Multiple paraneoplastic diseases associated with thymoma

Here we report a patient with a lymphoepithelial thymoma who developed in chronological sequence limbic encephalitis, neuromyotonia and myasthenia gravis.

The patient presented with limbic encephalitis associated with an invasive thymoma and improved after surgery and cytotoxic therapy. Two months after thymectomy, neuromyotonia associated with hyperhidrosis and mild motor neuropathy occurred and the patient was given plasma-exchange and prednisone therapy. Five months later he developed mild generalised myasthenia gravis. Anti-acetylcholine receptor antibodies, previously repeatedly negative, were found positive at the onset of clinical signs of myasthenia gravis.     

Development of generalized disease at 2 years in patients with ocular myasthenia gravis

BACKGROUND: Generalized myasthenia gravis will develop in more than 50% of patients who present with ocular myasthenia gravis, typically within 2 years. The optimal treatment of ocular myasthenia gravis, including the use of corticosteroids, remains controversial. In addition, the prevalence of thymoma and the optimal performance of the edrophonium chloride test for ocular myasthenia remain unknown. OBJECTIVE: To assess the effect of oral corticosteroid therapy on the frequency of development of generalized myasthenia gravis within 2 years, the incidence of thymoma, and the amount of edrophonium needed for a positive test result in patients with ocular myasthenia gravis. METHODS: We reviewed an ocular myasthenia gravis database of 147 patients. Patients underwent measurement of acetylcholine receptor (AChR) antibody levels and chest computed tomography. Unless contraindicated, patients with diplopia were recommended for therapy with prednisone, up to 40 to 60 mg/d, with the dosage tapered for 5 to 6 weeks. Most continued to receive daily or alternate-day doses of 2.5 to 10 mg to prevent diplopia. Patients not given prednisone (untreated group) received pyridostigmine bromide or no medication. After the diagnosis, we documented the signs and symptoms of ocular and generalized myasthenia gravis and performed 2-year follow-up in 94 patients. RESULTS: The mean dose of edrophonium chloride to give a positive response was 3.3 mg (SD, 1.6 mg) for ptosis and 2.6 mg (SD, 1.1 mg) for ocular motor dysfunction. Thymoma occurred in 1 patient (0.7%). Generalized myasthenia gravis developed within 2 years in 4 of 58 treated and 13 of 36 untreated patients. The odds ratio (OR) for development of generalized disease in the treated group was 0.13 (95% confidence interval [CI], 0.04-0.45) compared with the untreated group. The AChR antibody level was not predictive of development of generalized myasthenia gravis at 2 years, but the risk was greater in patients with abnormal AChR antibody levels (OR, 6.33; 95% CI, 1.71-23.42). Logistic regression that included age, abnormal AChR antibody level, and prednisone therapy yielded significance only for abnormal AChR antibody level (OR, 7.03; 95% CI, 1.35-36.64) and treatment (OR, 0.06; 95% CI, 0.01-0.30). CONCLUSIONS: At 2 years, prednisone treatment appears to reduce the incidence of generalized myasthenia gravis to 7% in contrast to 36% of patients who did not receive prednisone. Thymoma, although uncommon, occurs in ocular myasthenia gravis. Only small amounts of edrophonium are needed to diagnose ocular myasthenia gravis.     

Myasthenia gravis developing in an HIV-negative patient with Kaposi’s sarcoma

Myasthenia gravis is a disorder of neuromuscular transmission caused by autoimmune mechanisms. We reported a possible association between seropositive myasthenia gravis and Kaposi’s sarcoma in a HIV-negative subject and the observed interactions between the treatment regimen for these two conditions. A 62-year-old man came to our attention for ocular myasthenia gravis. He suffered from a classic form of Kaposi’s sarcoma since about 1 year. When myasthenic symptoms worsened, the patient was started on prednisone and azathioprine. The patient had a significant worsening of Kaposi’s sarcoma, so prednisone and azathioprine were reduced and he was treated with vinblastine, with improvement both in dermatologic than in neurological symptomatology. We propose some considerations: the potential correlation between Kaposi’s sarcoma and myasthenia gravis through immunological mechanism; myasthenia gravis as a paraneoplastic manifestation of Kaposi’s sarcoma, and the role of an antitumoral agent as a treatment for both the conditions.     

