Myasthenia gravis is an autoimmune disease characterized by muscle weakness. Myasthenic crisis is a life-threatening complication of myasthenia gravis precipitated by several factors. We experienced a myasthenic crisis after a deceased-donor kidney transplant in a 35-year-old woman who already had been diagnosed with myasthenia gravis. She received mechanical ventilatory support and intravenous immunoglobulin for treatment of the myasthenic crisis. During the early posttransplant period, she recovered with immediate graft function, and her graft functioning did not deteriorate during the myasthenic crisis. We suggest that physicians be aware of worsening of myasthenia gravis when patients with myasthenia gravis undergo a kidney transplant.
Key words : Kidney transplant, Myasthenia gravis, Intravenous immunoglobulin
Introduction
Myasthenia gravis (MG) is characterized by muscle weakness that fluctuates, worsening with exertion, and improving with rest. Although the cause of this disorder is unknown, the pathogenetic role of circulating antibodies against postsynaptic acetylcholine receptors in the motor end plate of skeletal muscles is well established.1
Myasthenic crisis, or respiratory failure caused by myasthenic weakness occurs in 20% of patients during the first year of the illness.2,3 It is precipitated by poor control of the generalized disease, concomitant use of certain antibiotics (eg, quinolones), muscle relaxants (eg, succinylcholine), benzodiazepines (eg, diazepam), β-blockers (eg, propranolol), steroids, and iodinated contrast; even emotional or physical stress can cause a myasthenic crisis.4,5
Solid-organ transplant recipients previously diagnosed with MG could be exposed to several risk factors that develop into an MG crisis during the perioperative period. Many agents including radiocontrast agents for preoperative computed tomography scans, anesthetic drugs, and immuno-suppressants may be administered. Recipients also have emotional and physical stress from surgery. To the best of our knowledge, myasthenic crisis after kidney transplant has not been reported. We describe a deceased-donor kidney transplant in a woman previously diagnosed with MG who experienced a myasthenic crisis after surgery.
Case Report
A 35-year-old woman who had undergone hemodialysis for 6 years, presented with end-stage renal disease due to lupus nephritis. Her lupus disease activity decreased, and it remained so with no specific treatment. She presented with proximal muscle weakness, ptosis, and recurrent respiratory failure requiring mechanical ventilation 14 months before her transplant. She was diagnosed with MG. The results of a serum acetylcholine receptor binding antibody titer were elevated. Repetitive nerve stimulation induced decremental responses. No evidence of thymoma could be found. The patient had symptomatic improvement after treatment with pyridostigmine (60 mg every 12 h). She was asymptomatic before her kidney transplant.
In March 2013, the patient underwent a deceased-donor kidney transplant. The number of HLA mismatches was 4, her panel reactive antibody titer was 0%, and the results of her crossmatch test were negative. Contrast-enhanced abdominal computed tomography was performed preoperatively. She received pyridostigmine until the day of surgery. Anesthesia was induced with fentanyl, sodium thiopental, and cisatracurium 6 mg. Anesthesia was maintained with desflurane and continuous infusion of remifentanil. After surgery, she began breathing spontaneously in the operating room after administering glycopyrrolate and pyridostigmine.
Surgery was uneventful. Fentanyl was given by patient-controlled anesthesia. Her immuno-suppressive regimen included prednisolone, tacrolimus, and mycophenolate mofetil. The initial dose of basiliximab (IL-2 receptor antagonist) was given 2 hours preoperatively, and the second dose was given 4 days after surgery. During the early posttransplant period, she recovered well with immediate graft function. Her serum creatinine level decreased to 79.56 μmol/L. Pyridostigmine was continued at the same dosage (60 mg every 12 h), and no notable symptoms were observed.
