[Pregnancy, birth and neurologic disease].
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Anticonvulsants↗
Biomedical subjects
Nils Erik Gilhus
Publications and source records attributed to Nils Erik Gilhus.
Morphological effects of myasthenia gravis patient sera on human muscle cells.
Myasthenia gravis (MG) is caused primarily by autoantibodies against the nicotinic acetylcholine receptor (AChR), but autoantibodies to other muscle proteins may be present. Many of these proteins have structural or signalling functions, the disruption of which may affect muscle cell morphology or viability. In order to investigate the role of such autoantibodies in MG, we examined the effect of MG patient sera, of different autoantibody composition and obtained at different stages of disease severity, on primary human muscle cells. Sera from MG patients induced changes in cell morphology from typical elongated cells to an irregular phenotype, caused the formation of inclusion bodies and intracellular vesicles, and led to a disordered arrangement of actin microfilaments. Sera from the most severely affected patients also induced cell death, which did not occur via classic apoptosis. The effects were not complement-mediated and were dose- and time-dependent. As the effects observed in the cell culture system correlated with disease severity, a greater understanding of the individual factors responsible for these effects may improve our understanding of MG pathogenesis and be of value in the assessment of disease in individual patients.
Autoantibodies↗
[Research positions for junior physicians as research resource].
BACKGROUND: Positions for junior doctors specially designated to research serve to promote this mission at university hospitals. MATERIAL AND METHODS: A questionnaire was sent to nine leading Norwegian hospitals in order to assess the status of junior doctors' research positions as well as plans and strategies for such positions. The answers involved both the hospital leadership and the individual departments. RESULTS: All hospitals supported positions for junior doctors in medical research. They aimed at more employees with double competence: a doctoral degree and a medical specialty. Several research positions were used at the post-doctoral level. So far the individual departments have been instrumental in establishing research positions for junior doctors. INTERPRETATION: In hospital research positions, at least 50 % of doctors' working time should be allocated to well-defined and sufficiently ambitious research projects. The major hospitals intend to establish more such positions. The Norwegian Medical Association should support this initiative by making these positions attractive for the institutions as well as for doctors, not least by giving the highest priority to medical research in its statements, negotiating stances and strategies.
Biomedical Research↗
Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease.
OBJECTIVE: To investigate the effect of maternal Charcot-Marie-Tooth disease (CMT) on pregnancy and delivery. METHODS: Data from the Medical Birth Registry of Norway 1967 to 2002 were surveyed. This registry has compulsory notification of all births. One hundred eight births by mothers with CMT were identified. The reference group consisted of all 2.1 million births by mothers without CMT. RESULTS: Women with CMT had a higher occurrence of presentation anomalies (9.3 vs 4.5%; p = 0.04) and bleeding post partum (12.0 vs 5.8%; p = 0.02). The rate of operative delivery was twice that of the reference group (29.6 vs 15.3%; p = 0.002), and forceps was used three times as often in the CMT group (9.3 vs 2.7; p < 0.001). The majority of CMT cesarean sections were emergency sections. CONCLUSION: Charcot-Marie-Tooth disease increases the risk for complications during delivery, which is linked to a higher occurrence of emergency interventions during birth.
Adult↗
Striational antibodies in myasthenia gravis: reactivity and possible clinical significance.
Myasthenia gravis is an autoimmune disease caused, in most cases, by antibodies attaching to the acetylcholine receptor. Some myasthenia gravis patients have antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections (striational antibodies). These antibodies react with epitopes on the muscle proteins titin and ryanodine receptor, are found mainly in sera of patients with thymoma and late-onset myasthenia gravis, and may correlate with myasthenia gravis severity. Their presence may predict an unsatisfactory outcome after thymectomy. The detection of titin and ryanodine receptor antibodies provides more specific clinical information than the immunofluorescent demonstration of striational antibodies.
Autoantibodies↗
The role of complement in myasthenia gravis: serological evidence of complement consumption in vivo.