Myasthenia gravis and acetylcholine receptor. Effect of steroids in clinical course and cellular immune response to acetylcholine receptor.

Lymphocytes from patients with myasthenia gravis (MG) were transformed when cultured in vitro with an acetylcholine receptor fraction extracted from the electric organ of an electric eel. Marked diminution of the cellular response to acetylcholine was shown in patients who improved clinically with prednisone treatment. The transient clinical deterioration during the first days of prednisone treatment was accompanied by a transient increase in lymphocyte response. These findings that an in vivo sensitization of lymphocytes to self-acetylcholine receptor may occur in MG, and that a cell-mediated autoimmune mechanism may be important in the pathogenesis of the neuromuscular block. The present observations indicate that prednisone provides a measure of immunosuppression in MG. The transient clinical deterioration during the first days of prednisone therapy may reflect an enhancement of cell reactivity by this drug.     

Immunosuppressive drug therapy in myasthenia gravis

We reviewed the records of 37 patients with myasthenia gravis treated with azathioprine (n = 10) or cyclophosphamide (n = 27). All patients had received prednisone and anticholinesterase therapy, and most had undergone thymectomy prior to immunosuppressive therapy. Thirty patients (81%) responded to treatment. Both azathioprine and cyclophosphamide were found to be effective in the treatment of myasthenia gravis. The degree of improvement was more pronounced in patients with thymoma.     

Late-onset myasthenia gravis successfully treated with local resection of cervical ectopic thymoma

A 78-year-old woman was admitted complaining progressive respiratory failure, neck weakness and gait disturbance. She was diagnosed as acetylcholine receptor antibody-positive myasthenia gravis crisis with ectopic cervical thymoma. After she recovered from crisis by plasmapheresis and administration of prednisone, we did not choose extended thymectomy but chose local resection of ectopic thymoma considering her age and complications. After the operation, she got minimal manifestations and no relapse of thymoma. Although international and Japanese guidelines recommend extended thymectomy for myasthenia gravis with thymoma, isolated local resection of ectopic thymoma may be enough for controlling myasthenia gravis especially in elderly patients.     

Juvenile seropositive myasthenia gravis with anti-MuSK antibody after thymectomy

We report the case of a 17.5-year old girl with generalized myasthenia gravis (MG). When she was 13, she started to complain of episodic diplopia, ptosis and mild fatigability of upper and lower extremity muscles. She was diagnosed with MG 3 years later, after exacerbation of her limb muscle weakness. Acetylcholine receptor antibody was positive (2.56 nmol/l, n < 0.4 nmol/l), anti-MuSK antibodies were not tested at that time. She was treated with a thymectomy. After the operation a gradual worsening of her MG was seen; she reported pirydostygmine intolerance. On retesting, acetylcholine receptor antibodies were negative and she was positive for anti-MuSK antibodies. She received immunosuppressive treatment with prednisone and azathioprine with clinical improvement. She is the third reported patient diagnosed with acetylcholine receptor antibody-positive MG, who became MuSK-positive after thymectomy. Recognition of such clinical patterns may be important for decision making in myasthenia gravis patients.     

Fusion protein of single-chain variable domain fragments for treatment of myasthenia gravis

Single-chain variable domain fragment(scFv)637 is an antigen-specific scFv of myasthenia gravis.In this study,scFv and human serum albumin genes were conjugated and the fusion protein was expressed in Pichia pastoris.The affinity of scFv-human serum albumin fusion protein to bind to acetylcholine receptor at the neuromuscular junction of human intercostal muscles was detected by immunofluorescence staining.The ability of the fusion protein to block myasthenia gravis patient sera binding to acetylcholine receptors and its stability in healthy serum were measured by competitive ELISA.The results showed that the inhibition rate was 2.0–77.4%,and the stability of fusion protein in static healthy sera was about 3 days.This approach suggests the scFv-human serum albumin is a potential candidate for specific immunosuppressive therapy of myasthenia gravis.     

