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PubMed1988

Experience with cyclophosphamide in multiple sclerosis: the cons.

Neurologists in the Kaiser-Permanente Medical Care Program recently designed a study to evaluate the utility of intensive immunosuppression with cyclophosphamide compared with folic acid in 44 patients with chronic progressive multiple sclerosis (MS). Although preliminary results based on incomplete data suggest cyclophosphamide may be safely administered in an outpatient clinic setting and modest benefits cannot be ruled out, it is doubtful that there are very substantial benefits to that therapy. Although several other studies have been cited as evidence of cyclophosphamide's favorable effect on the clinical course of patients with MS, many of these studies have had design shortcomings. If these flaws are considered, the hypothesis that cyclophosphamide has a favorable effect on the course of MS must be considered weak.

Adult↗
PubMed1992

Assessment of different methods to detect increased autochthonous production of immunoglobulin G and oligoclonal immunoglobulins in multiple sclerosis.

The formulae for immunoglobulin G (IgG) synthesis rate, IgG(loc), IgG index, and IgG extended index in determining increased autochthonous production (intra-blood-brain barrier synthesis) of IgG was assessed in 50 chronic progressive multiple sclerosis patients. The results of all four formulae clearly show elevated intra-blood-brain barrier IgG synthesis in 35 patients, 94% of whom had oligoclonal immunoglobulins detected by the method of isoelectric focusing with immunofixation and silver staining (IEF-IS). The results from the four formulae are all normal in seven patients (none have oligoclonal immunoglobulins by IEF-IS) and are discordant in eight patients (five have oligoclonal immunoglobulins by IEF-IS). Whenever intra-blood-brain barrier synthesis of IgG is suspected, IEF-IS should be used to assay for oligoclonal immunoglobulins because this method is more sensitive than agarose electrophoresis with either Coomassie blue dye or silver stain (94% vs. 74% vs. 54%).

Blood-Brain Barrier↗
PubMed1989

Tumor necrosis factor in serum and cerebrospinal fluid of patients with multiple sclerosis.

We measured levels of alpha-tumor necrosis factor (alpha-TNF) in cerebrospinal fluid and serum samples from 50 drug-free patients with multiple sclerosis, 25 patients with other neurological diseases, 27 patients with non-neurological diseases, and 10 normal subjects. The most elevated levels of alpha-TNF were found in patients with inflammatory or autoimmune diseases. Comparable serum levels of alpha-TNF were detected in normal control subjects, patients with multiple sclerosis, and patients with degenerative neurological diseases. In patients with multiple sclerosis, alpha-TNF levels were also unrelated to time elapsed between the occurrence of clinical exacerbation and the time of sample collection. Only 3 patients with chronic progressive multiple sclerosis had detectable alpha-TNF in the cerebrospinal fluid. Our data do not support a role for elevated levels of circulating alpha-TNF in the maintenance of the disease. However, we cannot rule out the possibility that a transient elevation of alpha-TNF triggers the cellular events leading to demyelination in multiple sclerosis.

Adolescent↗
PubMed1998

HLA class II (DRB1, DQA1 and DQB1) associated genetic susceptibility in Iranian multiple sclerosis (MS) patients.

The association of HLA class II alleles with multiple sclerosis (MS) has been amply documented. In the present study, the role of HLA class II (DRB1, DQA1 and DQB1) alleles and haplotypes was investigated in 43 unrelated Iranian chronic progressive multiple sclerosis (CP-MS) patients compared with 100 healthy individuals. HLA typing for DRB1, DQA1 and DQB1 was performed by restriction fragment length polymorphism (RFLP). Subtypes of DR4, DR15 and DR16 were defined using polymerase chain reaction (PCR) amplification with sequence-specific primers (PCR-SSP). The results show that, among DR2-positive MS patients and the control group, a positive association with the DRB1*1503, DQA1*0102, DQB1*0602 haplotype (21% vs. 2.7%, P = 0.057, RR = 9.8) and a negative association with the most frequent DR15 haplotype in the control group, DRB1*15021, DQA1*0103, DQB1*0601 (7% vs. 24.3%, P = 0.001), were observed. No significant association was found with the analysed HLA-DRB1, DQA1 and DQB1 alleles.

