Severe Forms Of Myasthenia Gravis Research Articles

Peripheral Neuropathy and Muscle Disorders as Immune-Related Adverse Events

Neurological immune-related adverse events (irAEs) associated with cancer treatment with immune checkpoint inhibitors (ICI) present diverse clinical characteristics. Neurological irAEs affect the peripheral nervous system and muscles more than they affect the central nervous system. Among the various subsets of peripheral neuropathies, polyradiculoneuropathy, which includes Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, stands out as the most severe form, leading to significant muscle weakness. ICIs can induce dysautonomia, including autoimmune autonomic ganglionopathy. Autonomic neuropathy represents a neurological irAE. Neurological irAEs of neuromuscular junctions include myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). Diagnosing MG or myositis independently can be challenging when they occur as irAEs. Myocarditis is sometimes observed as an irAE in patients with MG and can cause both severe heart failure and lethal arrhythmias, resulting in fatal outcomes. Anti-Kv1.4 antibodies are biomarkers of the severe form of MG and myocarditis. The administration of ICI in patients with small cell lung cancer increases the risk of LEMS. The distinction between LEMS is an irAE or a manifestation of paraneoplastic neurological syndrome is unclear as both conditions share common immunological mechanisms.

To measure musk ABS in ACHR AB negative sera: RIPA is more specific, and SPR is more sensitive

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is often a more severe form of MG that presents with a rapid onset and prominent bulbar symptoms. Today, the diagnosis of MuSK MG is heavily reliant on the antibody (Ab) status of the patient. In most laboratories worldwide, the Abs are measured by radio immune precipitation assay (RIPA). We have developed another testing platform using surface plasmon resonance (SPR) technology. Our aim was to measure the clinical sensitivity and specificity for two different MuSK Ab assays.

Clinical characteristics and outcomes of thymoma-associated myasthenia gravis.

Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG. This multicenter study was based on data from a Spanish neurologist-driven MG registry. All patients were aged >18years at onset and had anti-acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed. We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p<0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95-4.68, p<0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15-2.21, p=0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1year, 5years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43-3.63, p=0.001; hazard ratio: 2.46, 95% CI: 1.47-4.14, p=0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up. Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.

Thrombotic microangiopathy in rheumatology: a link between thrombosis and autoimmunity

Uncontrolled hypercoagulation and inflammation (thromboinflammation), which are both independent and closely related and amplifying each other pathological processes, form the basis for pathogenesis of a wide range of diseases and complications, including immuno-inflammatory (autoimmune) rheumatic diseases, with the development of potentially fatal injuries of internal organs. Thrombotic microangiopathy is one of the most prominent prototypes of thromboinflammatory pathological conditions. The close link between environmental factors, hemostasis genetic defects and the complement system, inflammation and autoimmunity as pathogenetic mechanisms of microthrombosis draws particular attention to studying thrombotic microangiopathy in immuno-inflammatory rheumatic diseases, primarily systemic lupus erythematosus, antiphospholipid syndrome and scleroderma renal crisis. In future, these studies may be important for expanding the idea of the role of autoimmune mechanisms in pathogenesis of critical hemostasis disorders in human diseases, and for developing new approaches to therapy. Recently, special attention has been paid to the treatment of systemic lupus erythematosus and antiphospholipid syndrome with eculizumab, which is humanized monoclonal IgG2/4k antibody that blocks the complement component C5a and the membrane attack complex (C5b-9) formation, and which is registered for the treatment of atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, as well as severe forms of myasthenia gravis and neuromyelitis optica. Further studies in this direction will create prerequisites for improving the prognosis not only in patients with orphan disorders, but also for widespread human diseases.

Role of myasthenia gravis auto-antibodies as predictor of myasthenic crisis and clinical parameters

