Multiple Sclerosis Journal

We report a patient who suffered from acute inflammatory CNS demyelination and underwent two consecutive diagnostic stereotactic brain biopsies during the early disease course. The first lesion was drawn 33 days after the onset of disseminated neurological symptoms. Macrophages and T lymphocytes diffusely infiltrated small vessel walls and the white matter. mRNA for tumor necrosis factor alpha (TNFa) and inducible nitric oxide synthase (iNOS) was abundantly expressed. Myelin sheaths were entirely preserved. The second biopsy 76 days later showed confluent demyelinating lesions with a diffuse infiltration of macrophages that were positive for myelin debris, activation markers and TNFa and iNOS mRNA. IgG and C9neo deposits were found along myelin sheaths. The patient had received intravenous immunoglobulins (IVIG) prior to biopsy. Findings from this single patient affirm that demyelination follows the migration of inflammatory cells from the circulation into the white matter with subsequent inflammation and demyelination. Inflammation alone may be sufficient to cause significant clinical deficits without demyelination. Inflammatory mediators such as TNFa and NO are involved at very early stages in the pathogenetic process. IVIG treatment may lead to the deposition of immunoglobulins and to the activation of the complement cascade, but the clinical relevance of this particular finding remains uncertain.

Multiple sclerosis is an inflammatory demyelinating CNS disease of putatively autoimmune origin. Novel models of experimental autoimmune encephalomyelitis (EAE) have demonstrated that T cells specific for various myelin and even nonmyelin proteins are potentially encephalitogenic. The encephalitogenic T cell response directed against different CNS antigens not only determines the lesional topography of CNS inflammation but also the composition of the inflammatory infiltrates. The heterogeneity of the lesional distribution seen in EAE might therefore be useful for the understanding of the various clinical subtypes seen in MS. In this review the possible candidate autoantigens in MS are discussed with special regard to the human T cell and B cell responses against various myelin and nonmyelin proteins.

The limited application of functional magnetic resonance imaging (fMRI) for investigations of multiple sclerosis (MS) patients has already shown that deficits of the motor, cognitive and visual systems may be identified by differences in the patterns of activation in response to a suitable stimulus. In MS patients with unilateral optic neuritis, the area of activation in the primary visual cortex, measured by fMRI techniques, is dramatically reduced in response to stimulation of the affected eye. The latency of the major positive component of the visual evoked potential (VEP) recorded upon stimulation of the affected eye is significantly increased in these patients, as compared to the unaffected eye and normal volunteers. We have found a correlation between the neural response measured using fMRI and the latency of the VEP. fMRI signal responses have the potential to provide more detailed topographic information relating to functional deficits in MS.

Objective: To determine if monocyte TNFa production from patients homozygous for a specific MS associated TNF gene haplotype is different from that produced in patients either heterozygous for, or without this haplotype. Background: The balance between pro- and anti-inflammatory cytokines is important in the clinical outcome of inflammatory reactions. Levels of TNFa, a pro-inflammatory cytokine, is raised in MS as well as being found in acute and chronic MS lesions. A previous population based study in Northern Ireland with polymorphisms spanning the TNF gene region identified a conserved MS associated haplotype in relation to three markers (130: 118: 127 TNF d: a: b) for which 19 MS patients were homozygous. Methods: Venous blood collected in EDTA to give a concentration of 10^{7 3} M was drawn from 16 patients with the conserved MS associated haplotype, 19 patients heterozygous for the haplotype and 17 patients without the haplotype. Mononuclear cells were separated and cultured by standard techniques and levels of TNFa and of TNF binding proteins I and II were determined by commercial enzyme-linked immunosorbent assays. Results: There were no significant differences in TNFa production in the 3 h (P=0.28) or 24 h cultures (P=0.18) or following stimulation with interferon-g (P=0.17) between the group positive for the conserved haplotype and the group negative for this haplotype. There was also no significant difference when compared to the heterozygote group. No association was found between the MS associated haplotype and levels of either TNF binding protein. A greater proportion of patients with the conserved haplotype had a benign clinical course (P=0.06). Conclusion: We conclude that whilst a trend exists, we have found no significant association between peripheral TNFa production and a specific MS associated TNF haplotype in this population. Paradoxically this haplotype may also predict a more favourable clinical course.

In a hospital-based study of 119 patients with definite multiple sclerosis, demographic and clinical factors were analysed with respect to their validity in assessing the long-term prognosis. Over a mean follow-up of 21.7 years, the following factors negatively influenced the prognosis by the univariate analysis: male sex, age at onset over 25, pyramidal involvement or spasticity at onset, 53 functional systems affected at onset or after 5 years, incomplete first remission, length of the first remission 41 year, 45 attacks in the first 10 years, secondary or primary-progressive disease, time to reach secondary progression over 5 years and time to reach EDSS 6 over 7 years. The multivariate model showed that in patients with relapsing-remitting disease, 5 years after onset, pyramidal involvement at onset and shorter time to reach EDSS 6 predicted poor outcome, while after 10 years, higher age at onset and incomplete first remission indicated poor prognosis. Ten years after onset, the predictors of poor outcome in the secondary-progressive group were shorter time to reach EDSS 6 or secondary progression and higher EDSS, while in the primary-progressive group those variables were spasticity or higher number of functional systems affected at onset, and higher EDSS after 5 and 10 years.

