Outcome of Thymectomy in Juvenile Myasthenia Gravis Surbhi Mathur General Surgery PGY1 smathur2@uw.edu

Agenda Case presentation Myasthenia Gravis Treatment Options Outcomes of Thymectomy in juvenile Myasthenia Gravis 2

Case Presentation Symptoms- Easy fatigability Patient Identification- MS is an 11-year-old kid with autoimmune juvenile Myasthenia Gravis who first developed symptoms approximately 3 years ago. Symptoms- Easy fatigability Oropharyngeal difficulty with problems speaking and swallowing He was formally diagnosed with myasthenia gravis in October 2012 3

Case Presentation Contd.. PAST MEDICAL HISTORY- None MEDICATIONS: Since his diagnosis in October 2012, he has been treated with Mestinon and the doses escalated and he required glycopyrrolate to counteract the side effects of the Mestinon He was at a maximum dose now and he still had symptoms of weakness - specifically trouble speaking and swallowing. Recently on his current doses he has been in pretty good condition, running and very active, although he still has days when he is more symptomatic with more fatigue and even difficulty swallowing He has been on his current medication dose for about the last 6 months of the Mestinon (pyridostigmine), 60 mg/5 mL syrup, he takes 7 mL 4 times a day at 6:00 and 11:00 a.m. and 2:00 and 5:00 p.m Thirty minutes before each of these doses he takes glycopyrrolate, 2 mg/mL solution, 0.4 mL before each of the the 2 morning doses and 0.5 mL before each of the afternoon doses. He is on no other regular medications. 4

Case Presentation BIRTH HISTORY: He was born about 4 weeks early, but his birth weight was 6 pounds 5 ounces. No notable perinatal problems. His only overnight hospitalization was for his myasthenia a little more than a year ago for the onset of his medications. OPERATIONS: His only operation was an outpatient myringotomy tube placement when he was roughly 2 years of age. FAMILY HISTORY: No family history of neurological problems or myasthenia. No one is ill at home. He has 3 older brothers and an older sister, all alive and well. No family history of bleeding. No family history of anesthetic problems. SOCIAL HISTORY: The family lives in Kalispell, Montana. They drove over to Seattle for these visits. Marcos is in the 5th grade. 5

Case Presentation Contd.. He underwent robotic thoracoscopic thymectomy on 1/10, He tolerated the above procedure very well and was admitted to the Pediatric Intensive Care Unit for hemodynamic monitoring on postoperative day zero. After uneventful post op course he was discharged on POD#2 On the evening of their discharge, the family noticed that he had an increasing red rash mainly over his anterior torso and some on his back and neck. With some Benadryl, this improved, possibly allergic reaction to oxycodone. Patholgy showed thymus completely normal for his age and condition – no tumor (benign or malignant) but just active thymus consistent with his diagnosis of myasthenia gravis. 6

Myasthenia Gravis Myasthenia gravis is the most common disorder of neuromuscular transmission. Weakness is the result of an antibody-mediated, T-cell dependent immunological attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (acetylcholine receptors and/or receptor- associated proteins). The cardinal feature of myasthenia gravis is fluctuating skeletal muscle weakness, often with true muscle fatigue. 7

Treatment Options Four basic therapies used to treat MG: Symptomatic treatments (anticholinesterase agents) Chronic immunomodulating treatments (glucocorticoids and other immunosuppressive drugs) Rapid immunomodulating treatments (plasmapheresis and intravenous immune globulin) Surgical treatment (thymectomy) Symptoms can be treated with acetylcholinesterase inhibitors (also called anticholinesterase medications). These medications are all that is ever needed for some patients. Pyridostigmine bromide (Mestinon) is the main cholinesterase inhibitor currently in use 8

Treatment Options Contd.. Plasmapheresis and intravenous immune globulin (IVIG) are rapid immunotherapies that work quickly but have a short duration of action These are usually reserved for certain situations, such as myasthenic crisis, preoperatively before thymectomy, as a "bridge" while initiating slower acting immunotherapies, or as an adjuvant to other immunotherapeutic medications in patients with refractory MG. 9

Osserman Criteria To evaluate the severity of MG symptoms. Group1- Ocular Group 2- Generalized disease that is mild(2a) or moderate (2b) Group 3- Severe generalized disease Group 4- Myasthenic crisis with respiratory impairment requiring intubation.

