"Recent myasthenia gravis publications are scanned daily from major neurology journals and updated here"
Archive Dec 2007 of myasthenia gravis articles:-
Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis. Related Articles
Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis.
Arthritis Rheum. 2007 Nov;56(11):3784-92
Authors: Walsh RJ, Kong SW, Yao Y, Jallal B, Kiener PA, Pinkus JL, Beggs AH, Amato AA, Greenberg SA
OBJECTIVE: To apply gene expression profiling to the study of peripheral blood mononuclear cells from patients with inflammatory myopathies, in order to provide insight into disease pathogenesis and identify potential biomarkers associated with disease activity. METHODS: We used Affymetrix whole-genome microarrays to measure the expression of approximately 38,500 genes in 65 blood and 15 muscle samples from 44 patients with dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), myasthenia gravis, or genetically determined myopathies and from 12 healthy volunteers. In 9 patients, 2 samples were obtained at different time points, when disease was either active or improving, and these paired blood samples were also compared. Bioinformatics techniques were used to identify genes with significant differential expression among diagnostic categories and in relation to disease activity. We corroborated the microarray data with quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Most patients with active DM or PM, but not patients with IBM, had significant and high up-regulation of the type I interferon-alpha/beta (IFNalpha/beta)-inducible genes in blood. Furthermore, the up-regulation of these genes correlated with disease activity in DM and PM, with down-regulation occurring when disease was controlled with treatment. CONCLUSION: DM and PM are diseases characterized by the systemic overexpression of IFNalpha/beta-inducible genes. The magnitude of the overexpression of these genes is higher in DM and correlates with disease activity in both disorders. Although PM and IBM have been modeled as having similar immunologic processes occurring within muscle, there are substantial differences in the expression of IFNalpha/beta-inducible genes in blood in these diseases.
PMID: 17968926 [PubMed - in process]Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review. Related Articles
Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review.
Arch Phys Med Rehabil. 2007 Nov;88(11):1452-64
Authors: Cup EH, Pieterse AJ, Ten Broek-Pastoor JM, Munneke M, van Engelen BG, Hendricks HT, van der Wilt GJ, Oostendorp RA
OBJECTIVE: To summarize and critically appraise the available evidence on exercise therapy and other types of physical therapies for patients with neuromuscular diseases (NMD). DATA SOURCES: Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, Medline, CINAHL, EMBASE (Rehabilitation and Physical Medicine), and reference lists of reviews and articles. STUDY SELECTION: Randomized clinical trials (RCTs), controlled clinical trials (CCTs), and other designs were included. Study participants had to have any of the following types of NMD: motoneuron diseases, disorders of the motor nerve roots or peripheral nerves, neuromuscular transmission disorders, or muscle diseases. All types of exercise therapy and other physical therapy modalities were included. Outcome measures had to be at the level of body functions, activities, or participation according to the definitions of the International Classification of Functioning, Disability and Health (ICF). DATA EXTRACTION: Two reviewers independently decided on inclusion or exclusion of articles and rated the methodologic quality of the studies included. All RCTs, CCTs, and other designs only if of sufficient methodologic quality were included in a best evidence synthesis. A level of evidence was attributed for each subgroup of NMD and each type of intervention. DATA SYNTHESIS: Initially 58 studies were included: 12 RCTs, 5 CCTs, and 41 other designs. After methodologic assessment, 19 other designs were excluded from further analysis. There is level II evidence ("likely to be effective") for strengthening exercises in combination with aerobic exercises for patients with muscle disorders. Level III evidence ("indications of effectiveness") was found for aerobic exercises in patients with muscle disorders and for the combination of muscle strengthening and aerobic exercises in a heterogeneous group of muscle disorders. Finally, there is level III evidence for breathing exercises for patients with myasthenia gravis and for patients with myotonic muscular dystrophy. Adverse effects of exercise therapy were negligible. CONCLUSIONS: The available evidence is limited, but relevant for clinicians. Future studies should be preferably multicentered, and use an international classification of the variables of exercise therapy and an ICF core set for NMD in order to improve comparability of results.
PMID: 17964887 [PubMed - in process]Different characteristics of nonthymomatous generalized myasthenia gravis with and without oropharyngeal involvement. Related Articles
Different characteristics of nonthymomatous generalized myasthenia gravis with and without oropharyngeal involvement.
Ann Thorac Surg. 2007 Nov;84(5):1694-8
Authors: Yu L, Li J, Ma S, Jiang J, Wang T, Gamliel Z, Jing Y, Zhang X, Krasna MJ
BACKGROUND: Thymectomy represents a safe and valid approach for patients with myasthenia gravis. However, some factors may influence the efficacy of thymectomy. The objective of this study was to evaluate the clinical characteristics of generalized myasthenia gravis with oropharyngeal involvement and compare the postoperative outcome of generalized myasthenia gravis without and with oropharyngeal involvement. METHODS: From 1991 to 2002, there were 202 patients with nonthymomatous generalized myasthenia gravis (GMG), who underwent thymectomy by the transsternal approach or thoracoscopy. According to the clinical classification of the Myasthenia Gravis Foundation of America (MGFA), these patients have been subdivided into two groups: GMG without oropharyngeal involvement and GMG with oropharyngeal involvement. Complete stable remission, as defined by the MGFA Medical Task Force, was the primary endpoint for efficacy. RESULTS: In all, 182 patients were followed up for at least 5 years. There were 135 cases of GMG without oropharyngeal involvement and 47 cases of GMG with oropharyngeal involvement. There were significant differences in postoperative pneumonia, ventilatory support time, and myasthenic crisis between patients with GMG with and without oropharyngeal involvement (p values were 0.040, 0.021, and 0.007, respectively). At 5 years of follow-up, the cumulative probability of reaching complete stable remission in GMG without oropharyngeal involvement was 18.5% at the end of the first year, and rose steadily in subsequent years (26.7%, 37.0%, 39.1%, and 40% at 2, 3, 4, and 5 years, respectively). In GMG with oropharyngeal involvement, it was 6.4%, 14.9%, 23.4%, 29.9%, and 31.9%, respectively, in the continual follow-up years. The first 3 years were associated with a significantly greater probability of achieving complete stable remission (p = 0.047 for the first year, p = 0.025 for the second one, and p = 0.048 for the third one). The later 2 years had no significant difference on complete stable remission. CONCLUSIONS: Laryngeal myasthenia gravis is more severe and the prognosis after thymectomy is not as optimistic as for patients without oropharyngeal involvement.
PMID: 17954087 [PubMed - indexed for MEDLINE]Thymoma, myasthenia gravis, encephalitis, and a novel anticytoplasmic neuronal antibody. Related Articles
Thymoma, myasthenia gravis, encephalitis, and a novel anticytoplasmic neuronal antibody.
Neurology. 2007 Sep 18;69(12):1302-3
Authors: Khella SL, Souyah N, Dalmau J
PMID: 17875920 [PubMed - indexed for MEDLINE]Neurologic outcomes of thymectomy in myasthenia gravis: comparative analysis of the effect of thymoma. Related Articles
Neurologic outcomes of thymectomy in myasthenia gravis: comparative analysis of the effect of thymoma.
J Thorac Cardiovasc Surg. 2007 Sep;134(3):601-7
Authors: Kim HK, Park MS, Choi YS, Kim K, Shim YM, Han J, Kim BJ, Kim J
OBJECTIVES: The objectives of this study were to compare the clinical features and the outcomes after thymectomy between patients with and without thymoma and to evaluate the influence of thymectomy on the subsequent clinical course of myasthenia gravis. METHODS: Between 1995 and 2003, 64 consecutive patients underwent thymectomy, and of these, 60 patients were followed up for at least 12 months postoperatively. The study population was divided into 2 groups based on the presence of thymoma. We performed a retrospective analysis to compare the neurologic outcomes of thymectomy between patients with thymomatous myasthenia gravis and those with nonthymomatous myasthenia gravis. RESULTS: Twenty-four patients had a thymoma. No significant differences were observed between the 2 groups regarding the preoperative severity of myasthenia gravis. There was no significant difference in the follow-up duration between the 2 groups. There was no significant difference in the overall remission rate between the 2 groups (P = .064). The mean time required to reach a remission was 10.6 months and 23.5 months in the thymoma and nonthymoma groups, respectively. The mean duration of remission was 43.1 months and 30.8 months in the thymoma and nonthymoma groups, respectively. In the early phase of follow-up, more patients reached remission in the thymoma group than those in the nonthymoma group (P = .040). CONCLUSIONS: Neurologic outcomes of the thymoma group were no worse than those of the nonthymoma group. It is expected that earlier thymectomy is likely to result in a better prognosis by shortening the disease period, even for patients with nonthymomatous myasthenia gravis.