Objective: To assess the frequency and quality of sensory symptoms in a population of patients with Multiple Sclerosis (MS) and compare them with controls. Design: Survey to target population and control group evaluating demographic data, data on disease course, presence of various symptoms of MS. Setting: Neurological practices affiliated with a tertiary community hospital. Participants: 224 patients with MS, 93 controls of similar age and sex. Results: Sensory symptoms were more common in MS patients than in controls, and differed in severity and quality. Fifty per cent described brief (seconds to hours) episodes of neurological dysfunction, significantly more often than in controls (P=0.001). Pain was present at some time in similar percentages in patients and controls, but active pain problems were present more often in MS patients (P=0.001). The qualitative description of pain in MS patients was more often neuropathic, with burning, itching, electric and formicatory pain, as opposed to throbbing, sharp or muscular pain. Pain was localized to arms, legs, trunk, hands, feet and face more often in the MS group. Lhermitte's phenomenon was present in two-thirds of patients at some time in their disease course. Twenty per cent of the patients identified themselves as having respiratory problems (Controls 7.5%, P=0.005). Fatigue limited activity in 78% of patients, but only in 17% of controls (P=0.001). Dizziness, memory dysfunction, and restless legs symptoms were all more frequent in patients. The self-rated `worst' symptoms of MS was pain in 12%, fatigue in 17% and dizziness in 5%, a total of 34% of `worst' symptoms. Sensory symptoms were present in patients with early disease and without disability as often as in disabled patients and in those with longer disease duration. There was however a strong correlation between the total number of sensory symptoms reported and the presence of disability in the MS patients. Conclusions: Sensory symptoms are common in MS patients. Pain syndromes, transient neurologic events, Lhermitte's phenomenon, fatigue, respiratory symptoms and vertigo were present significantly more frequently in patients with MS than in a control population and contributed to subjective morbidity. Future clinical trials assessing therapy in MS might include sensory symptoms as secondary endpoints to capture this `hidden reservoir' of disease morbidity.

Cytokines have a crucial role in initiation and perturbation of EAE that represents an animal model of multiple sclerosis (MS). Administration of transforming growth factor-β1 (TGF-β1) to EAE mice improves clinical EAE and prevents relapses by unknown mechanisms. Administering low doses of TGF-β1 nasally, we confirmed that TGF-β1 inhibited development and relapse of protracted-relapsing EAE (PR-EAE) in DA rats. Infiltration of CD4+ T-cells and macrophages within the central nervous system was clearly reduced, while proliferation and IFN-g secretion of mononuclear cells (MNC) was augmented in TGF-β1-treated EAE rats compared to PBS-treated control EAE rats. TGF-β1 administered nasally also increased nitric oxide production and CD4+ T cell apoptosis. TGF-β1 treated rats showed augmented proliferation of dendritic cells (DC) compared to MNC. These data imply that low doses of TGF-β1 given by the nasal route prevent PR-EAE and upregulate DC functions that may be involved for disease prevention.

The purpose of this study was to examine the relationship between patient management strategies employed by study personnel, and patient retention and adherence to treatment in the first year of a Phase III clinical trial of interferon beta-1b for treatment of secondary progressive multiple sclerosis (MS). Study staff from each of 35 sites were interviewed regarding patient management practices. Sites which were rated as more empathetic, as instilling a sense of purpose in the patient, and promoting less formal relationships with patients had high rates of adherence to treatment. In addressing specific patient concerns, attention to patients' emotional status and patients' expectations of trial participation were related to better adherence.

Extracorporeal photopheresis is a safe therapy for cutaneous T-cell lymphoma and may have efficacy in certain autoimmune disorders. We performed a randomized, double-blinded, placebo-controlled trial of monthly photopheresis therapy in 16 patients with clinically definite multiple sclerosis (MS). All patients had progressed during the preceding year with entry Expanded Disability Status Scale (EDSS) scores between 3.0 and 7.0. Patients received photopheresis or sham therapy for 1 year and were followed for an additional 6 to 12 months. Patients were clinically evaluated by three disability scales: (1) EDSS; (2) Ambulation index and (3) Scripp's quantitative neurologic assessment. No serious side effects occurred in either group. There were no differences between the photopheresis and sham therapy groups by the disability measures. Additionally, there were no differences in progression of MRI plaque burden or evoked potential latencies. In this limited study, photopheresis was found to be safe but did not significantly alter the course of chronic progressive MS.