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J Newsom-Davis

Publications and source records attributed to J Newsom-Davis.

At least 19 recordsLinked to original sources
PubMed2003

Treatment for Lambert-Eaton myasthenic syndrome.

BACKGROUND: Lambert-Eaton myasthenic syndrome is an autoimmune presynaptic disorder of neuromuscular transmission. Treatments have attempted to overcome the harmful autoimmune process, or to improve residual neuromuscular transmission, in order to reverse the principal neurological symptom of muscle weakness. OBJECTIVES: The objective was to examine the efficacy of all forms of treatment in Lambert-Eaton myasthenic syndrome. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised trials register (September 2002), MEDLINE (January 1966 to November 2002) and EMBASE (January 1980 to November 2002). We checked the bibliographies in reports of the randomised trials and contacted authors to identify additional published or unpublished data. SELECTION CRITERIA: Types of studies: all randomised or quasi-randomised trials. TYPES OF PARTICIPANTS: all adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell lung cancer. Types of interventions: any form of medical (pharmacological or physical) treatment. Types of outcome measures: Primary: change in the muscle strength scale score (Quantitative Myasthenia Gravis score), or limb muscle strength measured by myometry. Secondary: improvement in the mean amplitude of the resting compound muscle action potentials. The mean amplitude used was the mean of all muscles tested. DATA COLLECTION AND ANALYSIS: We identified three randomised controlled trials. Individual patient data were only available for one trial. MAIN RESULTS: The three eligible trials included two controlled trials of the effects of 3,4-diaminopyridine compared with placebo in a total of 38 patients with Lambert-Eaton myasthenic syndrome, one of which was of crossover design. A third crossover trial compared intravenous immunoglobulin treatment to placebo in nine patients with Lambert-Eaton myasthenic syndrome. A meta-analysis of the primary endpoint results of these trials was not possible because of differences in comparisons and endpoints and, in two trials, lack of individual patient data. EFFECTS OF 3,4-DIAMINOPYRIDINE: Two trials of 3,4-diaminopyridine reported a significant improvement in the primary endpoint of muscle strength score, or myometric limb measurement following treatment. Both trials also reported a significant improvement in the secondary endpoint of resting compound muscle action potential amplitude following 3,4-diaminopyridine, compared with placebo. A meta-analysis of the primary endpoint results was not possible because of marked differences in these two trials regarding primary outcome measures. However, a meta-analysis of the secondary endpoint (improvement in the amplitude of the mean resting compound muscle action potential) was possible. It was necessary to assume a known correlation (similarity) of the paired responses for each individual in the two treatment periods in order to properly allow for the crossover design of one of the two trials (the correlation coefficient was assumed to be 0.5 in calculations). Using this approach, meta-analysis revealed a significant overall benefit in compound muscle action potential amplitude after 3,4-diaminopyridine treatment. The overall weighted mean difference was 1.80 mV (95% confidence interval 0.82 to 2.78), favouring treatment. These results were not sensitive to the assumption made because the overall benefit estimated was still significant when the correlation was assumed to be less than 0.1. EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN: A crossover trial reported a significant improvement in the primary outcome measure of myometric limb strength when patients received intravenous immunoglobulin compared to placebo infusions. This trial also demonstrated an improvement in the secondary outcome measure of change in the mean resting compound muscle action potential amplitude following intravenous immunoglobulin, but this improvement did not reach significance. Clinical improvement lasted for up to eight weeks. REVIEWER'S CONCLUSIONS: Limited evidence from randomised controlled trials showed that either 3,4-diaminopyridine or intravenous immunoglobulin improved muscle strength scores and compound muscle action potential amplitudes in patients with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this treatment effect. Other possible treatments, such as plasma exchange, steroids and immunosuppressive agents have not been tested in randomised controlled trials.

4-Aminopyridine↗
PubMed2003

Autoantibodies to IL-12 in myasthenia gravis patients with thymoma; effects on the IFN-gamma responses of healthy CD4+ T cells.

