Shmuel Miron

Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis: implications for the treatment of acute relapses of multiple sclerosis

Dexanabinol (HU-211) is a synthetic non-psychotropic cannabinoid which suppresses TNF-alpha production in the brain and peripheral blood. The effects of dexanabinol in rat experimental autoimmune encephalomyelitis (EAE) were studied using different doses, modes of administration and time regimes. Dexanabinol, 5 mg/kg i.v. given once after disease onset (day 10), significantly reduced maximal EAE score. Increasing the dose or treatment duration resulted in further suppression of EAE. Drug administration at earlier phases during disease induction was not effective. Histological studies supported the clinical findings demonstrating reduction in the inflammatory response in the brain and spinal cord in animals treated with dexanabinol. The results suggest that dexanabinol may provide an alternative mode of treatment for acute exacerbations of multiple sclerosis (MS).

Automated Detection and Characterization of Multiple Sclerosis Lesions in Brain MR Images

In the present study an automatic algorithm for detection and contouring of multiple sclerosis (MS) lesions in brain magnetic resonance (MR) images is introduced. This algorithm automatically detects MS lesions in axial proton density, T2-weighted, gadolinium enhanced, and fast fluid attenuated inversion recovery (FLAIR) brain MR images. Automated detection consists of three main stages: (1) detection and contouring of all hyperintense signal regions within the image; (2) partial elimination of false positive segments (defined herein as artifacts) by size, shape index, and anatomical location; (3) the use of an artificial neural paradigm (Back-Propagation) for final removal of artifacts by differentiating them from true MS lesions. The algorithm was applied to 45 images acquired from 14 MS patients. The algorithms sensitivity was 0.87 and the specificity 0.96. In 34 images, 100% of the lesions were detected. The algorithm potentially may serve as a useful preprocessing tool for quantitative MS monitoring via magnetic resonance imaging.

IMMUNOGLOBULIN TREATMENT IN REFRACTORY MYASTHENIA GRAVIS

Failure to induce and maintain remission in severe exacerbations of myasthenia gravis (MG), despite optimal care, is a common problem. We evaluated the efficacy and safety of high‐dose intravenous immunoglobulin (IVIg) therapy in an open‐label study of 10 patients with severe generalized myasthenia and an acute deterioration unresponsive to conventional therapy including high‐dose corticosteroids, cyclosporine, and azathioprine. Intravenous Ig at a loading dose of 400 mg/kg was administered daily for 5 consecutive days, with maintenance IVIg treatment at a dose of 400 mg/kg, once every 6 weeks. Significant improvement occurred in all patients, beginning at 6 ± 2 days of treatment as measured by the Osserman scale, fatigue variables, muscle strength, and respiratory function tests. No side effects were observed during induction of remission. Further IVIg treatments were highly efficacious in maintaining the remission. The severity of the disease decreased by 2.5 ± 0.8 grades of the Osserman scale over a period of 1 year (P <0.001), in parallel with reduction of immunosuppressive therapy as well as a decrease in acetylcholine receptor antibody titers (P < 0.01). Intravenous Ig therapy seems to be highly potent for inducing rapid improvement in refractory myasthenia during acute deterioration as well as for maintaining remission.