PMID: 17723805 [PubMed - indexed for MEDLINE]Treatment of human myasthenia gravis with oral antisense suppression of acetylcholinesterase. Related Articles
Treatment of human myasthenia gravis with oral antisense suppression of acetylcholinesterase.
Neurology. 2007 Aug 14;69(7):699-700
Authors: Argov Z, McKee D, Agus S, Brawer S, Shlomowitz N, Yoseph OB, Soreq H, Sussman JD
PMID: 17698793 [PubMed - indexed for MEDLINE]Classification of myasthenia gravis based on autoantibody status. Related Articles
Classification of myasthenia gravis based on autoantibody status.
Arch Neurol. 2007 Aug;64(8):1121-4
Authors: Suzuki S, Utsugisawa K, Nagane Y, Satoh T, Terayama Y, Suzuki N, Kuwana M
OBJECTIVES: To investigate the autoantibody status of patients with myasthenia gravis (MG) and to evaluate its usefulness for disease classification. DESIGN: Retrospective cohort study of patients with MG, who have autoantibodies to receptors and ion channels expressed at neuromuscular junctions and in muscles that impair neuromuscular transmission. One of the autoantibodies studied was a recently identified, novel, MG-specific autoantibody to a voltage-gated potassium (Kv) channel, Kv1.4. SETTING: Keio University Hospital, Tokyo, and Iwate Medical University Hospital, Morioka. PATIENTS: Two hundred nine patients with MG. MAIN OUTCOME MEASURES: Anti-Kv1.4 antibody was measured by an immunoprecipitation assay with sulfur 35-labeled extract from rhabdomyosarcoma cells. Antititin antibody was detected with a commercially available enzyme-linked immunosorbent assay. RESULTS: Anti-acetylcholine receptor, anti-Kv1.4, and antititin antibodies were detected in 150 (72%), 26 (12%), and 50 (24%) of the 209 patients with MG, respectively. All of the patients who were positive for anti-Kv1.4 or antititin antibody were seropositive for the anti-acetylcholine receptor antibody. They were classified into 4 groups based on their status in regard to 3 MG-related autoantibodies: anti-Kv1.4, antititin, and anti-acetylcholine receptor. Clinical associations were found between anti-Kv1.4 and bulbar involvement, myasthenic crisis, thymoma, and concomitant myocarditis and/or myositis; between antititin and older-onset MG; between anti-acetylcholine receptor alone and younger-onset MG; and between seronegativity and ocular MG. In addition, patients with MG in the anti-Kv1.4 group had more severe manifestations of disease than those in the other 3 groups. CONCLUSION: Classification of patients with MG based on autoantibody status may be useful in defining clinical subsets.
PMID: 17698702 [PubMed - indexed for MEDLINE]Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status. Related Articles
Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status.
Am J Pathol. 2007 Sep;171(3):893-905
Authors: Leite MI, Jones M, Ströbel P, Marx A, Gold R, Niks E, Verschuuren JJ, Berrih-Aknin S, Scaravilli F, Canelhas A, Morgan BP, Vincent A, Willcox N
In early-onset myasthenia gravis, the thymus contains lymph node-type infiltrates with frequent acetylcholine receptor (AChR)-specific germinal centers. Our recent evidence/two-step hypothesis implicates hyperplastic medullary thymic epithelial cells (expressing isolated AChR subunits) in provoking infiltration and thymic myoid cells (with intact AChR) in germinal center formation. To test this, we screened for complement attack in a wide range of typical generalized myasthenia patients. Regardless of the exact serology, thymi with sizeable infiltrates unexpectedly showed patchy up-regulation of both C5a receptor and terminal complement regulator CD59 on hyperplastic epithelial cells. These latter also showed deposits of activated C3b complement component, which appeared even heavier on infiltrating B cells, macrophages, and especially follicular dendritic cells. Myoid cells appeared particularly vulnerable to complement; few expressed the early complement regulators CD55, CD46, or CR1, and none were detectably CD59(+). Indeed, when exposed to infiltrates, and especially to germinal centers, myoid cells frequently labeled for C1q, C3b (25 to 48%), or even the terminal C9, with some showing obvious damage. This early/persistent complement attack on both epithelial and myoid cells strongly supports our hypothesis, especially implicating exposed myoid cells in germinal center formation/autoantibody diversification. Remarkably, the similar changes place many apparent AChR-seronegative patients in the same spectrum as the AChR-seropositive patients.
PMID: 17675582 [PubMed - in process]Novel therapies target myasthenia gravis. Related Articles
Novel therapies target myasthenia gravis.
JAMA. 2007 Jul 11;298(2):163-4
Authors: Hampton T
PMID: 17622589 [PubMed - indexed for MEDLINE]Trials assess myasthenia gravis therapies. Related Articles
Trials assess myasthenia gravis therapies.
JAMA. 2007 Jul 4;298(1):29-30
Authors: Hampton T
PMID: 17609483 [PubMed - indexed for MEDLINE]Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current. Related Articles
Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current.
Neurology. 2007 May 29;68(22):1917-21
Authors: Wang Z, Low PA, Jordan J, Freeman R, Gibbons CH, Schroeder C, Sandroni P, Vernino S
BACKGROUND: Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated form of diffuse autonomic failure. Many patients have serum antibodies that bind to the ganglionic acetylcholine receptors (AChRs) that mediate fast synaptic transmission in autonomic ganglia. Previous clinical studies and observations in animal models suggest that AAG is an antibody-mediated neurologic disorder. METHODS: Using whole-cell patch clamp techniques, we recorded ganglionic AChR currents in cultured human IMR-32 cells and examined the effects of bath application of IgG derived from patients with AAG. RESULTS: IgG from seven patients with AAG all produced a progressive decline in whole-cell ganglionic AChR current, whereas IgG from control subjects had no effect. The effect was abolished at low temperature. Fab antibody fragments had no effect unless a secondary antibody was added concurrently. IgG from one patient also produced a more immediate reduction of ganglionic AChR current. CONCLUSIONS: The characteristics of antibody-mediated inhibition of ganglionic acetylcholine receptor (AChR) current are consistent with modulation and blocking of the membrane AChR, analogous to the effects of muscle AChR antibodies in myasthenia gravis. Our observations demonstrate that antibodies in patients with autoimmune autonomic ganglionopathy (AAG) cause physiologic changes in ganglionic AChR function and confirm that AAG is an antibody-mediated disorder.
PMID: 17536048 [PubMed - indexed for MEDLINE]C57BL/6 mice genetically deficient in IL-12/IL-23 and IFN-gamma are susceptible to experimental autoimmune myasthenia gravis, suggesting a pathogenic role of non-Th1 cells. Related Articles
C57BL/6 mice genetically deficient in IL-12/IL-23 and IFN-gamma are susceptible to experimental autoimmune myasthenia gravis, suggesting a pathogenic role of non-Th1 cells.