Alleles↗
PubMed1990

Quantitative multiple sclerosis plaque assessment with magnetic resonance imaging. Its correlation with clinical parameters, evoked potentials, and intra-blood-brain barrier IgG synthesis.

Magnetic resonance imaging (MRI) of the cerebrum, cerebellum, brain stem, and upper cervical cord was performed in 62 individuals with clinically definite chronic, progressive multiple sclerosis (MS). The total area of MRI-demonstrated lesions was measured from film enlargements for each region using an interactive image analysis system. While the MRI was abnormal in 60 (97%) of 62 patients, the visual-evoked potentials in 51 (85%) of 60 patients, the brain stem auditory-evoked potentials (BAEPs) in 24 (46%) of 52 patients, and the somatosensory-evoked potentials (SSEPs) in 45 (89%) of 54 patients, an abnormal intra-blood-brain barrier (BBB) IgG synthesis rate, IgG oligoclonal bands, or both were found in all 62 patients. The total area of MRI abnormality in the cerebrum was significantly correlated only with the intra-BBB IgG synthesis rate, abnormal visual-evoked potentials, impaired performance on the Symbol Digit Modalities Test (SDMT), and one test of standing duration in the quantitative examination of neurologic function (QENF). The brain stem lesion area correlated with the Kurtzke expanded disability status scale and brain stem functional systems score, the ambulation index, abnormal BAEPs, and impaired performance on the SDMT as well as multiple tests of upper and lower extremity function in the QENF. The cerebellar lesion area correlated with impaired performance on the SDMT and primarily upper extremity testing in the QENF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

A comparison of two neurologic scoring instruments for multiple sclerosis.

We examined the degree of association between two neurologic impairment scales, the Extended Disability Status Scale (EDSS) and the Scripps Neurologic Rating Scale (SNRS), with data from a randomized, double-blind, placebo-controlled clinical trial assessing the safety and efficacy of cladribine as treatment for chronic progressive multiple sclerosis (MS). We found that the EDSS and SNRS were not strongly correlated within individual patients, contrary to expectation; moreover, in 9 of the 48 evaluable patients, the directions of their changes from baseline values were not mutually consistent. The scales were differentially sensitive to clinical changes over time, with the EDSS indicating a more abrupt, and the SNRS a more gradual, change in the clinical course of disease. The validity of different impairment scales, and their sensitivity to detect clinical changes, should be formally assessed in future clinical trials using these scales as outcome measures.

Adult↗
PubMed1999

Long-term open-trial of mizoribine with prednisolone in 24 patients with multiple sclerosis: safety, clinical and magnetic resonance imaging outcome.

OBJECT: Mizoribine (MZR), imidazole nucleotide, inhibits purine synthesis and helper T cell functions. It is used as an immunosuppressant in chronic rheumatic arthritis in Japan. Twenty-four patients with relapsing-remitting and chronic progressive multiple sclerosis (MS) were studied for the long-term effects of MZR over 8 years. METHODS: Average daily MZR doses of 200 mg along with prednisolone (PSL) were administered in the patients studied. Ten of 24 patients were treated for more than 5 years. RESULTS: The mean relapse rate per year at entry (1.50 +/- 0.24, mean +/- SE, n = 22) decreased [0.46 +/- 0.24 (n = 19)] after two years. In 70% of the patients, the disability did not worsen. Eleven of 18 patients showed a mild decrease of the total lesion size in magnetic resonance imaging (MRI). CONCLUSION: MZR was well tolerated and could be used for long-term in MS as an adjunctive immunosuppressant to PSL, and the PSL doses could be decreased. A further randomized controlled trial with PSL is necessary.

Adolescent↗
PubMed1990

Decreased suppressor-inducer T lymphocytes in multiple sclerosis and other neurological diseases.