Alfacalcidol treatment in multiple sclerosis

To the Editor: Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. In recent years several immunomodulating drugs have been shown to decrease relapse rate and neurologic disability in relapsing–remitting MS patients by approximately 30%, and thus there is still the need to search for additional interventions (1). 1,25-Dihydroxyvitamin D3 [1,25-D3], the active form of vitamin D, has been shown to prevent clinical signs of experimental autoimmune encephalomyelitis—the animal model of MS. 1,25-D3 also prevents the progression of experimental autoimmune encephalomyelitis when administered with the appearance of the first symptoms of disability, thus affecting the disease process during both the immunization phase and after the onset of clinical signs (2). It was suggested that 1,25-D3 exerts its immunomodulatory effects within the central nervous system during an ongoing immune process and may thus represent a promising therapy for MS. Recently, 1,25-D3 has been showed to inhibit interleukin-12 production (3), which is known to induce interferon-gamma secretion, which is involved in the inflammatory process during active MS. The aim of the current study was to evaluate the effect of 1-alpha-hydroxy-D3 (Alfacalcidol) the activated form of vitamin D in MS patients, focusing on safety and toxicity. Five patients with definite MS and a relapsing–remitting course were included in the study. Patients were selected to participate if they had a relatively low exacerbation rate not qualifying them to receive accepted relapse preventive treatments. Patients received a detailed explanation, and all provided written informed consent. The study was approved by the ethical committees of the Israeli Ministry of Health. Patients (two women, three men; mean age, 47 years; age range, 45–51 years; mean disease duration, 6.4 years; range of disease duration, 4–12 years; mean EDSS score, 4.5 points; range of EDDS scores, 3.5–5.0 points) were treated with Alfacalcidol at a dosage of 1.5 μg/day for a period of 6 months. Neurologic examination was performed once monthly. Alfacalcidol serum levels were measured at baseline, and at 3 and 6 months. Brain magnetic resonance imaging (2 T, 3-mm slice, no gap; Elscint, Israel) was performed at baseline and on study completion. Throughout the study period patients felt well and no side effects were reported. None of the patients complained of symptoms associated with Alfacalcidol intoxication, and calcium blood levels were within normal range. Neurologic status of patients at the end of the study was as follows: three patients were stable, one patient improved, and one patient had an acute relapse and received treatment with methylprednisolone. The current findings implicate a role for Alfacalcidol in MS. It is possible that in addition to its hormonal effects on neurotransmitter levels and turnover, Alfacalcidol can also regulate myelin basic protein-specific T-helper cells through its effects on interleukin-12 production [8] and thus prevent the inflammatory process during active MS. We suggest that Alfacalcidol is safe and well tolerated by MS patients, and its potential role as an immunomodulating treatment should be investigated in large-scale studies.

Cerebellar volume as imaging outcome in progressive multiple sclerosis

Background and purpose To assess whether cerebellar volumes changes could represent a sensitive outcome measure in primary-progressive MS. Material and methods Changes in cerebellar volumes over one-year follow-up, estimated in 26 primary-progressive MS patients and 20 controls with Freesurfer longitudinal pipeline, were assessed using Wilcoxon test and tested for their correlation with disability worsening by a logistic regression. Clinical worsening was defined as EDSS score increase or change of >20% for 25-foot walk test or 9-hole peg test scores at follow-up. Sample sizes for given treatment effects and power were calculated. The findings were validated in an independent cohort of 20 primary-progressive MS patients. Results Significant changes were detected in brain T1 lesion volume (p<0.01), cerebellar T2 and T1 lesion volume (p<0.01 and p<0.05), cerebellar volume, cerebellar cortex volume, and cerebellar WM volume (p<0.001). Only cerebellar volume and cerebellar cortex volume percentage change were significantly reduced in clinically progressed patients when compared to patients who did not progress (p<0.01; respectively AUC of 0.91 and 0.96). Cerebellar volume percentage changes were consistent in the exploration and validation cohorts (cerebellar volume -1.90±1.11% vs -1.47±2.30%; cerebellar cortex volume -1.68±1.41% vs -1.56±2.23%). Based on our results the numbers of patients required to detect a 30% effect are 81 per arm for cerebellar volume and 162 per arm for cerebellar cortex volume (90% power, type 1 error alpha = 0.05). Conclusions Our results suggest a role for cerebellar cortex volume and cerebellar volume as potential short-term imaging metrics to monitor treatment effect in primary-progressive MS clinical trials.

Diffusion Tensor Imaging Analysis of Tumefactive Giant Brain Lesions in Multiple Sclerosis

Diffusion tensor imaging (DTI) quantifies the motion of water within brain tissue. Inflammation leads to tissue disruption, resulting in increased diffusivity and decreased directionality. We aimed to quantify the damage within tumefactive giant brain lesions (TGL) in multiple sclerosis (MS) using MRI and DTI methodology.