BACKGROUND: Antibodies to the acetylcholine receptor (AChR) titin and the ryanodine receptor (RyR) occur in myasthenia gravis (MG). These antibodies are capable of complement activation in vitro. The involvement of the complement system should cause consumption of complement components such as C3 and C4 in vivo. MATERIALS AND METHODS: Complement components C3 and C4 were assayed in sera from 78 AChR antibody-positive MG patients and 52 healthy controls. Forty-eight of the patient sera contained titin antibodies as well, and 20 were also RyR antibody-positive. RESULTS: MG patients with AChR antibody concentrations above the median (11.2 nmol/l) had significantly lower mean C3 and C4 concentrations in serum compared to those with AChR antibody concentrations below the median. Titin antibody-positive MG patients, titin antibody-negative early-onset MG patients, titin antibody-negative late-onset MG patients, and controls had similar C3 and C4 concentrations. Nor did mean C3 and C4 concentrations differ in MG patients with RyR antibodies. Patients with severe MG (grades 4 and 5) had similar C3 and similar C4 levels compared to those with mild MG (grades 1 and 2). CONCLUSION: An increased in vivo complement consumption was detected in MG patients with high AChR antibody concentrations, unrelated to MG severity and non-AChR muscle antibodies.
Antibodies↗
[Intravenous immunoglobulin in postpolio syndrome].
BACKGROUND: Postpolio syndrome is characterised by new muscular weakness, pain, and fatigue several decades after the acute polio, and affects approximately 1/4 of patients with previous paralytic polio. MATERIAL AND METHODS: A 47-year-old woman with a previous history of acute poliomyelitis developed progressive muscular weakness in her left arm and right leg with muscular pain and fatigue. Clinical examination, MRI, and electromyography gave no other explanation to her progressive muscular weakness and fatigue than postpolio syndrome. She was treated with 400 mg/kg immunoglobulin intravenously for five consecutive days. RESULTS: At follow-up two and three months later, she had a considerable increase in isokinetic muscle strength in knee extension and flexion on the right side, and experienced less fatigue. INTERPRETATION: This case suggests that stabilisation of an autoimmune dysfunction may be a therapeutic option in postpolio syndrome.
Electromyography↗
[Thymectomy and muscle antibodies in myasthenia gravis].
BACKGROUND: Thymectomy as a treatment for myasthenia gravis (MG) is widely carried out as there is good clinical evidence for post-thymectomy improvement in younger MG patients. MATERIAL AND METHODS: We examined the relationship between thymectomy, MG severity, the occurrence of muscle autoantibodies against acetylcholine receptor (AChR), titin, and ryanodine receptor (RyR), and pharmacological treatment in 52 early and 43 late-onset MG patients. RESULTS AND INTERPRETATION: Thymectomy in early-onset MG gave a rapid, highly significant, and long-lasting improvement during the first one to two years after surgery. Several patients had a remission. In late-onset MG, thymectomy did not provide the same improvement, but these patients responded well to immunosuppressive drug treatment, which was necessary in 75% of late-onset MG patients compared to only 25% of early-onset patients. The concentration of AChR, titin, and RyR antibodies did not predict the outcome of thymectomy. The occurrence of titin/RyR antibodies in late-onset MG indicated a less favorable prognosis.
Adolescent↗
Lifestyle and late effects after poliomyelitis. A risk factor study of two populations.
BACKGROUND: Patients with polio often experience new symptoms (muscle weakness, pain, fatigue and respiratory problems) many years after the acute disease. This study examined possible interactions between lifestyle factors (overweight, physical inactivity, smoking) and late polio with new symptoms. METHODS: A total of 148 patients hospitalized for acute polio in 1950-1954 at Haukeland University Hospital, Norway and 128 patients, hospitalized for acute polio in 1958 at Tartu University Hospital, Estonia responded to a mailed questionnaire regarding lifestyle and late polio with new symptoms. Multiple regression analysis, two samples t-test and chi-square analysis were undertaken. RESULTS: Mean body mass index (BMI) and percentage of smokers did not differ in the two cohorts, while polio patients were physically less active in Estonia. The physically active patients in both cohorts had significantly lower odds for experiencing polio-related late muscle pain (OR = 0.21; 95% CI = 0.08-0.55) and fatigue (OR = 0.32; 95% CI = 0.14-0.75). With increasing age the patients had significantly higher odds for experiencing new muscle weakness (OR = 1.03; 95% CI = 1.00-1.07), fatigue (OR = 1.04;95% CI = 1.01-1.07) and breath shortness (OR = 1.04; 95% CI = 1.00-1.07). CONCLUSION: Physically inactive patients are at a higher risk for late polio-related symptoms. An active lifestyle should be recommended for patients with polio sequels.