Myasthenia Gravis (MG) is an autoimmune disease of the neuromuscular junction. Like any other autoimmune disorder, it can flare up owing to certain predisposing factors, causing severe symptoms, named myasthenia crisis. The aim of this study is to ascertain any relation of variability of Myasthenia auto-antibodies to myasthenia clinical features especially crisis. It is a cross sectional study, carried out in Rashid Hospital, Dubai. MG patients between 2004-2010 were recruited and followed for minimum 5 years period. Relationship between disease severity, diversity, immunology and other variables was made through chisquare test mainly. A total of 143 patients were included in the study and 102 completed the follow up. Females predominated in number and their onset was relatively earlier than males (p<0.001). Total 58.8% of patients (67% AchR-Ab+ patients, all MuSK-Ab+ and 33% of seronegative) experienced crisis. Seropositive patients had 30% more tendency to develop crisis (p<0.05). Moreover, myasthenia crisis directly proportional to disease severity at presentation. Seropositive MG is severe form of MG and further in this group MuSK-Ab MG showed higher MGFA grading at presentation and more frequent MG crisis. seronegative patients develop crisis at relatively late age. Seropositivity, mechanical ventilation, old age and high starting MGFA grade indicated poor outcome after crisis.

Role of Myasthenia Gravis Auto-Antibodies as Predictor of Myasthenic Crisis and Clinical Parameters

Background: Myasthenia Gravis (MG) is an autoimmune disease of the neuromuscular junction. Like any other autoimmune disorder, it can flare up owing to certain predisposing factors, causing severe symptoms, named myasthenia crisis. Aim: The aim of this study is to ascertain any relation of variability of Myasthenia auto-antibodies to myasthenia clinical features especially crisis. Methods: It is a cross sectional study, carried out in Rashid Hospital, Dubai. MG patients between 2004-2010 were recruited and followed for minimum 5 years period. Relationship between disease severity, diversity, immunology and other variables was made through chisquare test mainly. Result: A total of 143 patients were included in the study and 102 completed the follow up. Females predominated in number and their onset was relatively earlier than males (p<0.001). Total 58.8% of patients (67% AchR-Ab+ patients, all MuSK-Ab+ and 33% of seronegative) experienced crisis. Seropositive patients had 30% more tendency to develop crisis (p<0.05). Moreover, myasthenia crisis directly proportional to disease severity at presentation. Conclusion: Seropositive MG is severe form of MG and further in this group MuSK-Ab MG showed higher MGFA grading at presentation and more frequent MG crisis. seronegative patients develop crisis at relatively late age. Seropositivity, mechanical ventilation, old age and high starting MGFA grade indicated poor outcome after crisis.

Complete stable remission and autoantibody specificity in myasthenia gravis

Patients with myasthenia gravis (MG) are subgrouped as acetylcholine receptor (AChR)-positive, muscle-specific kinase (MuSK)-positive, and AChR/MuSK-negative MG (or double negative [DN]) on the basis of autoantibody assay. We investigated the relationships between autoantibody specificity, main clinical features, and outcome of the disease, in particular the occurrence of complete stable remission (CSR), by means of a retrospective study on a cohort of 677 Italian patients with MG. A total of 517 (76%) patients with AChR-positive MG, 55 (8%) patients with MuSK-positive MG, and 105 (16%) patients with DN MG were included in the study. Kaplan-Meier and Cox proportional hazard regression analyses were used to evaluate associations between baseline characteristics, antibody specificity, and CSR. Clinical stage at onset and at maximal worsening was more severe for MuSK-positive patients: bulbar impairment at maximal worsening was found in 83.6% of MuSK-positive patients compared with 58.6% of AChR-positive patients and 43.8% of DN patients (p < 0.001). Baseline characteristics of AChR-positive and DN patients were similar. CSR was observed in 3.6% of MuSK-positive patients compared with 22.2% of AChR-positive and 21.9% of DN patients. In the whole MG cohort, onset before age 40 (hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.27-3.02, p = 0.002) and ocular and generalized clinical stages at maximal worsening were associated with CSR (ocular, HR = 8.05, 95% CI 1.88-34.53, p = 0.005; generalized, HR = 3.71, 95% CI 1.16-11.90, p = 0.023; bulbar, HR = 3.16, 95% CI 1.00-10.05, p = 0.051). MuSK antibodies identify a clinically distinguishable, more severe form of MG since the disease onset, with a lower occurrence of CSR. These features should be considered by the clinician in the management of this particular form of MG.

