Diagnostic sensitivity of the laboratory tests in myasthenia gravis.

The diagnostic sensitivity of three laboratory tests [serum antiacetylcholine receptor antibody (AChR-ab) assay, the repetitive nerve stimulation (RNS) test, and, the single fiber EMG (SFEMG)] for myasthenia gravis (MG) was compared in 120 patients. In all cases, at least one of the tests was abnormal. SFEMG was the most sensitive test, being abnormal in 92% of cases, followed by the RNS test (77%) and the AChR-ab assay (73%). SFEMG was abnormal in all cases with negative AChR-ab and RNS tests, in 97% of cases with negative AChR-ab assay, in 89% of cases with negative RNS test, and in 89% of cases with mild MG. We conclude that one of these three tests is abnormal in all cases of MG, and that the SFEMG is most sensitive in the diagnosis of MG.     

Seronegative myasthenia gravis: disease severity and prognosis

Around 10-20% of myasthenia gravis (MG) patients do not have acetylcholine receptor (AChR) antibodies (seronegative), of whom some have antibodies to a membrane-linked muscle specific kinase (MuSK). To examine MG severity and long-term prognosis in seronegative MG compared with seropositive MG, and to look specifically at anti-AChR antibody negative and anti-MuSK antibody negative patients. Seventeen consecutive seronegative non-thymomatous MG patients and 34 age and sex matched contemporary seropositive non-thymomatous MG controls were included in a retrospective follow-up study for a total period of 40 years. Clinical criteria were assessed each year, and muscle antibodies were assayed. There was no difference in MG severity between seronegative and seropositive MG. However, when thymectomized patients were excluded from the study at the year of thymectomy, seropositive MG patients had more severe course than seronegative (P < 0.001). One seropositive patient died from MG related respiratory insufficiency. The need for thymectomy in seronegative MG was lower than in seropositive MG. None of the seronegative patients had MuSK antibodies. This study shows that the presence of AChR antibodies in MG patients correlates with a more severe MG. With proper treatment, especially early thymectomy for seropositive MG, the outcome and long-term prognosis is good in patients with and without AChR antibodies.     

Frequency of seronegativity in adult-acquired generalized myasthenia gravis

We determined the prevalence of muscle acetylcholine receptor (AChR) antibodies in patients with adult-acquired generalized myasthenia gravis (MG), the seroconversion rate at 12 months, and the prevalence of muscle-specific tyrosine kinase (MuSK) antibody among persistently seronegative patients. We identified 562 consecutive Mayo Clinic patients with MG based on clinical and electrophysiological criteria. At presentation, 508 patients (90.4%) tested positive for AChR binding or AChR modulating antibodies. After 12 months, 15.2% of initially seronegative patients had become seropositive, yielding a seronegativity rate of 8.2% (95% confidence interval: 6.2-9.6%). Among seronegative patients not receiving immunosuppressants, 38% were MuSK antibody-positive and 43% were seropositive for nonmuscle autoantibodies. Classification as seronegative MG should be reserved for nonimmunosuppressed patients with generalized MG who lack muscle AChR binding, AChR modulating, or MuSK antibodies at presentation and at follow-up of at least 12 months.     

Single-fiber electromyography in limb and facial muscles in muscle-specific kinase antibody and acetylcholine receptor antibody myasthenia gravis

We examined the findings from single-fiber electromyography in extensor digitorum communis (EDC) and orbicularis oculi (OOc) in 13 myasthenia gravis (MG) patients with muscle-specific kinase antibodies (MuSK-MG) and 12 MG patients with acetylcholine receptor antibodies (AChR-MG) with similar clinical scores. More than 70% of AChR-MG patients had abnormal jitter in both EDC and OOc, but the majority of MuSK-MG patients had normal jitter in EDC despite abnormal jitter in OOc. These findings demonstrate clear differences between the neurophysiology of MuSK-MG and AChR-MG.     