Decreased numbers of CD4+CD45R+ suppressor-inducer T cells have been reported in patients with a variety of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis but not in patients with other neurological diseases. We now report our findings using murine monoclonal antibodies and two-color flow cytometric analysis on CD4+CD45R+ T cells in 22 patients with chronic progressive multiple sclerosis, 23 patients with other neurological diseases and 42 normal, healthy controls. Suppressor-inducer T cells were significantly reduced (p less than 0.001) in both patients with multiple sclerosis and other neurological diseases as compared to controls. Both patient populations had elevated helper T cell subset ratios. Thus, our data suggests that decreases in suppressor-inducer T cells may represent a common immunological defect among autoimmune and presumably non-autoimmune neurological disorders.

Adult↗
PubMed1997

Monoclonal remyelination-promoting natural autoantibody SCH 94.03: pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis.

Chronic inflammatory demyelination of the central nervous system is usually incompletely repaired. However, we previously reported that in vivo treatment with monoclonal antibody SCH 94.03 (produced using spinal cord homogenate as an immunogen) increased myelin repair 4-fold in the Theiler's virus mouse model of chronic progressive multiple sclerosis (Miller et al., 1994; J. Neurosci. 14: 6230-6238). A major issue regarding site and mechanism of action of this antibody is whether SCH 94.03 enters demyelinated CNS lesions and reacts with oligodendrocytes and myelin. To address this question, we radiolabeled SCH 94.03 and studied its distribution into tissues, pharmacokinetics, and binding to cells within demyelinating spinal cord lesions in vivo. SCH 94.03 distributed widely into extracellular water following intraperitoneal injection and was eliminated with a terminal half-life of 3-4.5 days. Only a portion of the total dose (0.4%) entered brain and spinal cord. SCH 94.03 accumulated 1.5-2.0-fold in brain between 1 and 7 days after injection, but its pharmacokinetics were otherwise similar to those of an isotype control IgMkappa antibody. Oligodendrocytes, myelin sheaths and, less frequently, axons were labeled within demyelinating lesions as detected by light and electron microscopic autoradiography. These findings suggest that remyelination-promoting autoantibodies could act within the demyelinating lesion of the central nervous system by binding to the oligodendrocyte, myelin, or axon.

Animals↗
PubMed1989

MHC-restricted autoantigen-reactive T cell clones in multiple sclerosis.

Multiple sclerosis is a demyelinating disease of the central nervous system with genetic, viral and autoimmune characteristics. Myelin basic protein (MBP) is a suspected target autoantigen since it induces experimental autoimmune encephalomyelitis, an animal model closely resembling multiple sclerosis. The disease is mediated by Class II restricted, MBP-reactive T cells possessing the T helper/inducer phenotype. In the present study, we have isolated MBP-reactive T cell clones from the peripheral blood of a chronic progressive multiple sclerosis patient. The clones displayed blastogenic memory responses when rechallenged with the autoantigen and irradiated autologous lymphocytes. MBP recognition by the autoantigen-reactive T lymphocytes was restricted by major histocompatibility complex Class II antigens. Both CD4+8- and CD4-8+ MBP-reactive T cell clones were obtained.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Assessment of therapeutic plasmapheresis in demyelinating neurologic disorders.

Considerable controversy exists with regard to therapeutic efficacy of plasmapheresis in the immune-mediated demyelinating disorders of the peripheral and central nervous system: acute inflammatory polyneuropathy (Guillain-Barré syndrome), chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis. In an effort to establish specific situations where plasmapheresis was of therapeutic value, we reviewed the experience at Southwestern Medical School, University of Texas Health Science Center at Dallas, and that published in the literature. In acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome), plasmapheresis may prevent progression of the illness, and it significantly increases the rate of recovery. For patients with chronic inflammatory polyneuropathy, plasmapheresis has produced clinical improvement in 50% of corticosteroid-refractory patients. The use of plasmapheresis in patients with acute or chronic progressive multiple sclerosis still remains controversial.

Adolescent↗
PubMed1993

Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis.