Acute Severe Animal Model of Anti–Muscle-Specific Kinase Myasthenia

To determine the pathogenesis of anti-muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies characterized by focal muscle weakness and wasting and absence of acetylcholine receptor antibodies, and to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ. Design, Setting, and Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically, and by repetitive stimulation of the median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy. Animals immunized with 100 μg of MuSK 60 developed severe progressive weakness starting at day 16, with 100% mortality by day 27. The weakness was associated with high MuSK antibody titers, weight loss, axial muscle wasting, and decrementing compound muscle action potentials. Light and electron microscopy demonstrated fragmented NMJs with varying degrees of postsynaptic muscle end plate destruction along with abnormal nerve terminals, lack of registration between end plates and nerve terminals, local axon sprouting, and extrajunctional dispersion of cholinesterase activity. These findings support the role of MuSK antibodies in the human disease, demonstrate the role of MuSK not only in the development of the NMJ but also in the maintenance of the mature synapse, and demonstrate involvement of this disease in both presynaptic and postsynaptic components of the NMJ.

Racial differences in myasthenia gravis in Alabama.

Demographic, clinical, and laboratory features were compared in 235 white and African-American (AA) patients with myasthenia gravis (MG) at the University of Alabama at Birmingham Neuromuscular Disease Clinic from May 2003 to January 2008. Seventy nine percent of patients were white. Acetylcholine receptor antibody was positive in 71% of white patients and in 59% of AA. In patients with seronegative generalized MG, the rate of positive muscle-specific tyrosine kinase antibody (MuSK-Ab) was significantly higher in AA than it was in whites (50% in AA vs. 17% in whites). Ocular MG was seronegative in 75% of AA patients. In AA, MG occurred earlier and more frequently in females, whereas, in whites, disease onset was later and more common in males. Another significant difference was a higher percentage of abnormality on repetitive nerve stimulation in AA. There was also a tendency for more severe forms of MG in AA. There are racial differences in MG between whites and AA in Alabama. These racial differences highlight the need to study biological factors in the pathogenesis of MG and to assess different approaches in diagnosis and treatment.

High doses of immunoglobulin g in the therapy for severe forms of myasthenia gravis and Guillain-Barré syndrome

High doses of immunoglobulin G (IVIG) have been recognized as a very important therapeutic modality in the treatment of neurological diseases. The aim of this report was to present our experience in the treatment of severe forms of myasthenia gravis (MG) and Guillain-Barré syndrome (GBS). We analyzed the efficacy and safety of immunoglobulin G therapy in 53 patients with severe forms of myasthenia gravis, and 27 patients with very severe forms of Guillain-Barré syndrome. At the end of the follow-up period, a significant improvement was noticed in 47 out of 53 patients with myasthenia gravis (88.7%). In the group of 27 patients with severe forms of Guillain-Barré syndrome an improvement was registered in 19 patients (70.3%). The side effects of this therapy were mostly mild, manifested as headache, myalgia, skin rash, adynamia, and other clinically insignificant effects. No severe side effects were recognized. Our study clearly demonstrated the high efficacy of IVIG therapy in the treatment of severe forms of myastehnia gravis and Guillain-Barré syndome.

Novel autoantibodies to a voltage-gated potassium channel K V1.4 in a severe form of myasthenia gravis

Sera from patients with myasthenia gravis (MG) were screened for autoantibodies to skeletal muscle-specific antigens by immunoprecipitation assay, using rhabdomyosarcoma and leukemia cell lines. Eleven of 61 MG sera immunoprecipitated a rhabdomyosarcoma-specific 70-kDa protein, which was identified as the voltage-gated K + channel 1.4 (K V1.4). This antibody specificity was not detected in 30 patients with polymyositis/dermatomyositis, 9 with thymoma alone, or 30 healthy controls. Clinical features associated with anti-K V1.4 antibody included bulbar involvement, myasthenic crisis, thymoma, myocarditis, and QT prolongation on electrocardiogram. These findings suggest that anti-K V1.4 antibody is a novel autoantibody associated with a severe MG subset and thymoma.