J Immunol. 2007 Jun 1;178(11):7072-80
Authors: Wang W, Milani M, Ostlie N, Okita D, Agarwal RK, Caspi R, Conti-Fine BM
Immunization with Torpedo acetylcholine receptor (TAChR) induces experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 (B6) mice. EAMG development needs IL-12, which drives differentiation of Th1 cells. The role of IFN-gamma, an important Th1 effector, is not clear and that of IL-17, a proinflammatory cytokine produced by Th17 cells, is unknown. In this study, we examined the effect of simultaneous absence of IL-12 and IFN-gamma on EAMG susceptibility, using null mutant B6 mice for the genes of both the IL-12/IL-23 p40 subunit and IFN-gamma (dKO mice). Wild-type (WT) B6 mice served as control for EAMG induction. All mice were immunized with TAChR in Freund's adjuvant. dKO mice developed weaker anti-TAChR CD4(+)T cells and Ab responses than WT mice. Yet, they developed EAMG symptoms, anti-mouse acetylcholine receptor (AChR) Ab, and CD4(+) T cell responses against mouse AChR sequences similar to those of WT mice. dKO and WT mice had similarly reduced AChR content in their muscles, and IgG and complement at the neuromuscular junction. Naive dKO mice had significantly fewer NK, NKT, and CD4(+)CD25(+)Foxp3(+) T regulatory (Treg) cells than naive WT mice. Treg cells from TAChR-immunized dKO mice had significantly less suppressive activity in vitro than Treg cells from TAChR-immunized WT mice. In contrast, TAChR-specific CD4(+) T cells from TAChR-immunized dKO and WT mice secreted comparable amounts of IL-17 after stimulation in vitro with TAChR. The susceptibility of dKO mice to EAMG may be due to reduced Treg function, in the presence of a normal function of pathogenic Th17 cells.
PMID: 17513756 [PubMed - indexed for MEDLINE]Evidence report: the medical treatment of ocular myasthenia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Related Articles
Evidence report: the medical treatment of ocular myasthenia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology. 2007 Jun 12;68(24):2144-9
Authors: Benatar M, Kaminski HJ,
OBJECTIVE: To perform a systematic review of the relevant literature and to provide evidence-based guidelines for the medical treatment of ocular myasthenia. METHODS: Medline, EMBASE, and the Cochrane Neuromuscular Disease Group Register were searched for articles of possible relevance to the medical treatment of ocular myasthenia. The titles and abstracts of all articles, as well as the full texts of all potentially relevant manuscripts, were read by both reviewers. Experts in the field were also contacted to identify other published or unpublished literature. All articles were evaluated using predefined criteria to evaluate their methodologic quality. Data from these articles were extracted to address two questions: 1) Are there any effective treatments for symptoms of ocular myasthenia? 2) Are there any treatments that reduce the risk of progression from ocular to generalized myasthenia gravis (MG)? RESULTS: A single randomized controlled trial compared the efficacy of intranasal neostigmine to placebo for the treatment of ocular symptoms. Methodologic limitations of this study preclude any firm conclusions. A second randomized controlled trial compared the efficacy of corticotropin with placebo, but outcome was reported in terms of a quantification of the range of eye movements. For this reason, the results of the second study could not be used to address the issues of improvement in ocular symptoms or the risk of progression to generalized MG. This review did not identify any randomized controlled trials addressing the risk of progression to generalized MG but did identify five observational studies reporting the effects of corticosteroids on progression to generalized MG, two of which also reported the effects of azathioprine. RECOMMENDATIONS: The absence of high-quality evidence means that it is not possible to make any evidence-based recommendations regarding the effects of cholinesterase inhibitors, corticosteroids, or other immunosuppressive agents with respect to improvement of ocular symptoms. There is similarly an absence of evidence regarding the effects of cholinesterase inhibitors on the risk of progression to generalized myasthenia gravis (MG). Based on data from several observational studies, corticosteroids and azathioprine are of uncertain benefit in terms of their effect on the risk of progression to generalized MG.
PMID: 17460154 [PubMed - indexed for MEDLINE]Clinical features of the DOK7 neuromuscular junction synaptopathy. Related Articles
Clinical features of the DOK7 neuromuscular junction synaptopathy.
Brain. 2007 Jun;130(Pt 6):1507-15
Authors: Palace J, Lashley D, Newsom-Davis J, Cossins J, Maxwell S, Kennett R, Jayawant S, Yamanashi Y, Beeson D
Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions ('synaptopathy') but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124_1127dupTGCC was common, present in 20 out of 24 kinships. All patients were found to have at least one allele with a frameshift mutation in DOK7 exon 7, suggesting that loss of function(s) associated with the C-terminal region of Dok-7 underlies this disorder. In 15 patients, we were able to study the clinical features in detail. Clinical onset was usually characterized by difficulty in walking developing after normal motor milestones. Proximal muscles were usually more affected than distal, leading to a 'limb-girdle' pattern of weakness; although ptosis was often present from an early age, eye movements were rarely involved. Patients did not show long-term benefit from anticholinesterase medication and sometimes worsened, and where tried responded to ephedrine. The phenotype can be distinguished from 'limb-girdle' myasthenia associated with tubular aggregates, where DOK7 mutations were not detected and patients respond to anticholinesterase treatments. CMS due to DOK7 mutations are common within our UK cohort and is likely to be under-diagnosed; recognition of the phenotype will help clinical diagnosis, targeted genetic screening and appropriate management.
PMID: 17452375 [PubMed - indexed for MEDLINE]Occurrence of CNS demyelinating disease in patients with myasthenia gravis. Related Articles
Occurrence of CNS demyelinating disease in patients with myasthenia gravis.
PMID: 17441229 [PubMed - indexed for MEDLINE]Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Related Articles
Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes.
Brain. 2007 Jun;130(Pt 6):1497-506
Authors: Müller JS, Herczegfalvi A, Vilchez JJ, Colomer J, Bachinski LL, Mihaylova V, Santos M, Schara U, Deschauer M, Shevell M, Poulin C, Dias A, Soudo A, Hietala M, Aärimaa T, Krahe R, Karcagi V, Huebner A, Beeson D, Abicht A, Lochmüller H
Dok ('downstream-of-kinase') family of cytoplasmic proteins play a role in signalling downstream of receptor and non-receptor phosphotyrosine kinases. Recently, a skeletal muscle receptor tyrosine kinase (MuSK)-interacting cytoplasmic protein termed Dok-7 has been identified. Subsequently, we and others identified mutations in DOK7 as a cause of congenital myasthenic syndromes (CMS), providing evidence for a crucial role of Dok-7 in maintaining synaptic structure. Here we present clinical and molecular genetic data of 14 patients from 12 independent kinships with 13 different mutations in the DOK7 gene. The clinical picture of CMS with DOK7 mutations is highly variable. The age of onset may vary between birth and the third decade. However, most of the patients display a characteristic 'limb-girdle' pattern of weakness with a waddling gait and ptosis, but without ophthalmoparesis. Respiratory problems were frequent. Patients did not benefit from long-term therapy with esterase inhibitors; some of the patients even worsened. DOK7 mutations have emerged as one of the major genetic defects in CMS. The clinical picture differs significantly from CMS caused by mutations in other genes, such as the acetylcholine receptor (AChR) subunit genes. None of the patients with DOK7 mutations had tubular aggregates in the muscle biopsy, implying that 'limb-girdle myasthenia (LGM) with tubular aggregates' previously described in literature may be a pathogenic entity distinct from CMS caused by DOK7 mutations.
PMID: 17439981 [PubMed - indexed for MEDLINE]Occurrence of CNS demyelinating disease in patients with myasthenia gravis. Related Articles
Occurrence of CNS demyelinating disease in patients with myasthenia gravis.
PMID: 17438233 [PubMed - indexed for MEDLINE]Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade. Related Articles
Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade.
J Immunol. 2007 Apr 15;178(8):5390-8
Authors: Liu L, Garcia AM, Santoro H, Zhang Y, McDonnell K, Dumont J, Bitonti A
The neonatal FcR (FcRn) plays a critical role in IgG homeostasis by protecting it from a lysosomal degradation pathway. It has been shown that IgG has an abnormally short half-life in FcRn-deficient mice and that FcRn blockade significantly increases the catabolism of serum IgG in mice. Therefore, reduction of serum IgG half-life may have therapeutic benefits in Ab-mediated autoimmune diseases. We have studied the therapeutic effects of an anti-rat FcRn mAb, 1G3, in two rat models of myasthenia gravis, a prototypical Ab-mediated autoimmune disease. Passive experimental autoimmune myasthenia gravis was induced by administration of an anti-acetylcholine receptor (AChR) mAb, and it was shown that treatment with 1G3 resulted in dose-dependent amelioration of the disease symptoms. In addition, the concentration of pathogenic Ab in the serum was reduced significantly. The effect of 1G3 was also studied in an active model of experimental autoimmune myasthenia gravis in which rats were immunized with AChR. Treatment with 1G3 significantly reduced the severity of the disease symptoms as well as the levels of total IgG and anti-AChR IgG relative to untreated animals. These data suggest that FcRn blockade may be an effective way to treat Ab-mediated autoimmune diseases.
