Case Discussion <Presentation of a Case> A 53 year-old woman with hypertension and mild right ptosis since 2 years ago was admitted because of chronic cough with occasional fever refractory to medications for 3 months prior to entry. She was seen at a local hospital for progressive dyspnea 2 months earlier. Because of worsening respiratory distress, she was intubated and was admitted to intensive care unit (ICU) then. She experienced several episodes of extubation failure. Dysphagia and poor saliva swallowing have been noted after successful extubation. Non-contrast brain CT revealed no definite lesions. She was discharged later. After discharge, dysphagia, poor oral intake, cough, and much salivary secretion persisted, so she was brought to our ER for help. An ENT specialist was consulted for suspected oropharnygeal lesions. However, only much saliva pooling over the vocal cord and pyriform sinus was noted. Respiratory distress occurred during ENT examination and emergent intubation was performed at ER. She was admitted to ICU for further management. On admission, physical examination showed a woman of 164 cm in height and 50 kg in weight. Her temperature was 36.6o C, blood pressure was 166/88 mmHg, pulse rate was 90 beats per minute, and respiratory rate was 22 breaths per minute. Her consciousness was clear. Her conjunctivae were pink, and the sclerae were anicteric. The pupils were isocoric with prompt light reflexes. The neck was supple without lymphadenopathy, engorged jugular veins, palpable thyroid gland or carotid bruits. The chest wall expansion was symmetric, and breath sounds were bilaterally coarse. The heart beats were regular without audible murmur. The abdomen was soft. Bowel sounds were normoactive and liver and spleen were impalpable. Her extremities were freely movable without edema, but the muscle power was about 3~4 score over four extremities symmetrically. <Laboratory Data> CBC/DC: WBC Hb Hct MCV Platelet Seg  Eos K/μL g/dL % fL k/μL % % 11.9 9.9 30.5 88.7 219 86.5 0.3 Baso Mon Lym ALB T-Bil AST ALT % % % g/dL mg/dL U/L U/L 0.1 3.2 9.9 3.95 0.49 28 15 BUN Cr LDH Na K CRP Glucose mg/dL mg/dL U/L mmol/L mmol/L mg/dL mg/dL 22.6  0.7 381 138 3.5 0.79  170 Urine analysis: Appearance Sp.Gr pH Protein Glucose Ketone OB       mg/dL mg/dL     Y, C 1.03 6 300 - - 1+ Urobilirubin Bilirubin Nitrate WBC RBC Epi Cast       HPF HPF HPF   + - - 2-5 2-4 0-2 0 <Course and Treatment> After admission, ampicillin-sulbactam was given for suspected aspiration pneumonia. Ventilator weaning was attempted and she was extubated. However, hypoventilation, respiratory distress, tachycardia, and frequent VPCs were noted after extubation. Re-intubation was performed soon. Ptosis and proximal muscle weakness were more obvious after extubation failure. Myasthenia gravis (MG) was suspected according to clinical symptoms and signs. Antibody to acetylcholine receptor was checked to reveal an elevated level of antibody against acetylcholine receptor (18.131 nmol/L), and myasthenic crisis was diagnosed. She underwent plasmapheresis for 5 consecutive days followed by prednisolone 50 mg qd. Muscle power improved gradually. The maximal pressure of inspiration (Pimax) improved from -40 cmH2O to -60 cmH2O, and the maximal pressure of expiration (Pemax) improved from 26 cmH2O to 60 cmH2O. She was extubated successfully without recurrent respiratory failure. Review of her previous chest CT at another hospital revealed a soft tissue density suggestive of thymoma. <Discussion> There are two clinical forms of myasthenia: ocular and generalized. In ocular myasthenia gravis (MG), the weakness is limited to the eyelids and extraocular muscles. In generalized disease, the weakness also affects ocular muscles, but it may involve a variable combination of bulbar, limb, and respiratory muscles. About half of the patients with purely ocular MG have positive antibody against acetylcholine receptor, compared with nearly four-fifths of those with generalized MG. About 10-15% MG patients have thymoma. The cardinal feature of MG is fluctuating skeletal muscle weakness, often with true muscle fatigue. The weakness may fluctuate throughout the day, but it is most commonly worse later in the day or evening, or after exercise. More than 50 percent of patients present with ptosis and/or diplopia. Patients who present with ocular manifestations, about half will develop generalized disease within two years. About 15 percent of patients present with bulbar symptoms, which include dysarthria, dysphagia, and fatigable chewing. Myasthenic crisis is a life-threatening condition, defined as weakness from acquired MG that is severe enough to necessitate intubation, or delay extubation following surgery. Myasthenic