The clinical course of the patient after her kidney transplant is summarized in Figure 1. On postoperative day 3, she developed shortness of breath, weakness of the proximal muscles of lower limbs, and ptosis. Her vital signs were blood pressure, 150/100 mm Hg; pulse, 120 beats/minute; respiratory rate, 25 breaths/minute; and O2 saturation by pulse oximetry on room air, 86%. The results of the chest radiograph showed no abnormal findings. Her symptoms improved temporarily after an intramuscular administration of pyridostigmine. She was intubated and transferred to the intensive care unit for initiation of ventilatory support. Intravenous immunoglobulin was given for 5 days at a dosage of 0.4 g/kg/d for the myasthenic crisis. Immunosuppressive agents that can prevent rejection of the transplanted kidney and also can be used to treat MG were maintained. Renal allograft dysfunction did not develop during this time. She was successfully extubated and discharged home. Until 1 month after the kidney transplant, the patient’s renal function has remained stable, and no symptoms of MG have been seen using the same dosage of pyridostigmine (60 mg every 12 h).
Discussion
Ten percent of MG patients have another autoimmune disorder. One study reported the incidence of autoimmune thyroiditis (10.4%) and systemic lupus erythematosus (8.3%) in the MG patients was clearly higher than reported in the general population. Rheumatoid arthritis also was found in MG patients (4.2%).6 This patient had been diagnosed with lupus nephritis that progressed to end-stage renal disease. After several years, she also had been diagnosed with MG. There were no signs of other autoimmune diseases like rheumatoid arthritis or autoimmune thyroiditis.
Myasthenic crisis is weakness of respiratory muscles severe enough for intubation or artificial respiratory support. It occurs in 15% to 20% of patients with MG during their life.7 This crisis may be precipitated by infection, surgery, menstruation, pregnancy, childbirth, tapering of immuno-suppressive medications, exposure to temperature extremes, pain, sleep deprivation, and physical or emotional stress.3-5 Several drugs interfere with neuromuscular transmission and worsen the symptoms of MG. Symptoms commonly occur several hours to days after exposure to the drugs. This is important for using certain antibiotics (eg, aminoglycosides, macrolides, monobactams, and quinolones), cardiac drugs (eg, β-blockers, procainamide, and quinidine), and magnesium.8,9 Although corticosteroids can be used to treat MG, initial treatment with prednisone can cause an exacerbation of MG.10
The exact cause of the myasthenic crisis in our patient is unclear. However, she had been exposed to several drugs, and she developed the clinical conditions associated with the exacerbation of MG.
She was administered intravenous contrast media for preoperative abdominal computed tomography. Several studies suggest that intravenous contrast can trigger myasthenic worsening.11,12 Conversely, 1 study has shown that occurrence of a myasthenic crisis because of intravenous injection of contrast is controversial.13 Most patients in the reported cases became apneic immediately after intravenous injection of contrast material. In our patient, no signs were observed immediately or shortly after administering the contrast injection.
Our patient exhibited fear before the transplant, and had pain for several days after surgery. These mental and physical stresses could have exacerbated her MG. Some anesthetics were administered to this woman to perform the operation. A previous report showed that cisatracurium caused a more marked neuromuscular block in myasthenic patients.14 One study indicated that anesthesia with desflurane combined with remifentanil is safe in patients with MG.15 Although general anesthetics may affect neuromuscular transmission, recent anesthetic approaches may be safely performed in myasthenic patients.16-21 Our patient was adequately monitored, and no abnormal signs were seen during surgery. She had no immediate adverse effects from the anesthetics.
The use of corticosteroids may have contributed to the exacerbation of MG in our patient. Pascuzzi and associates have described approximately 50% of patients with MG given treatment with high-dose corticosteroids have an early exacerbation; in about 10% of patients with MG, this exacerbation requires mechanical ventilation.10 Administering a moderate or high dosage of prednisone (1.0 mg/kg/d) is commonly recommended as the initial dosage to treat MG.22,23 However, transitory worsening of weakness occurs in patients treated initially with high-dose prednisone.10 To avoid the transitory worsening of weakness, some clinicians start at a lower dosage of prednisone (20 mg/d) and escalate the dosage slowly based on the patient’s clinical response.24 Rapid tapering also may precipitate myasthenic exacerbations. Therefore, corticosteroid tapering in MG should be done slowly. Patients must be reassessed at 4- to 8-week intervals. The prednisone dosage should be tapered by 10 mg on alternate days to 30 mg on alternate days, and then by 5 mg on alternate days to 20 mg on alternate days. Subsequent tapering by 2.5 mg on alternate days must be done for intervals longer than 12 weeks.25 Our patient received a large dosage of glucocorticoids consisting of a “pulse” intraoperative dosage of 1 gram of methylprednisolone after the tapering regimen (halving the dose every day). She had a sudden onset of dyspnea 4 days after the steroid treatment.