PMID: 17404325 [PubMed - indexed for MEDLINE]Microscopic-sized "microthymoma" in patients with myasthenia gravis. Related Articles
Microscopic-sized "microthymoma" in patients with myasthenia gravis.
Chest. 2007 Mar;131(3):847-9
Authors: Mori T, Nomori H, Ikeda K, Kobayashi H, Iwatani K, Yoshioka M, Iyama K
BACKGROUND: In 2005, Cheuk et al reported two patients with microscopic-sized thymomas and proposed the term microthymoma to distinguish it from the nodular hyperplasia of thymic epithelium, so-called microscopic thymoma. Here, we present microthymomas that were found in 196 patients with myasthenia gravis (MG) who had undergone thymectomy. MATERIALS AND METHODS: Thymic tissues in 196 patients with MG who underwent thymectomy or thymothymomectomy were examined. Of these patients, 73 patients had thymoma indicated by CT before surgery, and the other 123 patients had no mediastinal tumors. From the resected thymic tissues, an average of 14 hematoxylin-eosin-stained sections (range, 4 to 55 sections) were prepared for microscopic examination. The histologic type of the thymoma was classified according to the World Health Organization (WHO) classification. RESULTS: From the 196 patients, we found three microthymomas in 3 patients (1.5%). While these three tumors could not be seen grossly in pathology section, they were found microscopically (range, 2 to 4 mm). The histologic subtype according to the WHO classification system was B1 in one patient and B2 in two patients. CONCLUSION: Microthymoma was found in 3 of 196 patients (1.5%) with MG. Microthymoma might exist in thymus of patients with MG, even in patients who have no thymoma indicated by CT.
PMID: 17356102 [PubMed - indexed for MEDLINE]IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Related Articles
IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial.
Neurology. 2007 Mar 13;68(11):837-41
Authors: Zinman L, Ng E, Bril V
OBJECTIVE: We aimed to determine the effectiveness of IV immunoglobulin (IVIG) in the treatment of patients with myasthenia gravis (MG) and worsening weakness in a randomized, placebo-controlled, masked study. METHODS: Fifty-one patients with worsening weakness due to MG were randomized to infusion with 2 g/kg of IVIG or an equivalent volume of IV dextrose 5% in water. The Quantitative Myasthenia Gravis (QMG) Score for Disease Severity, a validated clinical composite scale, was calculated by a masked observer at baseline and days 14 and 28. RESULTS: In IVIG-treated patients, a clinically meaningful improvement in QMG Score for Disease Severity was observed at day 14 and persisted at day 28. The greatest improvement occurred in patients with more severe disease as defined by a QMG Score for Disease Severity greater than 10.5. CONCLUSION: This study provides level 1 evidence for the effectiveness of IV immunoglobulin in patients with worsening weakness due to myasthenia gravis.
PMID: 17353471 [PubMed - indexed for MEDLINE]IVIG in myasthenia gravis: getting enough "bang for the buck".
IVIG in myasthenia gravis: getting enough "bang for the buck".
Neurology. 2007 Mar 13;68(11):803-4
Authors: Meriggioli MN
PMID: 17353466 [PubMed - indexed for MEDLINE]Thiopurine methyltransferase activity in Spain: a study of 14,545 patients. Related Articles
Thiopurine methyltransferase activity in Spain: a study of 14,545 patients.
Dig Dis Sci. 2007 May;52(5):1262-9
Authors: Gisbert JP, Gomollón F, Cara C, Luna M, González-Lama Y, Pajares JM, Maté J, Guijarro LG
We sought to assess the activity of thiopurine methyltransferase (TPMT) in 14,545 Spanish patients with different diseases amenable to treatment with azathioprine/6-mercaptopurine (6-MP), and to evaluate the proportion of patients with low TPMT activity and therefore a higher risk of myelotoxicity with these drugs. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several clinical variables and TPMT activity was assessed by multiple linear regression. We included 14,545 patients: autoimmune hepatitis (n=359 patients), inflammatory bowel disease (n=7,046), multiple sclerosis (n = 814), myasthenia gravis (n=344), pemphigus (n=133), and other diseases (n=5,849). Mean TPMT activity was 20.1 +/- 6 U/mL, but differed depending on the disease (P<.001). TPMT distribution was low (<5) in 0.5%; intermediate (5.0-13.7) in 11.9%; or high (>or=13.8) in 87.6%. Only when TPMT activity was considered separately in each disease did it reveal a normal distribution. In the multivariate analysis, gender, hematocrit, and treatment with 5-aminosalicylates/steroids/azathioprine/6-MP statistically influenced TPMT activity, although, probably, in a clinically irrelevant manner. This study shows, in a large sample of 14,545 patients, that 0.5% had low TPMT activity, indicating a higher risk of myelotoxicity with azathioprine/6-MP, a figure similar or slightly higher than that reported in other areas. Nevertheless, the trimodal distribution of TPMT activity varied depending on disease, and the proportion of patients with low activity values ranged from 0-0.8%. The drugs prescribed for the treatment of autoimmune diseases, including azathioprine/6-MP, modified TPMT activity, but the magnitude of this effect was very small and the differences found are probably irrelevant from the clinical point of view.
PMID: 17334911 [PubMed - indexed for MEDLINE]Vocal cord paralysis in myasthenia gravis with anti-MuSK antibodies. Related Articles
Vocal cord paralysis in myasthenia gravis with anti-MuSK antibodies.
Neurology. 2007 Feb 20;68(8):621-2
Authors: Hara K, Mashima T, Matsuda A, Tanaka K, Tomita M, Shiraishi H, Motomura M, Nishizawa M
PMID: 17310039 [PubMed - indexed for MEDLINE]Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis. Related Articles
Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis.
Neurology. 2007 Feb 20;68(8):609-11
Authors: Deymeer F, Gungor-Tuncer O, Yilmaz V, Parman Y, Serdaroglu P, Ozdemir C, Vincent A, Saruhan-Direskeneli G
We compared 65 anti-acetylcholine receptor (AChR)-negative myasthenia gravis (MG) patients, including 32 anti-muscle-specific tyrosine kinase (MuSK)-positive (49%) and 33 anti-MuSK-negative (seronegative) (51%) patients, with 161 anti-AChR-positive MG patients. The anti-MuSK-positive group had a higher frequency of bulbar involvement and respiratory crises. The seronegative group was in between the anti-MuSK positive and the anti-AChR positive groups, being closer to the latter, with regard to the severity of the disease. At the end of follow-up, the outcome of the anti-MuSK-positive patients was not different from that of the anti-AChR-positive patients, although their maintenance corticosteroid dose was higher. The seronegative patients had better outcome than the other two groups.
PMID: 17310034 [PubMed - indexed for MEDLINE]Bilateral ocular paralysis: analysis of 31 inpatients. Related Articles
Bilateral ocular paralysis: analysis of 31 inpatients.
Arch Neurol. 2007 Feb;64(2):178-80
Authors: Keane JR
To my knowledge, no general study of complete ophthalmoplegia is available. This study was performed to determine the seats and causes of bilateral ocular paralysis. The personal records of 13 440 neurology and neurosurgery inpatients were reviewed. Eighteen (58%) of 31 patients had Fisher syndrome (13 cases) or Guillain-Barré syndrome (5 cases). Four cases resulted from midbrain infarction, 3 from myasthenia, and 1 each from pituitary apoplexy, skull base metastasis, botulism, mucormycosis, phenytoin toxicity, and trauma. Many conditions produce complete ophthalmoplegia on rare occasions, but Fisher syndrome, which paralyzes the eyes in nearly one third of cases, was by far the commonest cause.