Myasthenia Scale of Millichap and Dodge To evaluate the response to therapy GradeA- Complete remission and drug therapy is discontinued. Grade B- good improvement, both objective and subjective but continuation of drug therapy required in the same or lower dosage. Grade C- slight improvement but large doses of medication necssary. Grade D- no change or worse Grade E- Patient died

Juvenile myasthenia gravis: a twenty-year experience Performed a retrospective chart review of patients diagnosed with myasthenia in the pediatric neuromuscular clinics at UT Southwestern, between 1990 and 2010. Osserman classification and the response to therapy scale of Millichap and Dodge were used to compare each patient's severity of myasthenia and responsiveness to drugs before the surgery as a baseline and at the last visit, after thymectomy. RESULTS: Fifty-eight patients were included; 29 (50%) were African American, and 34 (58.6%) were female. Age of onset was 11 months to 17 years, and 38 patients (65%) presented as generalized myasthenia gravis. Forty-nine patients (84%) were acetylcholine receptor antibody (AchR-Ab) positive. Of the 32 to undergo thymectomy, 19 subjects (59%) experienced an improved response to B level on the Myasthenia Scale of Millichap and Dodge (good improvement, both objective and subjective, but continuation of drug therapy required in the same or lower dosage) and 75% experienced a drop in Osserman classification by at least 1. Of the 8 individuals who did not show improvement after thymectomy, 4 subjects (50%) underwent repeat thymectomy. They had initially less invasive fluoroscopic or thoracoscopic procedure. Thymic hyperplasia was found in 7 patients (21%) and thymoma in 2. CONCLUSIONS: Thymectomy was well tolerated by this group of children. There was clinical improvement after thymectomy in two thirds of the AchR-Ab-positive generalized myasthenia gravis patients. Thymic pathology was seen in less than one third of the patients who underwent thymectomy, with thymic hyperplasia being common.

Outcome of children with acetylcholine receptor (AChR) antibody positive juvenile Myasthenia Gravis following thymectomy Neuromuscul Disord. 2014 Jan;24(1):25-30. doi: 10.1016/j.nmd.2013.09.013. Epub 2013 Oct 1. Evaluated the outcome of children with generalized JMG who underwent thymectomy between 1996 and 2010 at 2 tertiary paediatric neurology referral centres in the United Kingdom. Twenty patients (15 female, 5 male), aged 13months to 15.5years (median 10.4years) at disease onset, were identified. Prior to thymectomy, disease severity was graded as IIb in 3, III in 11, and IV in 6 patients according to the Osserman classification. All demonstrated positive anti-acetylcholine receptor (AChR) antibody titres. All patients received pyridostigmine and 14 received additional steroid therapy. Transternal thymectomy was performed at the age of 2.7-16.6years (median 11.1years). 13

No benefit was observed in one patient with thymoma. Outcome of children with acetylcholine receptor (AChR) antibody positive juvenile Myasthenia Gravis following thymectomy At the last follow-up (10months to 10.9years, median 2.7years, after thymectomy), Majority - demonstrated substantial improvement, although some had required additional immune- modulatory therapies. About one third achieved complete remission. The postoperative morbidity was low. No benefit was observed in one patient with thymoma. Conclude that thymectomy should be considered as a treatment option early in the course of generalised AChR antibody-positive JMG. 14

Clinical characteristics and predictive factors of myasthenic crisis after thymectomy. Department of Neurology, Chonnam National University Hwasun Hospital,Republic of Korea. Aim of study was to assess the clinical characteristics of myasthenic crisis after thymectomy (MCAT) and to identify predictors affecting the occurrence of MCAT. Of 66 patients with myasthenia gravis (MG), MCAT occurred in 20 patients (30.3%). The median time interval from thymectomy to MCAT was 3.4 months. MCAT occurred in 65.0% of patients within the first 6 months of a thymectomy, and 35.0% after 6 months. A second MCAT occurred in nine (45.0%) patients who survived the first MCAT, and in seven (50.0%) of 14 patients with a history of a preoperative myasthenic crisis before thymectomy (MCBT). A history of MCBT, and clinical factors reflecting perioperative clinical severity at thymectomy, including preoperative Osserman's grade, bulbar symptoms, use of immunosuppressants, pulmonary function, and postoperative delayed ventilator weaning, were significantly correlated with the occurrence of MCAT on univariate analysis. MG patients with a history of MCBT are more susceptible to MCAT, particularly within the first 6 months of thymectomy. 15

Surbhi Mathur General Surgery PGY1 smathur2@uw.edu Thank You Surbhi Mathur General Surgery PGY1 smathur2@uw.edu