Magnetic resonance imaging is a highly sensitive method for the detection of the lesions of multiple sclerosis and renders possible the study and the evolution of early lesions. Previous reports on magnetic resonance imaging following gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) injection demonstrated that new lesions can be recognized by contrast enhancement. The pathological basis of these observations is uncertain. We have had the opportunity to study at autopsy the brain of a patient with chronic progressive multiple sclerosis who suffered acute worsening leading to death. Magnetic resonance imaging performed 10 days and 4 weeks prior to death showed new Gd-DTPA-enhanced lesions in the posterior hemispheric white matter adjacent to the lateral ventricles. Light microscopic examination of these areas demonstrated them to be fresh lesions comprising intense inflammatory activity and dense perivascular cuffs within an edematous lesion center and a striking parenchymal mononuclear cell infiltration at the margins of the lesions. Lesions that were demonstrated by increased signal on T2-weighted images, but were not enhanced following administration of Gd-DTPA, were all of the chronic type, either inactive or active. None of these showed the intense inflammatory activity of the acute lesions and most displayed fibrous astrogliosis.

Adult↗
PubMed2002

Theiler's virus-mediated autoimmunity: local presentation of CNS antigens and epitope spreading.

Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a neurotropic picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to those of chronic-progressive multiple sclerosis. Upon infection, TMEV-specific CD4+ T cells target persistent viral antigens in the CNS and initiate myelin damage. Later in the disease, myelin-specific CD4+ T cells are primed by epitope spreading, and these autoimmune T cells contribute to the pathogenesis of the chronic-progressive disease. This review focuses upon aspects of the initiation of a virally induced CD4+ T cell-mediated autoimmune response. First, the steps involved in the hierarchical activation of non-cross-reactive myelin-specific T cells in the SJL/J mouse after CNS infection with TMEV and the role of these autoreactive T cells in chronic myelin damage are discussed. Second, the process of epitope spreading and the role of CNS antigen presenting cells in the temporal presentation of self-antigens is considered. Finally, we will discuss aspects of T cell activation and antigen presentation, and how they can impact autoimmune disease.

Animals↗
PubMed1999

Assessing multiple sclerosis activity: is the in vitro production of tumor necrosis factor-alpha, interleukins 2, 6, 4, and 10, and immunoglobulin G of value?

Tumor necrosis factor (TNF) alpha, interleukins (IL) 2, 4, 6, and 10, and IgG oligoclonal bands (IgG OB) in vitro production was assessed, after whole-blood stimulation with lipopolysaccharide or concanavalin A, in 61 patients presenting with relapsing-remitting, relapsing-progressive, or chronic progressive multiple sclerosis. Multiple sclerosis patients were receiving no treatment or azathioprine (AZA), cyclosporin, cyclophosphamide, subcutaneous interferon (IFN) beta 1 a, or corticosteroids (CST). Statistical correlations significantly showed that: (a) AZA lowers TNF-alpha (P = 0.002) and increases IL-4 production (P = 0.0024), and IFN-beta 1 a increases TNF-alpha and decreases IL-4 levels; (b) CST has a negative effect on TNF-alpha, IL-6, and IL-4 synthesis; and (c) AZA, IFN-beta 1 a, and CST diminish IgG OB synthesis (P = 0.001). Although our study of the dynamics of TNF-alpha, IL-2, IL-4, IL-6, and IL-10 in vitro production generally found no statistically significant correlations (partly explained by the limited number of values in the various groups), IL-6 was shown to drop during the periods surrounding relapse (P = 0.05) in the absence of treatment, while TNF-alpha (P = 0.04) and IL-6 (P < 0.05) dropped before exacerbation in the presence of AZA. In vitro production of TNF-alpha was closely and positively correlated with that of IL-6, independently of clinical features. The enhanced production of IL-10 detected before or at relapse with AZA and IFN-beta 1 a (trends) may interfere with initiation of the immune reaction and with the development of new CNS lesions. Some discrepancies with previously published results stress the difficulties in studying the state of stimulation of different populations of leukocytes by using a variety of in vitro stimuli and in establishing a correlation between mRNA studies and the amount of final or active protein produced.