PMID: 17296832 [PubMed - indexed for MEDLINE]The thymic theme of acetylcholinesterase splice variants in myasthenia gravis. Related Articles
The thymic theme of acetylcholinesterase splice variants in myasthenia gravis.
Blood. 2007 May 15;109(10):4383-91
Authors: Gilboa-Geffen A, Lacoste PP, Soreq L, Cizeron-Clairac G, Le Panse R, Truffault F, Shaked I, Soreq H, Berrih-Aknin S
Cholinergic signaling and acetylcholinesterase (AChE) influence immune response and inflammation. Autoimmune myasthenia gravis (MG) is mediated by antibodies to the acetylcholine receptor and current therapy is based on anti-AChE drugs. MG is associated with thymic hyperplasia, showing signs of inflammation. The objectives of this study were to analyze the involvement of AChE variants in thymic hyperplasia. We found lower hydrolytic activities in the MG thymus compared with adult controls, accompanied by translocation of AChE-R from the cytoplasm to the membrane and increased expression of the signaling protein kinase PKC-betaII. To explore possible causal association of AChE-R changes with thymic composition and function, we used an AChE-R transgenic model and showed smaller thymic medulla compared with strain-matched controls, indicating that AChE-R overexpression interferes with thymic differentiation mechanisms. Interestingly, AChE-R transgenic mice showed increased numbers of CD4(+)CD8(+) cells that were considerably more resistant in vitro to apoptosis than normal thymocytes, suggesting possibly altered positive selection. We further analyzed microarray data of MG thymic hyperplasia compared with healthy controls and found continuous and discrete changes in AChE-annotated GO categories. Together, these findings show that modified AChE gene expression and properties are causally involved in thymic function and development.
PMID: 17272501 [PubMed - indexed for MEDLINE]The distribution of parenchyma, follicles, and lymphocyte subsets in thymus of patients with myasthenia gravis, with special reference to remission after thymectomy. Related Articles
The distribution of parenchyma, follicles, and lymphocyte subsets in thymus of patients with myasthenia gravis, with special reference to remission after thymectomy.
J Thorac Cardiovasc Surg. 2007 Feb;133(2):364-8
Authors: Mori T, Nomori H, Ikeda K, Kobayashi H, Iwatani K, Kobayashi T
OBJECTIVE: We sought to examine the distribution of parenchyma, follicles, and lymphocyte subsets in the thymus of patients with myasthenia gravis and to identify determinants of remission after thymectomy. METHODS: Sixty patients with myasthenia gravis who underwent thymectomy were examined. The thymus was divided into upper, middle, and lower parts. The upper part was defined as the superior horn, the lower part as the inferior horn, and the middle part as tissue located between the 2 horns. The percentage of parenchyma was measured morphometrically. The degree of follicular hyperplasia was classified into 5 grades. The densities of CD3+, CD4+, and CD8+ lymphocytes were classified into 5 grades. The remission of myasthenia gravis after thymectomy was examined with those variables in each part of the thymus. RESULTS: The middle part had the highest percentage of parenchyma, the highest grade of follicular hyperplasia, and the highest density of CD3+, CD4+, and CD8+ lymphocytes among the 3 parts (P < .001-.05). The grades of follicular hyperplasia in the middle and lower parts were significantly higher in patients with improvement of myasthenia gravis than in those without (P < .05). The densities of CD3+, CD4+, and CD8+ lymphocytes in the cortex of the middle part were significantly higher in patients with improvement than in those without improvement (P < .01-.05). CONCLUSIONS: The thymus has a heterogeneous distribution of parenchyma, follicles, and lymphocyte subsets. The middle part had the largest parenchyma, the highest grade of follicular hyperplasia, and the highest densities of CD3+, CD4+, and CD8+ lymphocytes among the 3 parts of the thymus. The grade of follicular hyperplasia and the density of these lymphocyte subsets are predictive of improvement in myasthenia gravis after thymectomy.
PMID: 17258565 [PubMed - indexed for MEDLINE]Overexpression of rapsyn in rat muscle increases acetylcholine receptor levels in chronic experimental autoimmune myasthenia gravis. Related Articles
Overexpression of rapsyn in rat muscle increases acetylcholine receptor levels in chronic experimental autoimmune myasthenia gravis.
Am J Pathol. 2007 Feb;170(2):644-57
Authors: Martínez-Martínez P, Losen M, Duimel H, Frederik P, Spaans F, Molenaar P, Vincent A, De Baets MH
The primary autoantigen in myasthenia gravis, the acetylcholine receptor (AChR), is clustered and anchored in the postsynaptic membrane of the neuromuscular junction by rapsyn. Previously, we found that overexpression of rapsyn by cDNA transfection protects AChRs in rat muscles from antibody-mediated loss in passive transfer experimental autoimmune myasthenia gravis (EAMG). Here, we determined whether rapsyn overexpression can reduce or even reverse AChR loss in muscles that are already damaged by chronic EAMG, which mimics the human disease. Active immunization against purified AChR was performed in female Lewis rats. Rapsyn overexpression resulted in an increase in total muscle membrane AChR levels, with some AChR at neuromuscular junctions but much of it in extrasynaptic membrane regions. At the ultrastructural level, most endplates in rapsyn-treated chronic EAMG muscles showed increased damage to the postsynaptic membrane. Although rapsyn overexpression stabilized AChRs in intact or mildly damaged endplates, the rapsyn-induced increase of membrane AChR enhanced autoantibody binding and membrane damage in severe ongoing disease. Thus, these results show the complexity of synaptic stabilization of AChR during the autoantibody attack. They also indicate that the expression of receptor-associated proteins may determine the severity of autoimmune diseases caused by anti-receptor antibodies.
PMID: 17255332 [PubMed - indexed for MEDLINE]Microarrays reveal distinct gene signatures in the thymus of seropositive and seronegative myasthenia gravis patients and the role of CC chemokine ligand 21 in thymic hyperplasia. Related Articles
Microarrays reveal distinct gene signatures in the thymus of seropositive and seronegative myasthenia gravis patients and the role of CC chemokine ligand 21 in thymic hyperplasia.
J Immunol. 2006 Dec 1;177(11):7868-79
Authors: Le Panse R, Cizeron-Clairac G, Bismuth J, Berrih-Aknin S
Myasthenia gravis (MG) is an autoimmune disease mainly caused by antiacetylcholine receptor autoantibodies (seropositive (SP) disease) or by Abs against unknown autoantigenic target(s) (seronegative (SN) disease). Thymectomy is usually beneficial although thymic hyperplasia with ectopic germinal centers is mainly observed in SP MG. To understand the role of thymus in the disease process, we compared the thymic transcriptome of non-MG adults to those of SP patients with a low or high degree of hyperplasia or SN patients. Surprisingly, an overexpression of MHC class II, Ig, and B cell marker genes is observed in SP but also SN MG patients. Moreover, we demonstrate an overexpression of CXCL13 in all MG thymuses leading probably to the generalized B cell infiltration. However, we find different chemotactic properties for MG subgroups and, especially, a specific overexpression of CCL21 in hyperplastic thymuses triggering most likely ectopic germinal center development. Besides, SN patients present a peculiar signature with an abnormal expression of genes involved in muscle development and synaptic transmission, but also genes implicated in host response, suggesting that viral infection might be related to SN MG. Altogether, these results underline differential pathogenic mechanisms in the thymus of SP and SN MG and propose new research areas.
PMID: 17114458 [PubMed - indexed for MEDLINE]Myasthenia gravis mimicking unilateral vocal fold paralysis at presentation. Related Articles
Myasthenia gravis mimicking unilateral vocal fold paralysis at presentation.
