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Biomedical subjects

K W Rammohan

Publications and source records attributed to K W Rammohan.

At least 19 recordsLinked to original sources
PubMed2002

Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study.

OBJECTIVE: To assess the efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis (MS). METHODS: Patients aged 18-65 years with a diagnosis of MS, a stable disability level < or =6 on the Kurtzke extended disability status scale (EDSS), and a mean score >4 on the fatigue severity scale (FSS) were eligible for the 9 week, single blind, phase 2, two centre study. Exclusion criteria included a diagnosis of narcolepsy, sleep apnoea, or clinically significant major systemic disease and recent use of medications affecting fatigue. All patients, who remained blinded for the treatment regimen, received placebo during weeks 1-2, 200 mg/day modafinil during weeks 3-4, 400 mg/day modafinil during weeks 5-6, and placebo during weeks 7-9. Safety was evaluated by unblinded investigators. Efficacy was evaluated by self rating scales, using the FSS, the modified fatigue impact scale (MFIS), a visual analogue scale for fatigue (VAS-F), and the Epworth sleepiness scale (ESS). Adverse events were recorded. RESULTS: Seventy two patients (MS type: 74% relapsing-remitting; 7% primary progressive; 19% secondary progressive) received treatment. After treatment with 200 mg/day modafinil for 2 weeks, a significant improvement in fatigue versus placebo run in was demonstrated. Mean scores after treatment with 200 mg/day modafinil were: FSS, 4.7 versus 5.5 for placebo (p<0.001); MFIS, 37.7 versus 44.7 (p<0.001); and VAS-F, 5.4 versus 4.5 (p=0.003). Fatigue scores for 400 mg/day modafinil were not significantly improved versus placebo run in. Mean ESS scores were significantly improved (p<0.001) with 200 mg/day modafinil (7.2) and 400 mg/day (7.0) versus the score at baseline (9.5). Serious adverse events were not found at either dose. The most common adverse events were headache, nausea, and aesthenia. Sixty five patients (90%) completed the study. CONCLUSIONS: These data suggest that 200 mg/day modafinil significantly improves fatigue and is well tolerated in patients with MS.

Adolescent↗
PubMed1994

Immunosuppressive treatment of motor neuron syndromes. Attempts to distinguish a treatable disorder.

OBJECTIVE: To determine if response to immunosuppressive treatment in motor neuron syndromes could be predicted on the basis of clinical features, anti-GM1 antibodies, or conduction block. DESIGN: Prospective, uncontrolled, treatment trial using prednisone for 4 months followed by intravenous cyclophosphamide (3 g/m2) continued orally for 6 months. SETTING: All patients were referred to university hospital medical centers. PATIENTS: Sixty-five patients with motor neuron syndromes were treated with prednisone; 11 patients had elevated GM1 antibody titers, and 11 patients had conduction block. Forty-five patients received cyclophosphamide, eight of whom had elevated GM1 antibodies and 10 had conduction block. RESULTS: One patient responded to prednisone, and five patients responded to cyclophosphamide treatment. Only patients with a lower motor neuron syndrome and conduction block improved with either treatment. Response to treatment did not correlate with GM1 antibodies. CONCLUSIONS: GM1 antibodies did not serve as a marker for improvement in patients with motor neuron syndrome treated with immunosuppressive drugs. Patients with amyotrophic lateral sclerosis failed to improve irrespective of laboratory findings.

Adult↗
PubMed1993

Mononuclear cell analysis of muscle biopsies in prednisone- and azathioprine-treated Duchenne muscular dystrophy.

Prednisone improves strength and function in patients with Duchenne dystrophy. Although the mechanism of this effect is uncertain, prior studies suggested that the benefit might result from immunosuppressive effects on T lymphocytes invading muscle. A recent randomized, double-blind, controlled trial of prednisone and azathioprine demonstrated that azathioprine had no effect in Duchenne dystrophy, raising questions about the role of immunosuppression in mediating clinical improvement. The goal of this current study was to compare the effects of prednisone and azathioprine on mononuclear infiltrates from biopsies performed at the end of the controlled clinical trial (reported separately in the article by Griggs et al on page 520). We studied 14 patients from the prednisone group (0.75 mg/kg/d), 10 from the combination therapy group (prednisone 0.3 mg/kg/d and azathioprine 2.5 mg/kg/d), and 13 from the azathioprine group (2.5 mg/kg/d), and used monoclonal antibodies for cell typing. There were no significant differences between the groups for total T cells, T-cell subsets, B cells, natural killer cells, total mononuclear cells, necrotic muscle fibers, or fibers focally invaded by mononuclear cells. These data indicate that azathioprine decreases mononuclear subsets infiltrating muscle to a similar degree as does prednisone, although azathioprine-treated patients do not show a clinical improvement. This implies that immunosuppressive actions on cellular infiltrates in muscle are probably not the primary mechanism of prednisone-induced clinical improvement.