crisis may be precipitated by a variety of factors including infection, surgery, or tapering of immunosuppression. The diagnostic approach to myasthenia is focused on confirming the clinical diagnosis by clinical history and typical examination findings. Bedside tests (the Tensilon test and the ice pack test) are easy to perform and are sensitive, but they have major limitations due to concerns about excess false-positive results with these techniques. More reliable laboratory methods that aid in the confirmation are serologic tests for auto-antibodies and electrophysiological studies (repetitive nerve stimulation studies and single-fiber EMG). Repetitive nerve stimulation (RNS) studies and single-fiber electromyography (SFEMG) have a diagnostic sensitivity of about 75 percent and 95 percent, respectively, in generalized myasthenia. In RNS study, the nerve is electrically stimulated 6 to 10 times at low rates (2 or 3 Hertz). The compound muscle action potential (CMAP) amplitude will not change in normal population, but it will decline progressively in MG patients. A RNS study is considered positive if the decrement is greater than 10 percent. Single-fiber electromyography (SFEMG) is more technically demanding than RNS and is less widely available, but it is the most sensitive diagnostic test for MG. SFEMG is positive in greater than 95 percent of those with generalized myasthenia. In ocular MG, it ranges from 90 to 95 percent. There are four basic therapies used to treat MG: symptomatic treatments (anticholinesterase agents, pyridostigmine bromide), chronic immunomodulating treatments (corticosteroids and other immunosuppressive drugs), rapid immunomodulating treatments (plasma exchange and intravenous immune globulin), and surgical treatment (thymectomy). Acetylcholinesterase inhibitors provide only symptomatic therapy and are usually not sufficient in generalized myasthenia. The administration of moderate or high doses of corticosteroids leads to remission in about 30 percent of patients and marked improvement in another 50 percent. The rapid immunomodulating therapy provides quick onset and transient benefit treatment. It is used in select situations, including: myathenic crisis, preoperatively before thymectomy or other surgery, bridge to slower acting immunotherapies and periodically maintain remission in patients that is not well controlled. Patients with thymoma clearly need surgical treatment. However, the need for thymectomy is less certain in those with nonthymomatous tissue. The likelihood of medication-free remission is about twice as high with thymectomy than without. The benefit of thymectomy is delayed and accrues over several years postoperatively. <References> Drachman, DB. Myasthenia gravis. N Engl J Med 1994; 330:1797. Meriggioli, MN, Sanders, DB. Myasthenia gravis: diagnosis. Semin Neurol 2004; 24:31. Saperstein, DS, Barohn, RJ. Management of myasthenia gravis. Semin Neurol 2004; 24:41. Vincent, A, Newsom-Davis, J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985; 48:1246. 繼續教育考題 1. (B) 關於myasthenia gravis的敘述何者為非? A  臨床有兩種表現型態 ocular form and generalized form B Ocular form 較容易偵測到acetylcholine receptor antibody C Generalized form之病患有可能會影響到吞嚥及呼吸功能 D 目前認為其屬於自體免疫疾病的一種 E 約10-15%病人合併有胸腺瘤（thymoma） 2. (D) 關於myasthenic crisis的敘述何者為非? A 為一嚴重影響生命之狀況 B 可因為感染、開刀或免疫抑制藥物調整等因素誘發 C 常導致病患呼吸衰竭需使用呼吸器 D 吞嚥功能通常不受影響 E 應入住加護病房接受密切觀察治療 3. (B) Myasthenia gravis的診斷方法，下列哪一項除外?  A 詳細之病史及理學檢查 B 肌肉酵素(creatine kinase)之升高 C Positive Tensilon test D Repetitive nerve stimulation (RNS) studies and single-fiber electromyography (SFEMG) E Positive acetylcholine receptor antibody 4. (E) Myasthenic crisis的治療不包含下列哪些選擇? A Ventilator support B High-dose corticosteroids C Intravenous immune globulin (IVIG) D Plasmapheresis E Rapid fluid supply 5. (B) 下列何項不可以當作myasthenic crisis開始進行呼吸器脫離訓練的評估條件? A Forced vital capacity (FVC) >15 mL/kg B Pimax > 10 cmH2O C No obvious parenchymal lung disease D No accessory muscle use E Patient can hold the head off the bed 6. (E) 關於myasthenia gravis 與 thymus 的敘述下列何者為錯? A Thymus可能在myasthenia gravis中扮演重要的治病機轉 B Myasthenia gravis病患約有60-70%有thymus hyperplasia C 有thymoma病患應考慮施行thymectomy D 在症狀較嚴重或myasthenic crisis病患應先藥物控制症狀再安排手術 E 無thymoma病患不應接受thymectomy 答案解說 【B】 Generalized form 較常偵測到 acetylcholine receptor antibody. 【D】 Myasthenic crisis除影響呼吸肌肉外亦常影響病患之吞嚥功能。 【B】 Myasthenia gravis不會造成肌肉酵素(creatine kinase)的增高。 【E】 Myasthenic crisis的治療主要是給予呼吸功能的輔助，同時使用IVIG或plasmapheresis來達成rapid immunomodulation，之後再給予皮質類固醇或其他免疫抑制劑來達成chronic immunomodulation。 【B】 Myasthenic crisis病患要開始進行呼吸器脫離訓練前須評估患者是否達成以下條件：呼吸肌肉力量恢復且FVC>15ml/kg, Pimax > 30 cmH2O。評估肌肉力量ㄧ個簡易的臨床方法為測試病人是否能夠將頭抬離床面。 【E】 無thymoma病患是否應接受thymectomy目前仍無定論，但某些研究指出無thymoma病患接受thymectomy，仍可讓myasthenia gravis獲得較佳之疾病緩解率。