In humans, interleukin-12 (IL-12) and interferon-alpha (IFN-alpha) normally favor IFN-gamma-producing "Th1" T cell responses. Myasthenia gravis (MG) patients with thymomas frequently have high-titer neutralizing autoantibodies against these cytokines, but not against IFN-gamma. Because they occasionally develop intractable (even fatal) infections, we have tested effects of their sera on the generation of IFN-gamma responses by healthy adult T cells to autologous lipopolysaccharide (LPS)-treated dendritic cells (DC). Anti-IL-12(+) sera consistently reduced IFN-gamma responses substantially, whether assessed by intracellular staining or ELISA. Therefore, thymoma patients with intractable infections might benefit from cautious IFN-gamma therapy. We discuss wider implications of the surprising rarity of clear clinical hazards-or benefits-of these autoantibodies.

Adult↗
PubMed2003

Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis.

We have screened for spontaneous anticytokine autoantibodies in patients with infections, neoplasms and autoimmune diseases, because of their increasingly reported co-occurrence. We tested for both binding and neutralizing autoantibodies to a range of human cytokines, including interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, interferon-alpha2 (IFN-alpha2), IFN-omega, IFN-beta, IFN-gamma, tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta-1 (TGF-beta1) and granulocyte-macrophage colony stimulating factor (GM-CSF), in plasmas or sera. With two notable exceptions described below, we found only occasional, mostly low-titre, non-neutralizing antibodies, mainly to GM-CSF; also to IL-10 in pemphigoid. Strikingly, however, high-titre, mainly IgG, autoantibodies to IFN-alpha2, IFN-omega and IL-12 were common at diagnosis in patients with late-onset myasthenia gravis (LOMG+), thymoma (T) but no MG (TMG-) and especially with both thymoma and MG together (TMG+). The antibodies recognized other closely related type I IFN-alpha subtypes, but rarely the distantly related type I IFN-beta, and never (detectably) the unrelated type II IFN-gamma. Antibodies to IL-12 showed a similar distribution to those against IFN-alpha2, although prevalences were slightly lower; correlations between individual titres against each were so modest that they appear to be entirely different specificities. Neither showed any obvious correlations with clinical parameters including thymoma histology and HLA type, but they did increase sharply if the tumours recurred. These antibodies neutralized their respective cytokine in bioassays in vitro; although they persisted for years severe infections were surprisingly uncommon, despite the immunosuppressive therapy also used in most cases. These findings must hold valuable clues to autoimmunizing mechanisms in paraneoplastic autoimmunity.

Adolescent↗
PubMed2002

Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes.

BACKGROUND: Slow-channel congenital myasthenic syndromes (SCCMS) typically show dominant inheritance. They are caused by missense mutations within the subunits of muscle nicotinic acetylcholine receptors (AChR) that result in prolonged ion channel activations. SCCMS mutations within the AChR subunit are located in various functional domains, whereas fully described mutations in AChR non- subunits have, thus far, been located only in the M2 channel-lining domain. The authors identified and characterized two -subunit mutations, located outside M2, that underlie SCCMS in three kinships. In two of the three kinships, the syndrome showed an atypical inheritance pattern. METHODS: These methods included clinical diagnosis, mutation detection, haplotype analysis, and functional expression studies using single-channel recordings of mutant AChR transiently transfected into HEK293 cells. RESULTS: The authors identified two SCCMS mutations in the AChR subunit, L78P and L221F. Both mutations prolonged ACh-induced ion channel activations. L78P is present in a consanguineous family and appears to be pathogenic only when present on both alleles, and L221F shows variable penetrance in one of the two families that were identified harboring this mutation. CONCLUSION: SCCMS mutations may show a recessive inheritance pattern and variable penetrance. A diagnosis of SCCMS should not be ruled out in cases of CMS with an apparent recessive inheritance pattern.

Adolescent↗
PubMed2002

Intravenous immunoglobulin in neurological disease: a specialist review.

Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

Drug Costs↗
PubMed2001

Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence?