Adolescent↗
PubMed1992

Central nervous system involvement in the eosinophilia-myalgia syndrome.

A patient with eosinophilia-myalgia syndrome developed progressive central nervosa system involvement that did not improve despite discontinuation of L-tryptophan therapy. Neurologic impairment was manifested initially by spastic monoparesis, which was improved by treatment with methyl-prednisolone and hydroxyurea. Recurrence of weakness was accompanied by gait ataxia, dysphagia, and complaints of a gradual decline in memory and concentration. Neuropsychological testing identified a broad pattern of cognitive deficits suggestive of a subcortical dementia, and magnetic resonance imaging demonstrated multiple high-signal lesions in the white matter. Cognitive deficits appear to be underrecognized in patients with the eosinophilia-myalgia syndrome. The response of our patient's initial symptoms to corticosteroid therapy suggests a possible role for autoimmune mechanisms in the pathogenesis of central nervous system involvement in the eosinophilia-myalgia syndrome. Neuropsychological evaluation should be performed in patients with cognitive complaints to delineate the full spectrum of central nervous system impairment associated with the eosinophilia-myalgia syndrome.

Central Nervous System Diseases↗
PubMed1992

Magnetic resonance imaging correlates of neuropsychological impairment in multiple sclerosis.

The authors examined whether specific neuropsychological abnormalities in multiple sclerosis (MS) are associated with focal lesion areas detected by MRI. Lesion area, regardless of distribution, correlated with performance on the vast majority of neuropsychological procedures. No significant difference appeared between groups with normal/mild and moderate overall cognitive impairment on any of the MRI measures. However, patients with severe cognitive impairment had greater lesion area, regardless of location, and had significant atrophy of the corpus callosum compared with the other two groups. These results suggest that severe atrophy of the corpus callosum reflects global disease and provides a relatively focal morphological marker of severe cognitive impairment in MS.

Adult↗
PubMed1991

The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis.

Accumulating evidence indicates that a complement-mediated microvasculopathy may play a pathogenic role in dermatomyositis. In a previous study, we demonstrated neoantigens of the C5b-9 complement membrane attack complex in the muscle microvasculature of childhood and adult cases of dermatomyositis. To further characterize the relationship between the vascular complement deposits and histologic changes, quantitative histopathologic analyses were performed on 39 dermatomyositis biopsy specimens (26 adult, 13 children). There was a significant correlation between the percentage of fascicles with fibers having focal myofibrillar loss, a change seen early in the evolution of ischemic muscle fiber damage, and the percentage of fascicles having capillary deposits of membrane attack complex. Conversely, in biopsy specimens with a higher percentage of fascicles with perifascicular atrophy, membrane attack complex deposits were significantly less common. A fascicle-by-fascicle analysis supported these observations. Patients whose biopsy specimens were negative for microvascular membrane attack complex had clinical weakness for a significantly longer time than those patients with vascular complement deposits. These data support the hypothesis that the complement-mediated vasculopathy is a primary immunopathogenic event in the evolution of muscle lesions in dermatomyositis.

Adult↗
PubMed1991

Dystrophin expression and somatic reversion in prednisone-treated and untreated Duchenne dystrophy. CIDD Study Group.

The mechanism by which prednisone improves muscle strength and function in Duchenne muscular dystrophy (DMD) is unknown. We addressed the possibility that clinical improvement was related to prednisone-induced alterations in skeletal muscle dystrophin. We performed muscle biopsies on patients at the conclusion of a randomized, double-blind, 6-month trial of prednisone and analyzed dystrophin content using Western blots and antibody staining of tissue sections. These studies demonstrated no significant differences in dystrophin content between treatment (prednisone 1.5 mg/kg/d, n = 12; prednisone 0.75 mg/kg/d, n = 9) and placebo (n = 12) groups. Of interest, however, was the presence of varying numbers of dystrophin-positive fibers (revertants) occurring individually or in clusters in antibody-stained tissue sections of more than one-half of the Duchenne patients. Mutation analysis revealed that revertants occurred in DMD patients with identifiable deletions half of the Duchenne patients. Mutation analysis revealed that revertants occurred in DMD patients with identifiable deletions or duplications, and in nondeletion patients. Prednisone treatment did not influence the prevalence of revertants. Revertants are most likely due to a second-site mutation occurring in a somatic cell allowing for restoration of the translational reading frame of the dystrophin transcript.