Thoracoscopic Thymectomy in Children with Myasthenia Gravis

Although conservative medical management is the mainstay in the treatment of myasthenia gravis (MG), severest forms of the disease often require surgical thymectomy. Thoracoscopic thymectomy (TT) represents a minimally invasive alternative to traditional thymectomy via sternotomy. We present our preliminary experience with TT as definitive treatment for severe forms of MG. The charts of 5 children (4 girls and 1 boy; age range, 11-17 years) who underwent TT for MG were retrospectively reviewed. TT was typically performed via left thoracoscopy using 4- or 5-mm ports with 1 of the ports enlarged at the end of the procedure for specimen retrieval. Thymic veins were identified and ligated with surgical clips in all cases. Surgical parameters assessed were the following: operating time, intra- and postoperative complications, length of postoperative stay, and resolution of symptoms. Follow-up ranged from 6 months to 2 years. All 5 TTs were successfully completed. In 1 case, right-sided thoracoscopy was added to ensure complete gland excision. Surgical pathology in all cases demonstrated complete excision. Mean operating time was 121 minutes (range 88 minutes to 188 minutes). There were no intra- or postoperative complications. Length of postoperative stay averaged 1.6 days (range, 1 to 3 days). Four of 5 (80%) had clear resolution of symptoms with 1 showing minimal resolution at 6 months. Thoracoscopic thymectomy is a safe and potentially attractive alternative to traditional thymectomy via median sternotomy in severe forms of myasthenia gravis. Complete thymectomy, the goal of traditional surgical treatment for myasthenia gravis, can effectively by achieved via this minimally invasive technique.

Distal Myasthenia Gravis With a Decrement, an Increment, and Denervation

We present two patients with distal myasthenia gravis poorly responsive to immunomodulatory therapy. In addition to a typical decrement on slow repetitive nerve stimulation, both had borderline to low compound muscle action potential (CMAP) amplitudes, a large increment in CMAP amplitude and area after exercise, and active denervation in distal muscles. Both had elevated acetylcholine receptor antibody (AChR Ab) levels, but normal voltage-gated calcium channel antibody levels. We hypothesize that these electrophysiological findings represent a more severe form of myasthenia gravis.

Titin and ryanodine receptor autoantibodies in dogs with thymoma and late-onset myasthenia gravis

Similar to human autoimmune myasthenia gravis (MG), canine MG occurs spontaneously and is associated with autoantibodies against the nicotinic acetylcholine receptor (AChR). In addition to AChR, human MG patients with thymoma or late-onset MG have antibodies against titin and ryanodine receptor (RyR). The objective of this study was to establish if dogs with confirmed MG (AChR antibody titer >0.6 nmol/l) also developed titin and RyR antibodies and identify possible associations with thymoma, late age of onset, or severity of clinical signs. Sera from dogs ( n=430) with previously diagnosed autoimmune MG ( N=415), other immune-mediated neuromuscular disorders including polymyositis (PM) and masticatory muscle myositis ( N=5), and control dogs ( N=10) were evaluated for the presence of titin antibodies in ELISA using MGT-30 as antigen, a peptide representing the main immunogenic region (MIR) for human titin antibodies. Titin antibody positive sera were further examined for RyR antibodies in Western blots using a RyR fusion protein (pc2–RyR) as antigen, which covers the MIR for human MG sera. Titin antibodies were found in sera of 80/430 dogs. Thymoma was present in 11/80 and age of onset was after 4 years in 66/80 titin positive dogs. Two of the titin positive dogs had PM. RyR antibodies were found in 13/80 sera (8/13 thymoma, 12/13 age of onset after 4 years, and 1/13 PM). Neither titin nor RyR antibodies were found in sera of healthy control dogs. Acute fulminating MG was described in five dogs with both titin and RyR antibodies. From these studies we conclude that titin and RyR antibodies in canine and human MG have a similar association with thymoma, late-onset MG, and possibly with more severe forms of MG.

Therapeutic apheresis in myasthenia gravis.

Plasma exchange (PE) is an easily applicable technique for rapid and massive removal of antibodies, and its beneficial role is well established in the management of myasthenia gravis (MG), an antibody-mediated disorder of the neuromuscular junction. PE is useful in myasthenic crisis, in most severe forms of MG before thymectomy, in the early postoperative period, and in cases of symptom worsening during tapering or initiation of immunosuppressive therapy. Clinical efficacy varies from 55% to 100%, and improvement rarely persists for more than 4-10 weeks; thus immunosuppressive therapy has to be associated. New apheretic techniques (double filtration plasmapheresis, immunoadsorption systems with staphylococcal protein A columns or thryptophan-polyvinyl alcohol gel columns) that allow the selective removal of IgG and anti-AChR antibody were recently used in the management of MG with positive effects. Whether their therapeutic effect and cost effect prove more favorable than those obtained by PE still must be demonstrated.