Adult↗
Guidelines by the European Federation of Neurological Societies (EFNS) subcommittee for Continuing Medical Education (CME)--modification 2003.
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Education, Medical, Continuing↗
Myasthenia gravis: consequences for pregnancy, delivery, and the newborn.
OBJECTIVE: To investigate the effect of maternal myasthenia gravis (MG) on giving birth and on the newborn. METHODS: A retrospective cohort study for 1967 through 2000 was undertaken, using data from the Medical Birth Registry of Norway, based on the compulsory notification of all births. The target group consisted of 127 births by mothers with MG. The reference group consisted of all 1.9 million births by mothers without MG. RESULTS: Women with MG had a higher rate of complications at delivery (40.9% vs 32.9%, p = 0.05), and in particular the risk of preterm rupture of amniotic membranes was three times higher in the MG group compared to the reference group (5.5% vs 1.7%, p = 0.001). The rate of interventions during birth was raised (33.9% vs 20.0%, p < 0.001) and cesarean sections doubled (17.3% vs 8.6%, p = 0.001). Five children (3.9%) born by MG mothers had severe anomalies, and three of them died. CONCLUSIONS: MG is associated with an increased risk for complications during delivery. This is linked to a higher occurrence of interventions during birth.
Adult↗
[The genetic basis of muscle disease].
BACKGROUND: Our understanding of the genetic basis of muscle disease has grown dramatically over the last few years. Gene tests are now available for the diagnosis of several conditions and molecular research is providing greater understanding of pathogenesis. MATERIAL AND METHODS: This article reviews some of these advances. RESULTS: Duchenne and Becker muscular dystrophies are allelic disorders that differ in age of onset and severity. This can be explained at the genetic level by different types of mutations, one giving total protein loss (Duchenne) whereas the other results in a less severe deficiency (Becker). Facioscapulohumeral muscular dystrophy is associated with deletion involving repeated DNA in the sub-telomeric region of chromosome 4. No single gene responsible for this disorder has been identified, but we know that deletion size correlates with disease severity. Interestingly, complete removal of this region does not result in disease. Limb girdle muscular dystrophies share a similar phenotype, but genetic and protein studies show that this can be the result of mutation in very different types of protein including a protease. There are now two forms of myotonic dystrophy, both caused by what are called expansions, an increased number of triplet repeats. Both forms demonstrate multisystem involvement and in both cases more than one genetic mechanism has been shown to be active. Certain muscle diseases appear more common in Scandinavia. Amongst these are the distal myopathies in which one type prevalent in Finland has been linked to defects in the titin protein. INTERPRETATION: The challenge is now to translate the advances in our understanding of genetic mechanism into potential forms of treatment. Unfortunately, while much research is focused on techniques such as gene therapy, myoblast transplantation and the use of stem cells, these have not yet born fruit.
Genetic Techniques↗
[Research and specialty associations of the Medical Society].
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Humans↗
Ryanodine receptor antibodies in myasthenia gravis: epitope mapping and effect on calcium release in vitro.