Adolescent↗
PubMed1991

Mononuclear cell analysis of muscle biopsies in prednisone-treated and untreated Duchenne muscular dystrophy. CIDD Study Group.

A recent double-blind, placebo-controlled trial has shown that prednisone improves strength in patients with Duchenne muscular dystrophy. To determine whether immunosuppressant effects were important in mediating this improvement, we performed immunohistochemical analyses on muscle biopsies obtained at the conclusion of the trial. We studied 33 patients: 12 from the placebo group, nine from the low-dose prednisone group (0.75 mg/kg/d), and 12 from the high-dose group (1.5 mg/kg/d). There was a significant difference in total T cells (CD2+) between the placebo group and both treatment groups. Similarly, the number of CD8+ cytotoxic/suppressor T cells was significantly decreased in both treated groups compared with placebo. The number of muscle fibers focally invaded by lymphocytes was also significantly decreased in the two treated groups compared with controls. There were no differences between the low- and high-dose groups. The numbers of B cells, natural killer cells, CD4+ cells, macrophages, and necrotic muscle fibers were not significantly different in the treated and control groups. This study suggests that prednisone may improve strength in Duchenne muscular dystrophy through primarily immunologic mechanisms involving T lymphocytes.

Adolescent↗
PubMed1990

Chromatic, spatial, and temporal losses of sensitivity in multiple sclerosis.

Chromatic, spatial, and temporal losses of sensitivity were measured in 15 eyes of 10 patients with recovered optic neuritis. Chromatic sensitivities (for both red-green and blue-yellow) were measured using color-mixture thresholds; the chromatic sensitivity loss was classified as "selective" if it was significantly greater than the achromatic loss. Spatial and temporal sensitivities were measured with contrast sensitivity functions and flicker modulation sensitivity, respectively; these losses were classified as selective if the losses at high (spatial or temporal) frequencies were significantly greater (or significantly less) than losses at low frequencies. All patients had central fixation and were optically corrected carefully. In 1 eye, selective losses of sensitivity for red-green and blue-yellow were combined with a selective loss of sensitivity at high spatial (but not temporal) frequencies. This type of loss may indicate a selective loss of small axons in the optic nerve. The 8 other eyes that showed significant losses were generally nonselective in their chromatic, spatial, and temporal losses; this may indicate a nonselective loss of small and large axons.

Adult↗
PubMed1989

Peripheral nerve vasculitis: immune characterization of the vascular lesions.

Quantitative immunohistochemical analyses were performed on 22 nerve biopsy specimens from patients with systemic vasculitis (n = 14) or isolated vasculitis of peripheral nerve (n = 8). In the vascular lesions the cellular infiltrates were composed primarily of T cells (71 +/- 18%; mean +/- SD) and macrophages (27 +/- 17%), and the majority of the T cells (65 +/- 20%) were cytotoxic/suppressor CD8 cells. B cells were seen in only 4 cases and constituted less than 2% of all cells. Natural killer cells and polymorphonuclear leukocytes were rare, and a leukocytoclastic response was not observed. Fourteen biopsy specimens had vascular deposits of immunoglobulins G and M and complement components C3 and C5b-9 membrane attack complex, while 4 had only the latter. The fact that the immunoglobulin and complement deposits were seen only in vessels that had corresponding intense cellular infiltrates suggests an important, but perhaps not primary, role for immune complexes in causing the vascular lesions. Statistical analysis revealed striking similarities in the lesions of patients with isolated nerve vasculitis and those with systemic vasculitides, suggesting a common pathogenic mechanism. Collectively, our observations suggest an important role for a T-cell-dependent cell-mediated process as a primary mechanism of vessel injury in peripheral nerve vasculitis.

Biopsy↗
PubMed1988

Magnetic resonance imaging and clinical correlations in multiple sclerosis.

We examined the relationship between magnetic resonance imaging (MRI) cerebral findings and clinical evaluations in 66 patients with clinically definite multiple sclerosis (MS). MRI observations included total number and location of lesions visualized, degree of periventricular involvement, degree of degeneration of the corpus callosum, and extent of generalized parenchymal atrophy. Overall physical disability was evaluated by the Kurtzke Expanded Disability Status Scale (EDSS) and individual symptoms were rated according to the Kurtzke Functional Systems (FS) scale. Our results suggest that MRI brain abnormalities are significantly related to the overall severity of disease, but MRI is not particularly useful to predict the presence or absence of individual symptoms. These findings do suggest that the MRI may provide useful information to monitor clinical progression of patients with MS, but the lesions visualized need not always be symptomatic nor are we sure that all symptomatic lesions, particularly in the spinal cord and optic nerves, will be visualized.