J Laryngol Otol. 2007 Feb;121(2):174-8
Authors: Hartl DM, Leboulleux S, Klap P, Schlumberger M
OBJECTIVES: To demonstrate the importance of detailed clinical analysis in the differential diagnosis of unilateral vocal fold paralysis, and to provide an update on current knowledge and treatment of myasthenia gravis. CASE REPORT: A female patient presented with left unilateral vocal fold immobility. Diagnostic investigation revealed a 10 mm thyroid adenoma, but no other abnormality likely to cause unilateral vocal fold paralysis. Follow-up flexible endoscopy at three months showed laryngeal remobilisation with persistent left vocal fold bowing and vertical asymmetry of the vocal folds on phonation. Over the following months, voice quality varied between normal and breathy, with the breathy periods lasting from three days to one month. Laryngeal electromyography (EMG) showed a slight bilateral paradoxical activation of both posterior crico-arytenoid muscles on phonation. Magnetic resonance imaging of the brain and brainstem was normal. A diagnostic test for myasthenia gravis with intravenous edrophonium bromide (Tensilon) lead to an immediate improvement in voice quality. The patient was subsequently treated with pyridostigmine bromide, with complete resolution of dysphonia. CONCLUSIONS: Myasthenia gravis affecting the larynx may mimic unilateral vocal fold paresis or paralysis. A personal or family history of auto-immune disease, fluctuating symptoms, motor deficits in cranial nerve territories, and normal or subnormal laryngeal EMG results should lead the physician to reconsider a diagnosis of idiopathic unilateral vocal fold paralysis and to perform specific testing.
PMID: 17112394 [PubMed - indexed for MEDLINE]Myasthenia gravis: past, present, and future. Related Articles
Myasthenia gravis: past, present, and future.
J Clin Invest. 2006 Nov;116(11):2843-54
Authors: Conti-Fine BM, Milani M, Kaminski HJ
Myasthenia gravis (MG) is an autoimmune syndrome caused by the failure of neuromuscular transmission, which results from the binding of autoantibodies to proteins involved in signaling at the neuromuscular junction (NMJ). These proteins include the nicotinic AChR or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering. Much is known about the mechanisms that maintain self tolerance and modulate anti-AChR Ab synthesis, AChR clustering, and AChR function as well as those that cause neuromuscular transmission failure upon Ab binding. This insight has led to the development of improved diagnostic methods and to the design of specific immunosuppressive or immunomodulatory treatments.
PMID: 17080188 [PubMed - indexed for MEDLINE]Myasthenia gravis exacerbation or unmasking associated with telithromycin treatment. Related Articles
Myasthenia gravis exacerbation or unmasking associated with telithromycin treatment.
Neurology. 2006 Dec 26;67(12):2256-8
Authors: Perrot X, Bernard N, Vial C, Antoine JC, Laurent H, Vial T, Confavreux C, Vukusic S
Telithromycin, a new ketolide antibiotic, has been implicated in the exacerbation or unmasking of myasthenia gravis. This retrospective study presents two clinical reports and summarizes eight other suspected cases notified to the French pharmacovigilance system, highlighting a potentially life-threatening risk of telithromycin treatment in myasthenic patients. An important common feature was that, in seven cases, symptomatology occurred within 2 hours of first telithromycin intake--notably in cases of severe exacerbation.
PMID: 17065592 [PubMed - indexed for MEDLINE]Outcomes after 151 extended transcervical thymectomies for myasthenia gravis. Related Articles
Outcomes after 151 extended transcervical thymectomies for myasthenia gravis.
Ann Thorac Surg. 2006 Nov;82(5):1863-9
Authors: Shrager JB, Nathan D, Brinster CJ, Yousuf O, Spence A, Chen Z, Kaiser LR
BACKGROUND: The ideal operative technique for thymectomy in myasthenia gravis (MG) remains controversial. We present the largest series of extended transcervical thymectomy to provide outcomes data to compare with transsternal procedures. METHODS: A retrospective chart review/interview was made of 164 patients operated upon from 1992 to 2004. Complete remission (CR) was defined as asymptomatic off medication for 6 months or asymptomatic on low-dose single-drug therapy (< or = 10 mg/d prednisone or < or = 150 mg/d azathioprine). A modified Osserman classification based upon the Myasthenia Gravis Foundation of America quantitative disease severity score was employed. RESULTS: The overall complication rate was 7.3%, and nearly all procedures were outpatient. Mean age at surgery was 43 years, and mean preoperative Osserman class was 2.3 (21% class 1; 39% class 2; 28% class 3; 12% class 4). Mean length of follow-up was 53 months. Mean postoperative Osserman class was 1.0. Nineteen percent of patients failed to improve. The crude cumulative CR rate was 37% (n = 58). Kaplan-Meier estimates of CR were 43% and 45% at 3 and 6 years, respectively. On multivariate analysis, only preoperative disease severity was significantly (inversely) associated with Kaplan-Meier CR rates. Longer-term follow-up (83 months) of only the earlier patients shows preserved CR rates (46%). CONCLUSIONS: This largest series of extended transcervical thymectomy for MG confirms that the 5-year Kaplan-Meier CR rate is comparable with that obtained after transsternal procedures. Patients with less severe disease have higher CR rates. Complete responses are durable, as the CR rate remains stable with extended follow-up.
PMID: 17062262 [PubMed - indexed for MEDLINE]Ptosis in myasthenia gravis: extended fatigue and recovery bedside test. Related Articles
Ptosis in myasthenia gravis: extended fatigue and recovery bedside test.
Neurology. 2006 Oct 24;67(8):1524
Authors: Toyka KV
PMID: 17060601 [PubMed - indexed for MEDLINE]Validation and test characteristics of a 10-item neuro-ophthalmic supplement to the NEI-VFQ-25. Related Articles
Validation and test characteristics of a 10-item neuro-ophthalmic supplement to the NEI-VFQ-25.
Am J Ophthalmol. 2006 Dec;142(6):1026-35
Authors: Raphael BA, Galetta KM, Jacobs DA, Markowitz CE, Liu GT, Nano-Schiavi ML, Galetta SL, Maguire MG, Mangione CM, Globe DR, Balcer LJ
PURPOSE: To determine whether a 10-Item Neuro-Ophthalmic Supplement increases the capacity of the 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) to capture self-reported visual dysfunction in patients with neuro-ophthalmologic disorders. DESIGN: A cross-sectional survey to examine the characteristics of a 10-Item Neuro-Ophthalmic Supplement to the 25-Item NEI-VFQ-25 in a cohort of patients with neuro-ophthalmologic disorders. METHODS: The 10-Item Neuro-Ophthalmic Supplement was designed previously by our research group by survey and focus-group methods. In the present study, the NEI-VFQ-25 and 10-Item Supplement were administered concurrently to patients and disease-free control subjects. High-contrast visual acuities with patient usual distance correction were measured with the use of Early Treatment Diabetic Retinopathy Study (ETDRS) charts. RESULTS: Diagnoses for patients (n = 215) included optic neuritis, multiple sclerosis, idiopathic intracranial hypertension, ischemic optic neuropathy, stroke, ocular myasthenia gravis, ocular motor palsies, and thyroid eye disease. Scores for the 10-Item Supplement had a significant capacity to distinguish patients vs disease-free control subjects that was independent of the NEI-VFQ-25 composite score (odds ratio in favor of patient vs control status for 10-point worsening in Supplement scores: 2.7 [95% confidence interval [CI], 1.6, 4.6]; P < .001, logistic regression models that account for NEI-VFQ-25 composite score, age, and gender). Patients with visual dysfunction (binocular Snellen equivalents worse than 20/20) had significantly lower mean scores (9-21 points lower); these differences remained significant after accounting for age and gender (P >or= .001, linear regression). Supplement items and composite scores demonstrated appropriate degrees of internal consistency reliability. CONCLUSION: The 10-Item Neuro-Ophthalmic Supplement demonstrates a capacity to capture self-reported visual dysfunction beyond that of the NEI-VFQ-25 alone, which supports validity for this new scale. The use of the 10-Item Supplement in clinical trials and epidemiologic studies will examine its capacity to demonstrate treatment effects in longitudinal cohorts.
