three preparations of recombinant interferon-beta were conducted in patients with MS, ushering in a new therapeutic era. These medications have demonstrable benefits and seem to be safe; they represent an important advance in MS treatment. All three formulations of interferon-beta had modest effects on relapses and short-term progression of disability, but the effects on MRI lesion parameters were more substantial. The benefits were greater in clinically isolated syndromes and relapsing-remitting MS than in secondary progressive MS. Although these drugs have been shown to be effective, however, their long-term impact on clinically relevant disability progression is uncertain, and there are many areas of controversy in the MS field regarding the use of these products. There is still a need for more effective treatments, which might include new agents or combination therapies.

Antibodies↗
PubMed1993

Thymectomy as treatment of autoimmune diseases other than myasthenia gravis.

This paper reviews the different series of thymectomies performed in patients with autoimmune diseases other than myasthenia gravis. It is possible that thymectomy can decrease the activity of T-helper lymphocytes or, alternatively, it may enhance the activity of T-suppressor lymphocytes, whose function is depressed in autoimmune diseases. Thymectomy was performed empirically for systemic lupus erythematosus and rheumatoid arthritis. The therapeutic benefits were questionable. Conflicting results were reported for thymectomy against autoimmune hemolytic anemia. Several trials were conducted to assess the therapeutic value of thymectomy in multiple sclerosis. Benefits were achieved only in relapsing-remitting but not in chronic-progressive multiple sclerosis. The effect of thymectomy in autoimmune diseases associated with myasthenia gravis were also reported. The authors conclude that thymectomy as treatment for autoimmune diseases other than myasthenia gravis is not elective therapeutic choice and it is acceptable only in selected cases.

Anemia, Hemolytic, Autoimmune↗
PubMed1992

Successful treatment of multiple sclerosis with magnetic fields.

The present communication concerns a 50 year-old woman with a 15 year history of chronic-progressive multiple sclerosis (MS) in whom extracranial application of picoTesla magnetic fields (MF) produced a dramatic and sustained improvement in disability. In contrast, administration of melatonin (3 mg, P.O.) produced in this patient a rapid exacerbation of disability which was reversed subsequently by treatment with MF. It is hypothesized that the therapeutic effects of picoTesla MF involve the mediation of the pineal gland which is known to act as a magnetosensor. The report demonstrates, for the first time, the remarkable efficacy of weak MF in the symptomatic treatment of chronic-progressive MS and underscores the pivotal role of the pineal gland in the pathophysiology of MS. If confirmed by a larger cohort of patients, extracranial application of picoTesla MF may prove as an extremely efficacious, nonpharmacological modality for the treatment of MS.

Brain↗
PubMed1999

Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study.

In experimental animal models of multiple sclerosis demyelinating antibody responses are directed against the myelin oligodendrocyte glycoprotein (MOG). We have investigated whether a similar antibody response is also present in multiple sclerosis patients. Using the recombinant human extracellular immunoglobulin domain of MOG (MOG-Ig) we have screened the sera and CSFs of 130 multiple sclerosis patients, 32 patients with other inflammatory neurological diseases (OIND), 30 patients with other non-inflammatory neurological diseases (ONND) and 10 patients with rheumatoid arthritis. We report that 38% of multiple sclerosis patients are seropositive for IgG antibodies to MOG-Ig compared with 28% seropositive for anti-myelin basic protein (MBP). In contrast, OIND are characterized by similar frequencies of serum IgG antibody responses to MOG-Ig (53%) and MBP (47%), whereas serum IgG responses to MOG-Ig are rare in ONND (3%) and rheumatoid arthritis (10%). Anti-MBP IgG antibodies, however, are a frequent finding in ONND (23%) and rheumatoid arthritis (60%). Our results provide clear evidence that anti-MOG-Ig antibodies are common in CNS inflammation. However, in OIND these antibody responses are transient, whereas they persist in multiple sclerosis. We demonstrate that the serum anti-MOG-Ig response is already established in early multiple sclerosis (multiple sclerosis-R0; 36%). In later multiple sclerosis stages frequencies and titres are comparable with early multiple sclerosis. In contrast, the frequency of anti-MBP antibodies is low in multiple sclerosis-R0 (12%) and increases during disease progression in relapsing-remitting (32%) and chronic progressive multiple sclerosis (40%), thus suggesting that anti-MBP responses accumulate over time. Finally we provide evidence for intrathecal synthesis of IgG antibodies to MOG-Ig in multiple sclerosis.

Adult↗
PubMed1993

Increased high affinity beta-adrenergic receptor densities and cyclic AMP responses of CD8 cells in multiple sclerosis.