Adult↗
PubMed1988

Immunological identification of a high molecular weight protein as a candidate for the product of the Duchenne muscular dystrophy gene.

An oligopeptide was synthesized based on translation of the nucleotide sequence of the putative exon region of clone pERT87-25 from the gene for Duchenne muscular dystrophy. Immunization of rabbits with this oligopeptide induced the formation of antibodies directed against a protein present in human, rat, and rabbit skeletal muscle. This protein, which is missing in the skeletal muscle of two patients with Duchenne muscular dystrophy, has a molecular mass of approximately equal to 320-420 kDa and is clearly different from the putative Duchenne muscular dystrophy-related protein nebulin. The data suggest that this 320- to 420-kDa protein is produced by the Duchenne muscular dystrophy gene.

Antigen-Antibody Complex↗
PubMed1987

Evidence for central nervous system demyelination in chronic inflammatory demyelinating polyradiculoneuropathy.

It is unclear whether sporadic reports of concurrent multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represent coincidence or whether these two demyelinating disorders are pathogenically related. We utilized the sensitivity of magnetic resonance imaging (MRI) in detecting central nervous system (CNS) lesions to investigate 16 patients with CIDP. Six of the 16 had periventricular, subcortical, and brainstem white matter lesions indistinguishable from those seen in MS. Three of these patients had definite clinical and laboratory evidence of MS; three others with abnormal MRIs had no findings indicative of CNS disease. Previous reports have indicated that a significant number of MS patients have peripheral nerve demyelination. Our study suggests that many CIDP patients have concurrent CNS demyelination. Taken together, these observations support the existence of a central-peripheral inflammatory demyelinating syndrome. Whether this combined demyelinating syndrome lies on a spectrum between MS and CIDP or is a separate pathogenic entity will require further investigation.

Adult↗
PubMed1986

Microvascular deposition of complement membrane attack complex in dermatomyositis.

We examined the role of the complement system in the pathogenesis of dermatomyositis. Using an antibody against the neoantigens of the terminal C5b-9 membrane attack complex, we performed immunocytochemical studies that localized this complex to the intramuscular microvasculature (arterioles and capillaries) of muscle biopsy specimens from 10 of 12 patients (83 percent) with childhood dermatomyositis and 5 of 19 patients (26 percent) with adult dermatomyositis. Fifty-two control specimens, including 14 from patients with polymyositis and 12 from patients with denervation atrophy (a condition known to be associated with necrotic capillaries), showed no deposition of membrane attack complex in the microvasculature. These findings indicate that the complement system is deposited, bound, and activated to completion within the intramuscular microvasculature of patients with dermatomyositis. In addition to providing further evidence for the presence of vasculopathy in dermatomyositis, these findings suggest a primary role for complement in mediating vessel injury in the disease, particularly in its childhood form.

Adult↗
PubMed1985

Monoclonal antibodies against five structural components of measles virus. II. Characterization of five cell lines persistently infected with measles virus.

Groups of monoclonal antibodies against measles virus nucleoprotein (NP), phosphoprotein (P), matrix (M), hemagglutinin (H) and fusion (F) components were used for characterization of 5 persistently infected cell lines. In four of these lines (Lu106 carrier, MaSSPE, MaPi, HEpPi) all cells were infected but the cells mostly produced noninfectious virus products. The fifth line (HNT in vero cells) did not produce any infectious virus and only a fraction of the cells were infected in most passages. In agreement with earlier findings the virus strains showed marked variations in the M epitope pattern and also some variation in the H epitope pattern. In addition epitope variations were found in both NP and P protein, which contrasted with conserved antigen characteristics of these components in lytically replicating virus. Restriction of fusion in the persistent infections was studied further. HNT and Lu 106 cells showed selective quantitative restriction in F protein synthesis. Lu106 cells were found to contain distinct epitopic F species. In contrast MaSSPE cells produced readily detectable cleaved F protein and in addition extracellular virus products carried hemolytic activity. The fact that no cell fusion occurred was interpreted to be due to particular properties of the Ma 106 cells, a concept supported by the absence of fusion of these cells when infected with syncytiogenic measles virus. It is concluded that (a) under conditions of persistence of measles-virus without requirement for synthesis of complete virions a more pronounced variation in epitope characteristics of virus components is encountered than in lytic infections; and b) that persistence of measles virus shows individualistic characteristics which may reflect changes in the virus and/or innate properties of the host cells.

Animals↗