BACKGROUND: Patients with MG often have other autoantibodies in addition to those against the acetylcholine receptor (AChR). It has been suggested that antibodies to the muscle protein titin may be diagnostic of a thymoma, but they have also been found in patients with late-onset MG. Antibodies to certain cytokines have also been detected in patients with MG and thymoma, and it is not clear whether these antibodies could be more useful clinically. The authors measured antibodies against titin and the cytokines interferon alpha (IFNalpha) and interleukin 12 (IL12) in patients with MG and thymoma or thymoma recurrence, and in patients with MG but without thymoma presenting before (early-onset MG) or after (late-onset MG) 40 years of age. METHOD: Levels of titin, IFNalpha, and IL12 antibodies were determined by radioimmunoassay in 191 patients with MG and 82 controls. RESULTS: As previously reported, titin antibodies were uncommon in patients with early-onset MG. However, in patients with late-onset MG, titin antibodies had similar prevalence and levels to those in patients with MG and thymoma, although the antibodies were uncommon in patients between 40 and 60 years of age presenting without a tumor. By contrast, cytokine antibodies were more common in patients with thymoma than in patients without thymoma, and cytokine antibodies typically increased substantially if the thymoma recurred. CONCLUSIONS: Measurement of titin antibodies has limited use in predicting the presence of a tumor, unless the patient is less than 60 years of age, but measurement of IFNalpha and IL12 antibodies may be helpful in identifying patients with a thymoma recurrence, particularly when mediastinal imaging is equivocal.

Adult↗
PubMed2001

Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis.

Antibodies to muscle acetylcholine receptors, to other muscle antigens, and to some cytokines are found in the majority of patients with thymic tumors (thymomas) and myasthenia gravis (MG). The role of the tumor in initiating autoimmunity, however, is unclear; in particular, it is not known whether the thymoma exports mature and long-lived T cells, which could provide help for antibody production in the periphery. Here, we quantified recently exported thymic T cells using the approach of measuring episomal DNA fragments [T-cell receptor excision circles (TRECs)], generated by T-cell receptor gene rearrangement. Compared to values in healthy individuals (n = 10) or in patients with late-onset MG (n = 8), TREC levels were significantly raised in both the CD4+ and CD8+ peripheral blood compartments of patients with thymoma and MG (n = 14, p = 0.002 and p = 0.0004 compared to healthy controls) but only in the CD8+ compartment of the three patients with thymoma without MG (p = 0.4 and p = 0.01 for CD4+ and CD8+). TREC levels decreased following thymectomy to values similar to controls but were substantially raised in patients who had developed tumor recurrence (n = 6, p = 0.04 and p = 0.02 for CD4+ and CD8+); this was associated with increased antibodies to interferon-alpha and interleukin-12 in the one case studied serially. Collectively, these results support the hypothesis that the neoplastic thymoma tissue itself can generate and export mature, long-lived T cells and that these T cells reflect the thymic pathology and are likely to be related to the associated autoimmune diseases. The results also provide a new approach for early diagnosis of thymoma recurrence.

Adult↗
PubMed2001

Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present. These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness. The pathogenic mechanisms acting in the 20% of patients with generalized MG who are seronegative for AChR-antibodies (AChR-Ab) have not been elucidated, but there is evidence that they also have an antibody-mediated disorder, with the antibodies directed towards another, previously unidentified muscle-surface-membrane target. Here we show that 70% of AChR-Ab-seronegative MG patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MuSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction. The MuSK antibodies were specific for the extracellular domains of MuSK expressed in transfected COS7 cells and strongly inhibited MuSK function in cultured myotubes. Our results indicate the involvement of MuSK antibodies in the pathogenesis of AChR-Ab-seronegative MG, thus defining two immunologically distinct forms of the disease. Measurement of MuSK antibodies will substantially aid diagnosis and clinical management.

Autoantibodies↗
PubMed2001

Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer.

OBJECTIVES: To determine the prognosis in patients with Lambert-Eaton myasthenic syndrome (LEMS) without small cell lung cancer (SCLC), and to analyse longitudinal clinical, electrophysiological, and immunological data on each patient to establish prognostic factors for long term outcome. METHODS: The retrospective and part prospective study of 47 patients with LEMS was undertaken from data recorded during visits to a specialist neuromuscular clinic. Serial measurements of muscle strength score in shoulder abduction, elbow extension and hip flexion, compound muscle action potential (CMAP) amplitude, and postcontraction increment in abductor digiti minimi (ADM), and anti-P/Q-type voltage gated calcium channel (VGCC) antibody titre were made at each visit. RESULTS: Muscle strength scores were improved in 88% of patients after a median duration of immunosuppressive treatment of 6 years (range 1.3 to 17 years); anti-VGCC antibody titres fell in 52% after treatment; and mean resting CMAP amplitude improved from 2.7 mV initially to 8.8 mV after 2 years of treatment p<0.001). Initial pretreatment anti-VGCC antibody titre did not correlate significantly with either CMAP amplitude, CMAP increment, or clinical score: from serial measurements made during follow up, significant correlation between antibody titre and CMAP amplitude was seen in only two patients. Sustained clinical remission was achieved by 20 (43%) of whom only four remained in remission without the need for immunosuppression. Using a Cox proportional hazards model, the only independent predictor of sustained clinical remission was initial pretreatment clinical score (p=0.03). Lymphoma presented in three patients during the study. CONCLUSIONS: The prognosis in patients with LEMS without SCLC is favourable, although patients often need significant doses of immunosuppressive treatment to remain clinically stable. Only initial clinical muscle strength measurements and not anti-VGCC antibody titres or electrophysiological recordings are predictive of long term outcome.