Beta-adrenergic receptor (beta R) density is increased on suppressor T-cells (Ts) from patients with chronic progressive multiple sclerosis (CPMS). We investigated the contribution of high-affinity (kh) beta R to cAMP responses of nongranular leukocyte subsets from CPMS patients and normal individuals (NL). CD8 beta R density was 1930 receptors/cell in CPMS compared to only 1020 receptors/cell in NL (t(18) = 2.73, P < 0.02). beta R densities on monocytes, B cells, and CD4 cells did not differ between groups. The increased density of beta R on CD8 cells in CPMS was entirely the result of an increase in the number of high affinity receptors. Basal level of cAMP in CD8 lymphocytes were 7.8 pmol/10(6) cells in CPMS and 3.5 pmol/10(6) cells in NL. Isoproterenol stimulation elevated cAMP levels in CD8 cells to 49.9 pmol/10(6) cells in CPMS patients and to 25.7 pmol/10(6) cells in NL (difference after activation: t(18) = 3.23, P < 0.005). No differences between groups were found in cAMP levels of other cell subsets. We also measured circulating catecholamine levels. Supine and standing epinephrine levels were not different between CPMS and NL. Supine norepinephrine (NE) levels were higher in CPMS (411 pg/ml) than in NL (268 pg/ml) (P < 0.03); upon standing, significant increases in NE occurred in both groups to 573 pg/ml in CPMS and to 494 pg/ml in NL. These results extend our previous findings of peripheral sympathetic dysregulation in CPMS and suggest a means whereby Ts function, hypothesized to play a role in the immune pathogenesis of CPMS, may be altered.

Adult↗
PubMed1988

Effect of total lymphoid irradiation on functional status in chronic multiple sclerosis: importance of lymphopenia early after treatment--the pros.

To determine whether immunosuppression by total lymphoid irradiation (TLI) slowed deterioration of chronic progressive multiple sclerosis (MS), functional impairment score and blood lymphocyte counts were compared at 6-month intervals through 4 years following treatment of MS patients by either TLI (n = 27) or sham irradiation (n = 21). At each interval, 20 to 30% fewer TLI-treated patients had deteriorated (p less than 0.05 at 6, 12, and 18 months), and the difference in mean functional impairment score between groups became progressively greater (p less than 0.01 at 42 and 48 months). Benefit accrued principally to the 17 TLI-treated patients with absolute blood lymphocyte counts less than 900/mm3 3 months after treatment, whose mean functional impairment score remained within 0.6 units of baseline (p = NS), whereas the ten TLI patients with higher post-treatment lymphocyte counts had progressive deterioration (p less than 0.05 to p less than 0.001 versus TLI-treated patients with lower lymphocyte counts at all intervals except 30 months) and had deteriorated by more than 5 functional scale units by 42 and 48 months. Side effects were minor and complications rare in TLI-treated patients, but one TLI-treated patient developed staphylococcal sepsis. Thus, TLI slows deterioration of chronic progressive MS, with what appears to be enduring benefit through 4 years compartmented to patients with greater induced lymphopenia. Modification of lymphoid irradiation regimens to increase the proportion of MS patients who achieve a favorable degree of lymphopenia and to avert functional hyposplenism may further improve the benefit/risk ratio.

Adult↗
PubMed1989

Multiple sclerosis intra-blood-brain-barrier IgG synthesis: effect of pulse intravenous and intrathecal corticosteroids.

Nine severely disabled clinically definite chronic progressive multiple sclerosis (MS) patients who had at least one determination of intra-blood-brain-barrier (BBB) IgG synthesis rate of greater than 7 mg/day (upper limit of normal = 3.3) participated in this study. Seven patients were given 1 gram of methylprednisolone sodium succinate (MP) by intravenous infusion over 30 minutes once a day for 3 days. Statistically significant (p less than .05) reduction in intra-BBB IgG synthesis (mg/day) was seen in 4/7 patients, but in only 2 were normal levels of synthesis rate (less than 3.3 mg/day) attained. Rebound of IgG synthesis to premedication rates occurred within 30 days in 2/4 patients. There was no change in intensity or pattern of cerebrospinal fluid (CSF) oligoclonal IgG bands by isoelectric focusing, immunofixation, and silver staining. A subsequent course of intrathecal methylprednisolone acetate (MPA) (80 mg twice a week for 5 weeks) was given to 5 of the 7 patients and to 2 additional patients not previously treated. In spite of signs of subarachnoid inflammation, a statistically significant depression of intra-BB synthesis, which far exceeded that from the pulse treatment occurred in all 7, including the 2 patients whose intra-BBB IgG synthesis rates were previously resistant to pulse steroid administration. Normal levels of synthesis were rapidly reached in 4/7 patients; however, an IgG synthesis rebound occurred in 3/7 patients which was just as rapid. One out of 7 patients showed a temporary reduction in the number of cathodic IgG oligoclonal bands in the CSF. Two patients required discontinuation of treatment due to aseptic meningitis in one and progressive weakness in the other. Clinically, these severely afflicted patients with fixed deficits remained unchanged with either treatment protocol. While MPA and ACTH have similar initial effect on the central nervous systems (CNS) inflammatory response in MS, the well documented risk of serious adversities with MPA prohibit its clinical use in MS in its present form.

Adult↗