Rituximab in refractory myasthenia gravis: Extended prospective study results

Introduction: Rituximab appears to be beneficial in treatment‐refractory myasthenia gravis (MG); however, prospective, long‐term durability data are lacking. Methods: In this prospective, open‐label study of rituximab in refractory MG, 22 patients (10 nicotinic acetylcholine receptor, 9 muscle‐specific tyrosine kinase, 3 seronegative) received rituximab at baseline, with repeat cycles driven by clinical worsening. Manual muscle testing (MMT) scores and CD19/CD20⁺ B‐cell counts were serially monitored. Results: At mean follow‐up of 28.8 ± 19.0 months (range, 6–66), mean MMT scores declined from 10.6 ± 5.4 to 3.3 ± 3.1 (P < 0.0001). Mean prednisone dosage declined from 25.2 ± 15.1 to 7.3 ± 7.1 mg/d (P = 0.002). Ten relapses occurred, with average time to first relapse of 17.1 ± 5.5 months (range, 9–23). CD19/CD20⁺ count recovery did not predict relapse. Three patients experienced prolonged B‐cell depletion (range, 24–45 months) after 1 cycle. Discussion: Sustained clinical improvement was associated with rituximab after 1 cycle, with prolonged time to relapse and reduction in steroid dosage. Muscle Nerve 58 : 453–456, 2018     

MuSK-positive myasthenia gravis is rare in the Polish population

Background and purpose:  MuSK-positive myasthenia gravis (MG) is diagnosed in 0–48% of cases with generalized seronegative MG in different populations. The presence of anti-MuSK antibodies generally relates to a severe course and lack of response to thymectomy. We analyzed for the first time the serology and clinical characteristics of MuSK-positive MG in the Polish population.
Methods:  One hundred and fifty-one patients were tested for the presence of anti-AChR and anti-MuSK antibodies: 62 with seronegative MG, including 14 with ocular seronegative MG, 48 age-matched patients with seropositive MG and 41 controls.
Results: All patients with seropositive MG and the disease controls were MuSK-negative. Anti-MuSK antibodies were detected only in four patients with seronegative MG (8.7% of generalized seronegative cases): three women and one man. All four had predominantly bulbar involvement, and underwent thymectomy, with no apparent benefit. All of them improved clinically after immunosuppressive treatment with remissions lasting up to 7 years.
Conclusion: MuSK-positive MG is rare in Polish population accounting for only 8.7% of seronegative cases with generalized MG. This is consistent with emerging evidence for lower MuSK antibodies at more northerly latitudes.     

Thymectomy in late-onset myasthenia gravis

Two cases of late-onset myasthenia gravis were successfully treated by thymectomy using a sternal splitting technique, in spite of the fact that no thymomas could be detected preoperatively. One patient was seriously ill, the other patient responded to medical treatment. Thymolipoma and malignant thymoma, respectively, were removed from the patients. It is stressed that not all thymomas produce antibodies to striated muscles and that CT-scan of the mediastinum is of limited value in the diagnosis of thymoma. It is suggested that patients with late-onset myasthenia gravis be offered thymectomy, even in the absence of detectable thymomas.     

Thymectomy in myasthenia gravis a review

The role of thymectomy in the management of myasthenia gravis is reviewed in the light of the published data and of a personal series. The patients in whom the operation is most successful are non thymomatous patients aged between 10 and 40 years with an MG history of less than 3 years. There is no sex prevalence. Lasting improvement may be expected. There are no proven correlations between biological indices like the germinal centers in the thymus and/or AChR antibody titers and the postoperative course of the disease. Complete removal of the thymus seems to be crucial and hence the transsternal approach is preferred. The operation, less effective in patients with thymona than in those with an active thymus, is nonetheless necessary to in these patients prevent putative damage to surrounding organs from thymona infiltration. Why thymectomy should be effective in patients with an active thymus and not in those with a thymona may be revealed by in vitro studies of the interactions between thymic cells and peripheral B cells, now in progress.

---

Sommario Viene rivisto alla luce dei dati della letteratura e della casistica personale il ruolo della timectomia nella terapia della miastenia. Dei pazienti non portatori di timoma i migliori risultati si ottengono in quelli di età fra i 10 e i 40 anni con una durata della malattia minore di tre anni. Non vi è prevalenza di sesso. Ci si può attendere un miglioramento duraturo. Non vi sono prove di una correlazione tra gli indici biologici germinativi quali i centri germinali nel timo e o il titolo degli anticorpi contro i ricettori acetilcolinici e il decorso post-operatorio della malattia. É fondamentale la completa asportazione del timo e perciò è preferibile la scelta della tecnica di approccio transternale. Nei pazienti con timoma la timectomia è meno efficace ma l'intervento è necessario per evitare danni derivanti dall'infiltrazione del timoma sugli organi circostanti. Il perché della efficacia della timectomia nei pazienti con un timo attivo ma non in quelli con timoma potrà essere chiarito dagli studi in vitro sulle interazioni tra cellule timiche e quelle periferiche B, studi che sono ormai in stadio avanzato.