Previous reports have described that the weakness from steroids develops 7 to 10 days after treatment and may last up to 1 week.10,26 In our case, corticosteroid therapy began at a larger dosage than the initial high dosage for treating MG, and it was tapered rapidly. We suggest a low-dose steroid administration strategy or a steroid-free protocol (no avoidance or withdrawal) may be used to minimize life-threatening myasthenic crisis. Also, slow tapering of steroids must be done in a patient with MG.
The mechanism for exacerbating MG with steroids is unclear. In experimental studies, some direct effects of steroids on neuromuscular transmission including depolarization of nerve terminals, reduced acetylcholine release, and altered miniature end plate potentials have been saying.27,28 Some studies describe an alternate mechanism related to the immune response. In MG patients, lymphocytes are sensitized to acetylcholine receptors that produce antiacetylcholine receptors antibodies. Therefore, thymectomy, with the resultant removal of acetylcholine receptors-specific CD4+ T cells, helps alleviate symptoms in MG patients.29 Abramsky and associates found increased lymphocyte transformation in vitro in patients with prednisone-induced aggravated weakness. Nonreactive lymphocytes can be destroyed by corticosteroids, leading to enhanced proliferation of sensitized lymphocytes.30
Patients with myasthenic crisis must be offered mechanical ventilation with careful bedside measurements and observations.5 Plasma exchange and intravenous immunoglobulin to reduce levels of pathogenic antibodies are effective during a myasthenic crisis.31 A controlled randomized study failed to show any difference between these 2 treatment options.32 Both treatments are expensive, but intravenous immunoglobulin is a simpler procedure and may be superior, from a completely economic perspective.33 Our patient recovered from weakness only after she had been given intravenous immunoglobulin therapy at a dosage of 0.4 g/kg/d for 5 days. Plasma exchange or intravenous immuno-globulin also may be used before surgery.34 Seggia and associates demonstrated the perioperative value of plasmapheresis in patients with MG, which significantly improved respiratory function and muscle strength, and decreased hospital cost and stay.35 In our patient, a deceased-donor kidney transplant was performed, leaving no chance to perform preoperative plasmapheresis.
Several factors are associated with the exacerbation of MG in our patient. Some of the conditions may or may not have been controlled to prevent the myasthenic crisis. Most importantly, patients with MG who undergo a kidney transplant must be monitored by the intensive care specialists, nephrologists, neurologists, surgeons, and anesthesiologists. It is crucial that physicians are aware of worsening of MG during the perioperative period.
References:
Volume : 12
Issue : 6
Pages : 555 - 558
DOI : 10.6002/ect.2013.0203
From the Department of 1Internal Medicine, the Department of
2Neurology, Pusan National University School of Medicine, Yangsan; the
3Research Institute for Convergence of Biomedical Science and
Technology, Pusan National University Yangsan Hospital, Yangsan; and the 4Medical
Research Institute, Pusan National University Hospital, Busan, South Korea
Acknowledgements: The authors received no grant support for this study
and have no conflicts of interest to declare.
Corresponding author: Soo Bong Lee, MD, Division of Nephrology,
Department of Internal Medicine, Pusan National University Yangsan Hospital,
Beomeo-ri, Mulgeum-eup, Yangsan, 626-770, Gyeongsangnam-do, South Korea
Phone: +82 55 360 2371
Fax: +82 55 360 1605
E-mail: sbleemd@pusan.ac.kr
Figure 1. Clinical Course of the Patient After a Deceased-Donor Kidney Transplant