Adjuvants, Immunologic↗
PubMedDate not supplied

Multiple sebaceous adenomas and extraocular sebaceous carcinoma in a patient with multiple sclerosis: case report and review of literature.

BACKGROUND: Sebaceous carcinomas are relatively rare cutaneous tumors; there are fewer than 600 cases reported. They most commonly arise within the meibomian gland of the eyelid; fewer than 150 of the reported cases were extraocular. These tumors have a high incidence of local recurrence and regional metastasis. The relationship of sebaceous tumors and visceral malignancy is well established in the literature. OBJECTIVE: We describe a 44-year-old white female with chronic progressive multiple sclerosis who developed multiple scalp sebaceous adenomas and a solitary sebaceous carcinoma. CONCLUSION: Extraocular sebaceous carcinomas are rare tumors with high incidence of local recurrence and regional metastasis. Surgery with wide surgical margins is the standard treatment. We report the first case of multiple sebaceous tumors in a patient with multiple sclerosis. The presence of sebaceous tumors warrants a search for an internal malignancy. Literature on sebaceous tumors and their relationship with visceral malignancies and immunologic disorders is discussed. Literature on sebaceous carcinoma with special attention to extraocular sebaceous carcinoma is also discussed.

Adenocarcinoma, Sebaceous↗
PubMed1996

Resolution of partial cataplexy in multiple sclerosis by treatment with weak electromagnetic fields.

Cataplexy, an ancillary symptom of narcolepsy, involves the sudden loss of muscle tone without altered consciousness usually brought on by sudden excitement or emotional influence and extreme exertions (Guilleminault et al., 1974; Parks et al., 1974; Guilleminault, 1976; Aldrich, 1992; 1993; Scrima, 1981; Baker, 1985). Attacks of generalized cataplexy produce complete atonic, areflexic partial or complete paralysis of striated muscles commonly involving the leg muscles resulting in collapse of the knees and falling while milder forms often termed partial cataplexy may manifest by sagging of the face, eyelid, or jaw, dysarthria, blurred vision, drooping of the head, weakness of an arm or leg, buckling at the knees, or simply a momentary sensation of weakness that is imperceptible to observers (Guilleminault, 1976; Aldrich, 1993). The duration of cataplexy is usually a few seconds, although severe episodes can last several minutes and rarely several hours or days in the case of "status cataplecticus" (Parkes et al., 1974; Guilleminault, 1976; Billiard & Cadilhac, 1985; Aldrich, 1992; 1993). This report concerns a 51 year old man with chronic progressive multiple sclerosis who exhibited daily episodes of partial cataplexy which resolved within 3 weeks after he received treatment with picotesla electromagnetic fields.

Brain↗
PubMed1989

Long-term use of antecubital veins for plasma exchange. The Canadian Cooperative Multiple Sclerosis Study Group.

True or sham plasma exchange was done weekly for 20 weeks in patients in two of the randomization groups in a prospective, blind clinical trial of experimental treatments for multiple sclerosis. Because patients could be randomized to receive sham plasma exchange and placebo medications, it was decided when the trial was designed that the use of fistulae, arteriovenous shunts, venous cutdowns, or other aggressive forms of venous access would not be permitted for any patient. Accordingly, patients judged to have inadequate superficial antecubital veins were ineligible for the trial. To date, only 13 (4.4%) of 294 patients considered for entry into the trial have been rejected on these grounds. In only 4 of the 93 patients undergoing exchange was it necessary to discontinue plasma exchange because of inadequate venous access. In 79.3 percent of the 1207 exchanges done in these patients, there were no problems of any kind with venous access. In 5.4 percent of these 1207 exchanges, it was necessary to terminate the procedure prematurely because of difficulties with patients' veins. Thus, the great majority of patients free of serious systemic illness (other than chronic progressive multiple sclerosis) can undergo weekly plasma exchange for up to 20 weeks using superficial antecubital veins without the need to resort to more invasive methods of venous access.

Bloodletting↗