PMID: 17046704 [PubMed - indexed for MEDLINE]The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Related Articles
The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade.
Am J Respir Crit Care Med. 2007 Jan 1;175(1):9-15
Authors: Eikermann M, Vogt FM, Herbstreit F, Vahid-Dastgerdi M, Zenge MO, Ochterbeck C, de Greiff A, Peters J
RATIONALE: Partial neuromuscular transmission failure by acetylcholine receptor blockade (neuromuscular blockade) or antibody-mediated functional loss (myasthenia gravis), even with a magnitude of muscle weakness that does not evoke respiratory symptoms, can evoke dysphagia and decreased inspiratory airflow, and increases the risk of susceptible patients to develop severe pulmonary complications. OBJECTIVES: To assess whether impaired neuromuscular transmission predisposes individuals to inspiratory upper airway collapse, we assessed supraglottic airway diameter and volume by respiratory-gated magnetic resonance imaging, upper airway dilator muscle function (genioglossus force and EMG), and changes in lung volume, respiratory timing, and peripheral muscle function before, during, and after partial neuromuscular blockade in healthy, awake volunteers. MEASUREMENTS AND MAIN RESULTS: Partial neuromuscular blockade (train-of-four [TOF] ratio: 0.5 and 0.8) was associated with the following: (1) a decrease of inspiratory retropalatal and retroglossal upper airway volume to 66 +/- 22 and 82 +/- 12% of baseline, which was significantly more intense in the retropalatal area; (2) an attenuation of the normal increase in anteroposterior upper airway diameter during forced inspiration to 74 +/- 18% of baseline; (3) a decrease in genioglossus activity during maximum voluntary tongue protrusion to 39 +/- 19% (TOF, 0.5) and 73 +/- 29% (TOF, 0.8) of baseline; and (4) no effects on upper airway size during expiration, lung volume, and respiratory timing. CONCLUSIONS: Thus, impaired neuromuscular transmission, even to a degree insufficient to evoke respiratory symptoms, markedly impairs upper airway dimensions and function. This may be explained by an impairment of the balance between upper airway dilating forces and negative intraluminal pressure generated during inspiration by respiratory "pump" muscles.
PMID: 17023729 [PubMed - indexed for MEDLINE]Suppression of experimental autoimmune myasthenia gravis by granulocyte-macrophage colony-stimulating factor is associated with an expansion of FoxP3+ regulatory T cells. Related Articles
Suppression of experimental autoimmune myasthenia gravis by granulocyte-macrophage colony-stimulating factor is associated with an expansion of FoxP3+ regulatory T cells.
Dendritic cells (DCs) have the potential to activate or tolerize T cells in an Ag-specific manner. Although the precise mechanism that determines whether DCs exhibit tolerogenic or immunogenic functions has not been precisely elucidated, growing evidence suggests that DC function is largely dependent on differentiation status, which can be manipulated using various growth factors. In this study, we investigated the effects of mobilization of specific DC subsets-using GM-CSF and fms-like tyrosine kinase receptor 3-ligand (Flt3-L)-on the susceptibility to induction of experimental autoimmune myasthenia gravis (EAMG). We administered GM-CSF or Flt3-L to C57BL/6 mice before immunization with acetylcholine receptor (AChR) and observed the effect on the frequency and severity of EAMG development. Compared with AChR-immunized controls, mice treated with Flt3-L before immunization developed EAMG at an accelerated pace initially, but disease frequency and severity was comparable at the end of the observation period. In contrast, GM-CSF administered before immunization exerted a sustained suppressive effect against the induction of EAMG. This suppression was associated with lowered serum autoantibody levels, reduced T cell proliferative responses to AChR, and an expansion in the population of FoxP3+ regulatory T cells. These results highlight the potential of manipulating DCs to expand regulatory T cells for the control of autoimmune diseases such as MG.
PMID: 17015715 [PubMed - indexed for MEDLINE]Pharmacokinetics of pyridostigmine in a child with postural tachycardia syndrome. Related Articles
Pharmacokinetics of pyridostigmine in a child with postural tachycardia syndrome.
Pediatrics. 2006 Nov;118(5):e1563-8
Authors: Filler G, Gow RM, Nadarajah R, Jacob P, Johnson G, Zhang YL, Christians U
Pyridostigmine has been proposed for the treatment of postural orthostatic tachycardia syndrome in adults at a dose of 60 mg twice daily, but no dosing recommendation exists for children. With the approval of our local ethics board, we tested the pharmacokinetics of pyridostigmine in 6 children with myasthenia and a pediatric index patient with severe postural orthostatic tachycardia syndrome whose condition failed all conventional therapy and who had developed significant postural hypertension. Pyridostigmine was quantified by using a validated, semiautomated, and specific high-performance liquid chromatography/tandem mass spectrometry assay in combination with online column-switching extraction and turbo electrospray ionization. The patient with postural orthostatic tachycardia syndrome showed a dose-dependent favorable response to oral pyridostigmine. Pharmacokinetic evaluation revealed a short half-life of 2.29 hours, similar to the 2.0 +/- 0.63 hours in the patients with myasthenia. The patient with postural orthostatic tachycardia syndrome has subsequently been treated at a dose of 45 mg in the morning, 30 mg at lunchtime, and 15 mg at bedtime; after 9 months, there has been persistent positive effect and without additional blood pressure medication. No major adverse effects occurred. Pyridostigmine has been a safe and effective treatment modality for this child with postural orthostatic tachycardia syndrome. The short half-life suggests that dosing 3 times per day is preferable.
PMID: 17015495 [PubMed - indexed for MEDLINE]Occurrence of CNS demyelinating disease in patients with myasthenia gravis.
Occurrence of CNS demyelinating disease in patients with myasthenia gravis.
Neurology. 2006 Sep 12;67(5):881-3
Authors: Gotkine M, Fellig Y, Abramsky O
An increased incidence of multiple sclerosis (MS) has been reported in patients with myasthenia gravis (MG). We reviewed records of 214 patients with MG. CNS demyelinating disease (CNSDD) occurred in five patients (2.3%). CNSDD always occurred after the diagnosis of MG. Myelitis (including recurrent myelitis) was the most common CNS manifestation. All patients had antinuclear antibodies. CNSDD occurs more frequently in patients with MG and may be related to immune-modulating treatments including thymectomy.
PMID: 16966558 [PubMed - indexed for MEDLINE]Progressive cervical kyphosis associated with botulinum toxin injection. Related Articles
Progressive cervical kyphosis associated with botulinum toxin injection.
South Med J. 2006 Aug;99(8):888-91
Authors: Hogan KA, Manning EL, Glaser JA
Weakness of the neck extensors can lead to "dropped head syndrome", a condition of progressive cervical kyphosis in which a patient is unable to hold their head up against the force of gravity. This condition can be associated with structural abnormalities of the spine as found in ankylosing spondylitis and vertebral fractures. Neuromuscular disorders, such as myasthenia gravis, muscular dystrophies, inflammatory myopathies, and motor neuron disorders such as amyotrophic lateral sclerosis (ALS) have also been reported as etiologies of dropped head syndrome. In this article, we describe an elderly woman with rapidly progressive cervical kyphosis following an injection of botulinum toxin A into her neck extensor musculature.
PMID: 16929888 [PubMed - indexed for MEDLINE]Thoracoscopic thymectomy mid-term results. Related Articles
Thoracoscopic thymectomy mid-term results.