Parenteral Administration of an Activating Monoclonal Antibody to the α1β1 Integrin in Dogs

In mice, monoclonal antibody (mAb) to the alpha1 integrin abrogate gastro-intestinal damage during graft-versus-host-disease (GVHD), suggesting anti alpha1 mAb as candidates for treatment in humans as well. Our current data show that one such reagent, mAb 1B3.1, when immobilized to plastic wells via rabbit- anti murine (ram) immunoglobulin (Ig) induces a protein kinase-dependent spreading of activated human T cells. Furthermore, it significantly increases the proliferative response, and expression of interleukin-2 (IL-2) receptors (R) and CD69, of resting T cells, expressing minimal integrin on the cell surface, to sub-optimal stimulation by anti-CD3 mAb. We found, in addition, that mAb 1B3.1 a) immuno-precipitates alpha1beta1 integrins from cell-surface iodinated canine epithelial cells b) is highly reactive with canine T cells after their activation and c) inhibits adhesion of canine T cells to collagen IV. Despite the potential ability of the mAb to co-activate T cells in vitro, two dogs that received 4 injections of 0.5-0.3 mg/Kg of mAb 1B3.1 remained healthy, developing only marginal transient lymphopenia. Injection of 0.75mg/Kg in a third dog induced a more marked lymphopenia, and an additional dose of 1.0 mg/Kg 2 weeks later was followed by gastrointestinal hemorrhage. importantly, the lymphopenia was associated with a greater and more persistent decrease of CD8+ than of CD4+ T cells, leading to an increase in the CD4/CD8 ratio 24 hours after the injection. Thus, despite its co-activating effects in vitro, administration of this mAb in vivo is feasible when appropriately dosed, and may have immuno-modulatory effects.

Intravenous immunoglobulin and multiple sclerosis

Intravenous immunoglobulin (IVIg) has been used as an immunomodulatory therapy for the treatment of multiple sclerosis (MS). In the current review, we summarize the up-to-date data related to IVIg clinical trials in MS, and the suggested mechanisms of action by which IVIg modulates the relevant immunological pathways impaired in MS.

Brain Lesion Load and Anatomic Distribution in Patients With Juvenile Clinically Isolated Syndrome Predicts Rapidly Advanced to Multiple Sclerosis

The aim was to assess brain lesion load and anatomical distribution in patients with juvenile clinically isolated syndrome and define magnetic resonance imaging (MRI) variables associated with rapidly advancing to multiple sclerosis. Patients were followed for one year after disease onset. Patients who experienced a second relapse were defined as those who rapidly advanced to multiple sclerosis. In all, 46 juvenile patients with a clinical presentation suggestive of multiple sclerosis were evaluated; 21 with gadolinium-enhancing lesions on initial brain MRI were excluded as they had already fulfilled the diagnosis criteria for multiple sclerosis. A total of 25 patients, 10 males and 15 females (mean ± SE age at onset 15.6 ± 0.6 years), met the definition of clinically isolated syndrome. The presence of a corpus callosum lesion at onset significantly differentiated between sustained clinically isolated syndrome and patients who rapidly advanced to multiple sclerosis.

PO-0846 Tumefactive Demyelinating Lesions In Juvenile-onset Multiple Sclerosis

Background The pathogenesis of large demyelinating lesions is still controversial. Atypical tumefactive demyelinating lesions (TDL) associated with acute inflammation, peri-lesional oedema and gadolinium ring enhancement are infrequently described in patients with juvenile-onset multiple sclerosis (MS). Objective To describe the clinical, imaging and micro-structural metrics of TDLs and chronic MS lesions in patients with juvenile-onset MS. Methods Ten patients diagnosed with MS were analysed for the presence of TDLs and chronic non enhancing MS lesions. The MS lesions were defined by a region of interest encircling the lesion centre on 2–3 consecutive slices. DTI images were acquired along 31 independent orientations using a single shot echo-planar imaging sequence. Results Four patients with 6 TDL, developed acute neurological symptomatology. The two girls presented with acute ataxia and aphasia, and the two boys with severe ataxia. Three patients progressed rapidly to develop seizures, became stuporotic and were admitted to the paediatric intensive care unit. Brain MRI demonstrated six TDLs. Analysis of the whole group (10 patients) disclosed 21 chronic non enhancing lesions. Assessment of DTI metrics of TDL as compared to chronic MS lesions disclosed significant differences. Conclusion TDL are a possible presentation of demyelinating disorders, posing a diagnostic and therapeutic dilemma towards neoplastic lesions. The micro-structural analysis of TDL suggests a severe tissue disruption probably due to the acute inflammatory process and oedema. Our analysis provides metrical tools that together with MR spectroscopy and perfusion may aid to identify accurately TDLs, potentially sparing young patients unnecessary and possibly debilitating brain biopsy.