Patients with myasthenia gravis can have antibodies against skeletal muscle ryanodine receptor (Ry1), the sarcoplasmic reticulum calcium-release channel, which plays a crucial role in excitation-contraction coupling. We have screened a panel of overlapping Ry1 fusion proteins with Ry1 antibody-containing myasthenia gravis sera to identify the main immunogenic region. The pc2 Ry1 fusion protein representing a Ry1 region close to the N-terminus (residues 799-1172) was identified as the main immunogenic region for the antibodies. The binding kinetics of the Ry1 antibodies to the pc2 Ry1 fusion protein were tested using an optical biosensor. Ry1 antibodies in the IgG fraction from sera of patients with myasthenia gravis bound with high affinity and with a stoichiometry of 1:1. The functional effect of these Ry1 antibodies was tested in an in vitro Ca2+-release assay. The Ry1 antibodies induced a twofold increase of the half-maximal concentration for 4-Cl-m-cresol-induced Ca2+ release from terminal cisternae vesicles but had no effect on V(max). The effect on 4-Cl-m-cresol-induced Ca2+ release was specific, as preincubation of the active IgG fraction with the pc2 Ry1 fusion protein abolished the inhibition. These data suggest that the Ry1 sequence defined by residues 799-1172 is involved in the regulation of Ry1 function, and that this regulation could be functionally affected in vivo in patients with myasthenia gravis.
Autoantibodies↗
Pathogenesis of myositis and myasthenia associated with titin and ryanodine receptor antibodies.
Some myasthenia gravis (MG) patients have antibodies against skeletal muscle antigens in addition to the acetylcholine receptor (AChR). Two major antigens for these antibodies are the Ca(2+) release channel of the sarcoplasmic reticulum, the ryanodine receptor (RyR), and titin, a gigantic filamentous muscle protein essential for muscle structure, function, and development. RyR and titin antibodies are found in MG patients with a thymoma and in a proportion of late-onset MG, and they correlate with severe MG disease. The RyR antibodies recognize a region near the N-terminus important for channel regulation. They inhibit Ca(2+) release from sarcoplasmic reticulum in vitro. There is electrophysiological evidence for a disordered excitation-contraction coupling in MG patients. The presence of titin antibodies, which bind to key regions near the A/I junction and in the central I-band, correlates with myopathy in MG patients. However, so far, there is no direct evidence that antibodies against the intracellular antigens RyR and titin are pathogenic in vivo.
Animals↗
Myasthenia gravis in individuals over 40.
Myasthenia gravis (MG) in individuals over 40 years of age comprises three groups: early-onset MG with prolonged disease duration, late-onset MG with thymoma, and late-onset of nonthymomatous MG. The clinical features do not differ between the three groups, except that early-onset patients with prolonged disease duration usually have a less severe disease. More than 60% of our MG patients are now more than 50 years of age, often with disease onset after age 40. Although 2 out of the 3 patients in Erb's original description had onset of myasthenic symptoms after age 40, this was apparently infrequent in 1879, when the disease was first identified. Onset of MG after age 40 is now common. For example, in our material, 88/184 (47.8%) had onset of MG after age 40. Eighteen (20.5%) had a thymoma. The female:male ratio in the early-onset group was 2.4:1, whereas it was 1:1.1 among those with onset after age 40. There was no human leukocyte antigen association for MG with thymoma. Antibodies to the acetylcholine receptor were detected in 88% of sera from nonthymomatous MG and in 100% of those with late-onset MG with thymoma. Antibodies to titin were found in sera from 85.7% of MG patients with thymoma (all age groups) and in 58% of nonthymomatous MG with late onset and acetylcholine receptor antibodies. Late-onset, nonthymomatous MG comprises two subgroups, one corresponding to delayed early onset and one immunologically similar to that seen in patients with MG and thymoma.
Adult↗
Three forms of immune myasthenia.
We propose a new classification for immune myasthenia based on antibody pattern. The types of immune myasthenia presently characterized by known antibody targets segregate into three groups: type 1, in which the muscle target is the acetylcholine receptor only; type 2, in which titin antibodies are present in addition to acetylcholine receptor antibodies; and type 3, in which muscle-specific kinase antibodies are present in the absence of acetylcholine receptor antibodies. The immune target is unknown in the patients with immune myasthenia not associated with these antibodies. This classification has advantages over the present classifications as regards homogeneity of groups, etiology, mechanism of disease, and prognosis.
Antibodies↗