     

Cardiac involvement in myasthenia gravis

Non-specific ECG changes and histological changes in the myocardium in patients with myasthenia gravis (MG) have been described. In this study, the left ventricular function using systolic time intervals (STI) was assessed in patients with MG. 4 patients out of the 10 studied showed abnormalities of the STI which reverted towards normal after injection of neostigmine. This finding suggests that myocardial involvement in MG may be more common than clinically suspected.     

The cerebrospinal fluid in myasthenia gravis

We examined the number of leucocytes and the concentration of total protein, albumin and IgG in the cerebrospinal fluid (CSF) from 46 patients with myasthenia gravis (MG) and 50 controls. Mean leucocyte number in the MG patients was 1634 cells/ml (controls 1244), mean total protein 0.38 g/l (controls 0.32), mean IgG 0.034 g/l (controls 0.025) and mean albumin 0.199 g/l (controls 0.176). No evidence of intrathecal IgG synthesis was demonstrated. The CSF was normal in most cases. When pathological changes occurred they were slight and could be attributed to associated diseases or to iatrogenic blood contamination of the CSF. We demonstrated that an artificial blood contamination of the CSF, although macroscopically undetectable, increased the CSF albumin concentration and the CSF albumin/serum albumin ratio considerably.     

Epidemiology of myasthenia gravis in Norway

The number of patients with myasthenia gravis diagnosed and registered in Norway from 1912-1981 has been collected, representing essentially all diagnosed cases during these 70 years. Until 1948, Oslo University Hospital, the National Hospital, had the only neurological department. in Norway. Since then, neurological departments have been established throughout our country. All these departments and all practising neurologists in Norway responded to the appeal for the necessary information on their diagnosed patients up to the end of 1981. The majority of the results are based on the period 1951-1981. The National Bureau of Statistics has registered the deaths of myasthenia gravis cases since 1951, and since 1956 where it has constituted an underlying or contributory cause. The incidence rate by diagnosis per million population 1951-1981 is 2.6 for males, 5.3 for females and 4 for both sexes. The prevalence per million population is 52 for males, 127 for females and 90 for both sexes. The mortality in males is 144% and in females 155% of the mortality in the population. The excess mortality is much greater in patients below 60 years of age, especially in females where a value of 483% if found.     

Acetylcholine receptor antibody in myasthenia gravis

Radioimmunoassay techniques were used to detect antibodies to the acetylcholine receptor (AAChR) in 164 patients with adult-onset myasthenia gravis. AAChR levels above 0.6 nM/l were considered pathological and were found in 67% of the patients with an average value of 58.99 +/- 125.02 nM/l (0.6-900.0). Correlation, with clinical functional status, the histopathological thymus alterations and the different therapeutics used did not disclose any statistically significant differences.     

Lifetime course of myasthenia gravis

Between 1940 and 2000 a total of 1976 patients with myasthenia gravis (MG) were studied. Diagnosis was made by improvement in weakness after anticholinesterase medication. The historical developments in diagnosis and treatment of MG are reviewed. We analyzed the clinical course of MG as influenced by age, gender, thymectomy, thymomectomy, and the presence of antibodies to acetylcholine receptors (AChR). The clinical course of MG was significantly influenced by age and gender, and these need special attention in managing patients. The most severe level of weakness and high mortality occurred during the first 1 to 2 years of the disease, after which many patients experienced improvement. For treating MG patients the usefulness of thymectomy remains to be proven, and novel drugs need to be developed to increase the number as well as normal functioning of the AChRs and other components of the neuromuscular system.     