Corticosteroids in the treatment of myasthenia gravis. Study of 12 cases with review of the literature]

The results of treatment of myasthenia gravis in 12 patients are reported. There were 10 cases with severe generalized form and two cases with moderate generalized form, one of which associated with polymyositis. Seven patients had prior thymectomy and one of them had a thymoma. All the patients were receiving anticholinesterase drugs with poor response or without any response. One patient received a short, intensive course of dexametazone, and other patient used prednisone after a more prolonged dexametazone course. The remaining patients received prednisone, always beginning with high (100 mg) alternate day oral single-doses. This therapy has been maintained for a period thought to be sufficient to suppress the symptoms, as well as to allow remission or an improvement for remaining even when prednisone had been slowly decreased, after a scheduled of one to two years of treatment.     

Characterization of acetylcholine receptor antibodies in a patient with primary biliary cirrhosis

Antibodies against the acetylcholine receptor were found in a patient with primary biliary cirrhosis. The patient had no clinical or electrophysiological evidence of disturbed neuromuscular function. The antibodies were of both IgG and IgM isotype. Following passive transfer, these antibodies showed the same capacity to bind in vivo to mouse muscle receptors as immunoglobulins from patients with myasthenia gravis. The affinity of the antibodies was high and comparable to that found in myasthenia gravis patients.     

Myasthenia gravis and premature ovarian failure

We describe a patient who developed seropositive myasthenia gravis 16 years after she was diagnosed with autoimmune premature ovarian failure with antibodies to the receptor for follicle-stimulating hormone (FSH). Although thymectomy led to improvement of her myasthenic symptoms, menses did not resume. Such combined seropositivity for antibodies to acetylcholine and ovarian hormone receptors in a patient with myasthenia gravis and premature ovarian failure may reflect common disease mechanisms, although the precise pathogenesis of these disorders remains ill-defined.     

Benefits of FK506 (tacrolimus) for residual, cyclosporin- and prednisone-resistant myasthenia gravis: one-year follow-up of an open-label study

Thirteen patients with myasthenia gravis, unresponsive to prednisone and cyclosporin after thymectomy, received KF506 (tacrolimus) for 12 months, at starting doses of 0.1 mg/kg per day b.i.d. and then adjusted to achieve plasma concentrations between 7 and 8 ng/mL. The doses of prednisone were progressively reduced and finally discontinued. Anti-acetylcholine antibodies and myasthenia gravis score for disease severity decreased significantly and muscular strength increased by 37%. All patients achieved pharmacological remission, 11 were asymptomatic and two had minimal weakness of eyelid closure. Tacrolimus was well tolerated and appears a suitable approach after unsuccessful treatment with conventional immunosuppressants in patients with disabling myasthenia.     

Prolonged improvement after rituximab: two cases of resistant muscle-specific receptor tyrosine kinase + myasthenia gravis

Forty percent to 50% of acetylcholine receptor antibody-seronegative patients with myasthenia gravis have muscle-specific receptor tyrosine kinase antibodies. Many muscle-specific receptor tyrosine kinase + myasthenia gravis patients remain refractory with conventional therapies. Rituximab is an anti-CD20 monoclonal antibody used in refractory B-cell disorders. Currently there is no standard dosing schedule for rituximab. We present two muscle-specific receptor tyrosine kinase + myasthenia gravis patients clinically refractory to conventional therapy who, after a single course of rituximab, became asymptomatic and discontinued all medication.     

Prednisone use in concurrent autoimmune diseases.

A 40-year-old woman with clinical and laboratory features of myasthenia gravis, hyperthyroidism, and polymyositis responded to treatment with prednisone alone. Symptoms of myasthenia gravis appeared first followed by hyperthyroid symptoms. Triiodothyronine, thyroxine, and thyroid uptake were elevated as were serum levels of CPK, SGOT, SGPT, and LDH. Muscle biopsy specimen showed mild type II fiber atrophy and a small focus of inflammatory cells. Two weeks after initiation of prednisone, 100 mg every other day, the ESR declined from 44 to 12 mm/hr, serum enzyme values became normal, and the weakness improved. Over the ensuing four months, the thyroid function values returned to normal and the patient no longer needed any anticholinesterase drug. At present, she is functionally normal except for mild defects in eye movement and she takes no medication. Physicians should consider treating patients who have several concurrent autoimmune diseases with prednisone to see if all conditions can be brought under control with one simple therapy.     