Ann Thorac Surg. 2006 Sep;82(3):1003-7
Authors: Tomulescu V, Ion V, Kosa A, Sgarbura O, Popescu I
BACKGROUND: Results of thymectomy in patients with myasthenia gravis need to be reported in a standardized way to allow accurate comparison. METHODS: A retrospective study was conducted of 107 patients with myasthenia gravis without thymoma. Patients were followed-up for more than 12 months after thoracoscopic thymectomy and analyzed according to Myasthenia Gravis Foundation of America Recommendations for Clinical Research Standards. RESULTS: The study population was aged 8 to 60 years old and included 15 men (14%) and 92 women (86%). A right-side approach was used in 36 patients, and the remaining 71 patients had a left-side approach. Mortality was 0% and morbidity was 9.34%. The mean operative time was 90 +/- 45 minutes. The histologic diagnosis of the resected thymus was hyperplasia (78.5%), atrophy (15%), and normal status (6.5%). The mean length of hospitalization was 2.3 days (range, 2 to 6 days). The mean follow-up was 36.4 months (range, 12 to 74 months). The rate of complete stable remission was 59.5% by the end of postoperative year 6. An earlier onset age and early operation were significantly associated with complete stable remission and pharmacologic remission. A comparison of right side versus left side approach showed similarities in mean operative time, mean length of hospitalization, histopathologic results, and remission rates. CONCLUSIONS: Outcomes of the thoracoscopic approach in myasthenia gravis without thymoma were similar to those provided by open surgery, with the acknowledged benefits of minimally invasive surgery and good patient acceptance.
PMID: 16928524 [PubMed - indexed for MEDLINE]Plasma exchange in neuroimmunological disorders: part 2. Treatment of neuromuscular disorders. Related Articles
Plasma exchange in neuroimmunological disorders: part 2. Treatment of neuromuscular disorders.
Arch Neurol. 2006 Aug;63(8):1066-71
Authors: Lehmann HC, Hartung HP, Hetzel GR, Stüve O, Kieseier BC
Plasma exchange is a well-established therapeutic procedure commonly used in many neurological disorders of autoimmune etiology. In this second part of our review, we assess the role of plasma exchange in the treatment of neuromuscular disorders. In Guillain-Barré syndrome and other immune-mediated neuropathic disorders, randomized controlled trials have demonstrated the therapeutic efficacy of plasma exchange. Myasthenia gravis and Lambert-Eaton syndrome represent neuromuscular disorders where plasmapheresis might be of potential efficacy.
PMID: 16908731 [PubMed - indexed for MEDLINE]Anti-MuSK antibodies: correlation with myasthenia gravis severity. Related Articles
Anti-MuSK antibodies: correlation with myasthenia gravis severity.
Neurology. 2006 Aug 8;67(3):505-7
Authors: Bartoccioni E, Scuderi F, Minicuci GM, Marino M, Ciaraffa F, Evoli A
The authors measured anti-muscle-specific tyrosine kinase (anti-MuSK) antibodies (Abs) in 83 serum samples from 40 patients and evaluated their correlation with myasthenia gravis severity and treatment response. Ab concentrations were often reduced by immunosuppression but not after thymectomy. Both in individual cases and in the whole population, a correlation between Ab levels and disease severity was found.
PMID: 16894117 [PubMed - indexed for MEDLINE]Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia'. Related Articles
Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia'.
Brain. 2006 Aug;129(Pt 8):2061-76
Authors: Slater CR, Fawcett PR, Walls TJ, Lyons PR, Bailey SJ, Beeson D, Young C, Gardner-Medwin D
The properties of neuromuscular junctions (NMJs) were studied in motor-point biopsy samples from eight patients with congenital myasthenic syndromes affecting primarily proximal limb muscles ['limb-girdle myasthenia' (LGM)]. All had moderate to severe weakness of the proximal muscles, without short-term clinical fatigability but with marked variation in strength over periods of weeks or months, with little or no facial weakness or ptosis and no ophthalmoplegia. Most had a characteristic gait and stance. All patients showed decrement of the compound muscle action potential (CMAP) on repetitive stimulation at 3 Hz, and increased jitter and blocking was detected by SFEMG, confirming the presence of impaired neuromuscular transmission. None of the patients had serum antibodies against acetylcholine receptors (AChRs). Two of the patients had similarly affected siblings. Intracellular recording from isolated nerve-muscle preparations revealed that the quantal content (the number of ACh quanta released per nerve impulse) was only approximately 50% of that in controls. However, the quantal size (amplitude of miniature end-plate currents) and the kinetic properties of synaptic potentials and currents were similar to control values. The area of synaptic contact and extent of post-synaptic folding were approximately 50% of control values. Thus, the quantal content per unit area of synaptic contact was normal. The number of AChRs per NMJ was also reduced to approximately 50% of normal, so the local AChR density was normal. Immunolabelling studies revealed qualitatively normal distributions and abundance of each of 14 proteins normally concentrated at the NMJ, including components of the basal lamina, post-synaptic membrane and post-synaptic cytoskeleton. DNA analysis failed to detect mutations in the genes encoding any of the following proteins: AChR subunits, rapsyn, ColQ, ChAT or muscle-specific kinase. Response of these patients to treatment was varied: few showed long-term improvement with pyridostigmine and some even deteriorated with treatments, while others had intolerable side-effects. Several patients showed improvement with 3,4-diaminopyridine, but this was generally only transient. Ephedrine was helpful in half of the patients. We conclude that impaired neuromuscular transmission in these LGM patients results from structural abnormalities of the NMJ, including reduced size and post-synaptic folding, rather from any abnormality in the immediate events of neuromuscular transmission.
PMID: 16870884 [PubMed - indexed for MEDLINE]Light on limb-girdle myasthenia.
Light on limb-girdle myasthenia.
Brain. 2006 Aug;129(Pt 8):1938-9
Authors: Engel AG
PMID: 16870882 [PubMed - indexed for MEDLINE]The "slurp" test: bedside evaluation of bulbar muscle fatigue. Related Articles
The "slurp" test: bedside evaluation of bulbar muscle fatigue.
Pediatrics. 2006 Aug;118(2):e530-3
Authors: Hudspeth MP, Holden KR, Crawford TO
Patients with myasthenia gravis or other neuromuscular disorders are subject to increasing weakness of bulbar-innervated muscles, with resulting aspiration or catastrophic airway compromise. The available practical assessments of bulbar function in children are inadequate. We report our experience with the "slurp" test, a new bedside measure of bulbar function, in children with myasthenia gravis. Our experience suggests that the test is valuable for identifying patients with probable serious compromise of bulbar function, for monitoring such children during times of intercurrent illness, and for guiding therapy.
PMID: 16847079 [PubMed - indexed for MEDLINE]Infantile onset myasthenia gravis with MuSK antibodies. Related Articles
Infantile onset myasthenia gravis with MuSK antibodies.
Neurology. 2006 Jul 11;67(1):174
Authors: Murai H, Noda T, Himeno E, Kawano Y, Ohyagi Y, Shiraishi H, Motomura M, Kira J
PMID: 16832105 [PubMed - indexed for MEDLINE]Sleep apnea in patients with myasthenia gravis. Related Articles
Sleep apnea in patients with myasthenia gravis.
Neurology. 2006 Jul 11;67(1):140-2
Authors: Nicolle MW, Rask S, Koopman WJ, George CF, Adams J, Wiebe S
To assess the prevalence of obstructive sleep apnea (OSA) in myasthenia gravis, the authors identified patients at risk of OSA using the multivariable apnea prediction index. OSA was diagnosed with polysomnography. The prevalence of OSA was 36% compared to an expected prevalence of 15 to 20% in the general population. When including the presence of daytime sleepiness (OSA syndrome), the prevalence was 11% compared to 3% in the general population.
PMID: 16832094 [PubMed - indexed for MEDLINE]Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of inflammatory central nervous system disorders. Related Articles
Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of inflammatory central nervous system disorders.
Arch Neurol. 2006 Jul;63(7):930-5
Authors: Lehmann HC, Hartung HP, Hetzel GR, Stüve O, Kieseier BC
Plasma exchange is a well-established therapeutic procedure commonly used in many neurological disorders of autoimmune etiology. It is thought that the beneficial effects of plasma exchange occur through the elimination of pathognomonic inflammatory mediators, including autoantibodies, complement components, and cytokines. In various neurological disorders, randomized controlled studies have demonstrated the efficacy of plasma exchange (eg, in Guillain-Barré syndrome and other forms of immune neuropathies). Although widely used, the potential benefit of plasma exchange in the treatment of multiple sclerosis, myasthenia gravis, and Lambert-Eaton syndrome is less clear.