Adolescent↗
PubMed2001

Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita.

Limitation of movement during fetal development may lead to multiple joint contractures in the neonate, termed arthrogryposis multiplex congenita. Neuromuscular disorders are among the many different causes of reduced fetal movement. Many congenital myasthenic syndromes (CMSs) are due to mutations of the adult-specific epsilon subunit of the acetylcholine receptor (AChR), and, thus, functional deficits do not arise until late in gestation. However, an earlier effect on the fetus might be predicted with some defects of other AChR subunits. We studied a child who presented at birth with joint contractures and was subsequently found to have a CMS. Mutational screening revealed heteroallelic mutation within the AChR delta subunit gene, delta 756ins2 and delta E59K. Expression studies demonstrate that delta 756ins2 is a null mutation. By contrast, both fetal and adult AChR containing delta E59K have shorter than normal channel activations that predict fast decay of endplate currents. Thus, delta E59K causes dysfunction of fetal as well as the adult AChR and would explain the presence of joint contractures on the basis of reduced fetal movement. This is the first report of the association of AChR gene mutations with arthrogryposis multiplex congenita. It is probable that mutations that severely disrupt function of fetal AChR will underlie additional cases.

Action Potentials↗
PubMed2000

Asymptomatic maternal myasthenia as a cause of the Pena-Shokeir phenotype.

We report six sibs with arthrogryposis multiplex congenita and a Pena-Shokeir phenotype, born to a healthy woman who was discovered to have asymptomatic myasthenia gravis (MG). This is the first report of anti-acetylcholine receptor (AChR) antibodies causing fetal akinesia/hypokinesia sequence in the offspring of an asymptomatic mother.

Abnormalities, Multiple↗
PubMed2000

Autoantibodies in thymoma-associated myasthenia gravis with myositis or neuromyotonia.

BACKGROUND: About 50% of patients with thymoma have paraneoplastic myasthenia gravis (MG). Myositis and myocarditis or neuromyotonia (NMT) will also develop in some. Patients with thymoma-associated MG produce autoantibodies to a variety of neuromuscular antigens, particularly acetylcholine receptor (AChR), titin, skeletal muscle calcium release channel (ryanodine receptor [RyR]), and voltage-gated potassium channels (VGKC). OBJECTIVE: To examine whether neuromuscular autoantibodies in patients with thymoma correlate with specific clinical syndromes. METHODS: Serum and plasma samples from 19 patients with thymoma-associated MG, of whom 5 had myositis and 6 had NMT, underwent testing for antibodies to AChR, titin, RyR, and VGKC. RESULTS: Antibodies to AChR and titin were found in 19 and 17 patients, respectively. Antibodies to RyR correlated with the presence of myositis (P = .03); they were found in all 5 patients with myositis and in only 1 patient with NMT, but also in 4 of 8 patients with neither disease. Antibodies to VGKC were found in 4 patients with NMT, 1 of 3 patients undergoing testing for myositis, and 2 of 7 patients undergoing testing with neither comorbidity. Presence of RyR antibodies correlated with high levels of titin antibodies. CONCLUSIONS: The results appear to distinguish partially between 3 groups of patients with thymoma-associated MG: the first with RyR antibodies and myositis or myocarditis, the second with NMT without RyR antibodies, and the third without RyR antibodies, myositis, or NMT. Differences in the thymoma may underlie these pathologic associations.

Adult↗