Mitochondrial ophthalmoplegia with fatigable weakness and elevated acetylcholine receptor antibody.

A 25-year-old man with chronically progressive ptosis and bilateral ophthalmoplegia displayed fatigability and fluctuation of ptosis, an abnormal single-fiber electromyogram, and a markedly elevated acetylcholine receptor antibody level. Yet a muscle biopsy showed clear evidence of a mitochondrial cytopathy, and the clinical features did not improve after treatment with prednisone. This case emphasizes the difficulty in differentiating mitochondrial cytopathy from myasthenia gravis and points out that elevated acetylcholine receptor antibody levels may occur in nonmyasthenic conditions.     

Penicillamine-associated myasthenia gravis

Electroneuromyographic studies have been reported as abnormal in only 9 of 23 cases of penicillamine-associated myasthenia gravis (MG). We report a patient with rheumatoid arthritis who developed clinical and electrodiagnostic evidence of myasthenia 7 months after beginning penicillamine therapy. Six months after discontinuing penicillamine, it was possible to discontinue anticholinesterase medications. With clinical improvement, electrodiagnostic studies (including single-fiber electrmyography) improved, serum antibody titers to human muscle acetylcholine receptor fell, and lymphocytes became more responsive to the nonspecific mitogen phytohemagglutinin. Evidence suggests that penicillamine-associated myasthenia is a distinct syndrome rather than the chance occurrence of two diseases. This syndrome is clinically and electrophysiologically distinguishable from idiopathic myasthenia only by the high remission rate after penicillamine is discontinued.     

Myasthenia gravis after allogeneic bone marrow transplantation: relationship to chronic graft-versus-host disease

Three patients with chronic graft-versus-host disease (GVHD) developed myasthenia gravis (MG) 762 to 1,180 days after allogeneic bone marrow transplantation. Symptoms of MG were observed after taper or discontinuation of immunosuppressive treatment of chronic GVHD. All patients developed antibodies to acetylcholine receptor, and one had antibody formation to striated muscle. One patient died of complications of treatment of MG. The severity of disease underscores the importance of the differential diagnosis and the need for prompt therapy of this late complication after human bone marrow transplantation.     

“Warming yang and invigorating qi” acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis

Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. “Warmingyang and invigoratingqi” acupuncture treatment has been shown to reduce serum inlfammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental au-toimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following “warmingyang and invigoratingqi” acupuncture therapy. Needles were inserted at acupressure pointsShou-sanli (LI10),Zusanli(ST36),Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was signiifcantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These ifndings suggest that “warmingyangand invigoratingqi” acu-puncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.     

Plasmapheresis therapy in myasthenia gravis

Plasmapheresis in the treatment of myasthenia gravis has led to disparate results when applied by different investigators because of considerable differences in the volume, number, and tempo of plasmaphereses and in the type and amount of concomitant immunosuppressive drug therapy. Used as short-term crisis intervention, plasmapheresis produces temporary clinical improvement and reduction in titer of antibody to acetylcholine receptor, even without accompanying drug therapy. When applied as long-term primary therapy under optimal conditions, plasmapheresis is capable of generating stable improvement in most patients. This response appears to result from a synergistic action with immunosuppressive drugs, since it is characterized by a sustained reduction in titer of antibody to acetylcholine receptor. Where clinical circumstances warrant cytotoxic immunosuppression in patients with myasthenia gravis, consideration should be given to the simultaneous employment of plasmapheresis, in order to maximize benefit to the patient from a given exposure to drug therapy.     

Familial autoimmune myasthenia gravis with different pathogenetic antibodies.

Two cases of familial myasthenia gravis are reported. One patient is a typical case of autoimmune myasthenia with positive anti acetylcholine receptor antibodies, while in the second patient the impairment of neuromuscular transmission is likely to be due to antibodies directed against determinants other than the acetylcholine receptors.