Atrophy of the Tongue with Persistent Articulation Disorder in Myasthenia Gravis: Report of 10 Patients

Ten patients with atrophy of the tongue, from a group of 752 with generalized acquired myasthenia gravis (MG), were studied. Tongue atrophy developed late in the majority of patients and was accompanied by tongue paresis (70% of the cases) and eventually associated to atrophy of other muscles of the palate, especially the uvula. All the patients exhibited severe forms of MG with bulbar involvement, mainly persistent dysphonia and dysphagia, almost always refractory to treatment. There is no correlation among atrophy of the tongue, sex, and thymus pathology. There is correlation between severeness of symptoms and early, persistent and treatment refractory dysphonia and dysphagia.

Immunosuppressive treatment for juvenile myasthenia gravis.

The result of immunosuppressive treatment in 20 cases of generalized myasthenia gravis with onset before age 16 were analysed. The patients age at the beginning of immunosuppressive treatment ranged from 10 to 22 years. Thirteen patients suffered from a severe form of myasthenia gravis with respiratory attacks, the remaining 7 demonstrated a moderately severe form with bulbar symptoms dominating the clinical picture. Indication for immunosuppressive treatment was lack of or only slight improvement after thymectomy. Prednisone was used in 17 cases, high dosage of methylprednisolone in 8 (in one case twice), azathioprine in 11 and cyclophosphamide in 10. Best results were obtained with cyclophosphamide since significant improvement was recorded in 14/20 of patients. Corticosteroids, i.e. prednisone and high-dose methylprednisolone proved to be of limited value.

Long-term results of corticosteroid therapy in patients with myasthenia gravis.

We studied the long-term outcome of prednisone therapy in 104 patients with myasthenia gravis (MG). At the end of the follow-up period, good therapeutic results were recorded in 85 patients (81.7%), poor results in 13 (12.5%) and no significant change of MG status in 6 (5.8%). We found a correlation between the duration of treatment and the incidence of steroid side effects. The presence of thymoma and severe forms of MG were associated with relapsing disease requiring prolonged corticosteroid regimens. The age at the start of therapy did not influence significantly the response to treatment.

A short plasma exchange protocol is effective in severe myasthenia gravis

Plasma exchange has been reported to be a successful therapeutic procedure for the treatment of severely compromised myasthenic patients, but the optimal regimen in terms of costs or clinical benefit has not so far been determined. We have investigated the efficacy of a short plasmapheresis protocol of two exchanges 1 day apart in a series of 70 patients with severe forms of myasthenia gravis. Patients were evaluated before and 7 days after the first exchange. A positive outcome was observed in 70% of the plasma exchange cycles performed. Disease severity did not seem to be a negative prognostic factor for the efficacy of this short protocol, which was well tolerated by patients. In only 1 case were major side-effects observed. In spite of its short duration, the exchange treatment plus concomitant immunosuppressive drug therapy was not followed by early clinical deterioration.

Effect of prethymectomy plasma exchange on postoperative respiratory function in myasthenia gravis

The effect of prethymectomy plasma exchange on postoperative mechanical ventilation requirement and length of stay in the intensive care unit were studied retrospectively in 37 patients with myasthenia gravis. We found a significantly decreased time on mechanical ventilation (mean 1.02 +/- 0.40 versus 3.43 +/- 0.60 days) and a shorter stay in the intensive care unit (mean 3.09 +/- 0.99 versus 5.15 +/- 0.66 days) for 11 patients with respiratory weakness who were treated with preoperative plasma exchange compared with 26 patients who did not receive plasma exchange. Patients with respiratory weakness who received prethymectomy plasma exchange required less time on mechanical ventilation (mean 1.02 +/- 0.40 versus 2.73 +/- 0.88 days) and a shorter stay in the intensive care unit (mean 3.09 +/- 0.99 versus 4.46 +/- 1.08 days) than those patients without respiratory weakness who did not receive plasma exchange. Eleven patients met the criteria for plasma exchange but did not receive it. They required significantly more time on mechanical ventilation (mean 4.43 +/- 0.94 versus 1.02 +/- 0.40 days) and in the intensive care unit (mean 6.09 +/- 0.86 versus 3.09 +/- 0.99 days) than patients who received plasma exchange. Our results indicate that patients with severe forms of myasthenia gravis treated with prethymectomy plasma exchange require less mechanical ventilation and less time in the intensive care unit postoperatively.