Juvenile myasthenia gravis

Juvenile myasthenia gravis shares a similar pathophysiologic origin with adult myasthenia gravis, but there are important differences, mostly relating to epidemiology, presentation, and therapeutic decision making. Gender ratios and the proportion of seropositive patients differ in the pre‐ and postpubertal age groups. The diagnostic evaluation is similar to that in adults, although special techniques are sometimes necessary to perform single‐fiber electromyography in younger patients. Therapeutic decisions in affected children and adolescents are complicated by the greater long‐term consequences of using steroids, and thus other interventions, such as intravenous immunoglobulin (IVIg) and plasmapheresis, may play a greater therapeutic role in this population than in adults. Steroid‐sparing agents may contribute to the management of refractory cases, but they should be used with caution due to the risk of malignancy. Muscle Nerve, 2008     

Myasthenia gravis: Antibodies to acetylcholine receptor in ocular myasthenia gravis

Summary To improve the sensitivity of the radioimmunoassay method for anti-AChR-antibody, large amounts of sera from patients with myasthenia gravis, and higher concentrations of antigens and rabbit anti-human-IgG-antiserum, were used. These procedures enabled measurement of the titre value of over 0.04 pmol/ml serum and this value revealed a sensitivity about 10 times higher than that predicted using the previous model.Antibodies against AChR were found in 13 out of 17 ocular myasthenia patients (70%) and 35 of 37 with generalized myasthenia (90%). However, the average titre value of sera in those with ocular myasthenia was significantly lower than the value obtained in the generalized cases. Even in the patients with ptosis or ophthalmoparesis, in the early stage (less than one year) of ocular myasthenia, anti-AChR-antibodies were not detectable using this more sensitive assay method.

---

Zusammenfassung Um die Empfindlichkeit der Radioimmunoassay-Methode für Anti-AChR-Antikörper zu verbessern, wurden eine große Menge des myasthenischen Serums, höhere Konzentration des Antigens und Kaninchen-Anti-Menschen-IgG-Antiserum gebraucht.Mit dieser Methode konnten wir den Wert über 0.04 pmol/ml Serum vermessen. Diese neue Methode zeigt etwa zehnfach höhere Empfindlichkeit als die vergangenen Methoden.Antikörper gegen AChR waren in 13 von 17 okulären Myastheniepatienten (70%) und in 35 von 37 generalisierten Myastheniepatienten (90%) gefunden worden. Aber der durchschnittliche Messungswert des Serums im Patienten der okulären Form war signifikant niedriger als der der generlisierten Form. Wenn der Patient auch Augenptose oder Augenparese hatte, waren die Anti-AChR-Antikörper mit unserer empfindlichen Methode im Frühstadium (innerhalb eines Jahres) nicht nachgewiesen worden.

     

Cytokines and the pathogenesis of myasthenia gravis

Myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG) are caused by autoantibodies against nicotinic acetylcholine receptor (AChR) in skeletal muscle. The production of anti-AChR antibodies is mediated by cytokines produced by CD4⁺ and CD8⁺ T helper (Th) cells. Emerging investigations of the roles of cytokines in MG and EAMG have revealed that the Th2 cell related cytokine interleukin 4 (IL-4), an efficient growth promoter for B-cell proliferation and differentiation, is important for anti-AChR antibody production. IL-6 and IL-10 have similar effects. The Th1 cytokine IFN-γ is important in inducing B-cell maturation and in helping anti-AChR antibody production and, thereby, for induction of clinical signs and symptoms. Results from studies of time kinetics of cytokines imply that IFN-γ is more agile at the onset of EAMG, probably being one of the initiating factors in the induction of the disease, and IL-4 may be mainly responsible for disease progression and persistance. Even though other Th1 cytokines like IL-2, tumor necrosis factor α (TNF-α), and TNF-β as well as the cytolytic compound perforin do not directly play a role in T-cell-mediated help for anti-AChR antibody production, they are actually involved in the development of both EAMG and MG, probably by acting in concert with other cytokines within the cytokine network. In contrast, transforming growth factor β (TGF-β) exerts immunosuppressive effects which include the down-regulation of both Th1 and Th2 cytokines in MG as well as EAMG. Suppressive effects are also exerted by interferon α (IFN-α). Based on elucidation of the role of cytokines in EAMG and MG, treatments that up-modulate TGF-β or IFN-α and/or suppress cytokines that help B-cell proliferation could be useful to improve the clinical outcome. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 543–551, 1997     

High-dose cyclophosphamide in refractory myasthenia gravis with MuSK antibodies

We describe a 48-year-old woman with seronegative myasthenia gravis (MG) and high-titer of anti-MuSK antibody. She had severe bulbar and respiratory weakness with minimal limb weakness for 2 years. Her disease responded poorly to all the conventional immunosuppressive regimens. Treatment with immunoablative dose of cyclophosphamide led to dramatic and sustained remission of her symptoms. High-dose cyclophosphamide is an effective alternative in patients with unusually refractory disease.