864497 research-article20192019 TAN0010.1177/1756286419864497Therapeutic Advances in Neurological DisordersJ Gamez, M Salvadó, Therapeutic Advances in Neurological Disorders Original Research Intravenous immunoglobulin to prevent Ther Adv Neurol Disord 2019, Vol. 12: 1–13 myasthenic crisis after thymectomy and DOI: 10.1177/ https://doi.org/10.1177/1756286419864497 https://doi.org/10.1177/1756286419864497 1756286419864497 other procedures can be omitted in © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- patients with well-controlled permissions myasthenia gravis Correspondence to: Josep Gamez Department of Neurology, Vall d’Hebron University Josep Gamez , María Salvadó, Francesc Carmona, Miriam de Nadal, Laura Romero, Hospital, Vall d’Hebron Daniel Ruiz, Alberto Jáuregui, Olga Martínez, Javier Pérez, Pilar Suñé and María Deu Research Institute (VHRI), European Reference Network on Rare Neuromuscular Diseases Abstract (ERN EURO-NMD), Department of Medicine, Background: Myasthenic crisis (MC) is a potentially life-threatening complication of Universitat Autònoma de myasthenia gravis. Its precipitating factors include surgical procedures, particularly Barcelona. Passeig de la Vall d’Hebron 119-129, thymectomy. The role of preoperative intravenous immunoglobulin (IVIg) in preventing MC in Barcelona E-08035, Spain josepgamez.bcn@gmail. patients scheduled for thymectomy and other surgery with general anaesthesia is unknown. com Our objective was to test the hypothesis that preoperative IVIg is effective in preventing jgamez@vhebron.net myasthenic crisis in patients with myasthenia gravis scheduled for surgery under general María Salvadó Department of Neurology, anaesthesia, including thymectomy. Vall d’Hebron University Methods: A prospective, randomized, double-blind, single-centre study was conducted Hospital, Barcelona, Spain Department of Medicine, over a 4-year period. The treatment group received IVIg, 0.4 g/kg/day preoperatively for Universitat Autònoma de 5 consecutive days, and the placebo group received saline solution under the same conditions. Barcelona, Barcelona, Spain The two groups were age-matched, with similar functional status, and Myasthenia Gravis Francesc Carmona Foundation of America class. All patients had well-controlled myasthenia gravis with minimal Department of Genetics, Microbiology and manifestations before surgery. The primary outcome measured was MC. Intubation times, Statistics, University of time in the recovery room, number of postoperative complications, and days of hospitalization Barcelona, Barcelona, Spain were the secondary outcomes measured. Miriam de Nadal Results: A total of 47 patients were randomized, 25 to the IVIg group and 22 to placebo. There Department of Anesthesiology and were 19 men and 28 women, with a mean age of 58.6 years, mean body mass index of Intensive Care, Universitat 27.8 kg/m2, and mean acetylcholine receptor antibodies of 12.9 nmol/l. The mean forced vital Autònoma de Barcelona, Barcelona, Spain capacity was 84.4%. The mean quantitative myasthenia gravis sum score was 6.3. Ten patients Laura Romero (five in each arm) had a history of MC. Thymectomy was performed in 16 patients. Only one Department of Thoracic Surgery, Vall d’Hebron patient in the placebo group presented with MC requiring non-invasive ventilation (but no University Hospital, Barcelona, Spain reintubation) for 6 days. Neither differences between groups in the univariate analysis nor risk Daniel Ruiz factors for MC in the multivariate analysis were found. Department of Conclusions: Preoperative IVIg to prevent MC does not appear to be justified in well-controlled Anesthesiology and Intensive Care, Universitat myasthenia gravis patients. This study provides class I evidence that preparation with IVIg Autònoma de Barcelona, Barcelona, Spain to prevent MC is not necessary in well-controlled myasthenia gravis patients scheduled for Alberto Jáuregui surgery with general anaesthesia. Department of Thoracic Surgery, Vall d’Hebron University Hospital, Barcelona, Spain Keywords: clinical trial, immunoglobulin, myasthenia, myasthenic crisis, thymectomy Olga Martínez Department of Received: 26 March 2019; revised manuscript accepted: 26 June 2019. Anesthesiology and journals.sagepub.com/home/tan 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Neurological Disorders 12 Intensive Care, Universitat Autònoma de Barcelona, Introduction experience with the use of IVIg as preparation Barcelona, Spain Myasthenic crisis (MC) is a serious and poten- before surgery to control perioperative and post- Javier Pérez tially life-threatening complication of myasthenia operative complications in MG patients is limited Department of Thoracic Surgery, Vall d’Hebron gravis (MG) that occurs in approximately 15–20% to a few studies and noncontrolled randomized University Hospital, of patients during their lifetime.1 It is character- trials.24–26 Although these results are encouraging, Barcelona, Spain ized by severe weakness of the bulbar or respira- the design of a prospective, randomized, double- Pilar Suñé Department of Hospital tory muscles, sufficient to cause respiratory blind, placebo-controlled trial is needed to pro- Pharmacy, Vall d’Hebron failure and to require respiratory support. vide class I evidence of the effectiveness of IVIg in University Hospital, Barcelona, Spain Patients with MG undergoing a surgical proce- the preoperative setting. A clinical trial with these María Deu dure needing intubation and who experienced characteristics was therefore conducted. The Department of Thoracic delayed extubation of >24 h after surgery are also main objective was to assess the effectiveness of Surgery, Vall d’Hebron University Hospital, considered to experience MC.2 Common pre- IVIg as preparation before thymectomy and other Barcelona, Spain cipitating factors for MC include respiratory surgical procedures under general anaesthesia in infection, aspiration, sepsis, exposure to drugs MG patients to prevent postoperative MC. that may increase myasthenic weakness, preg- nancy and surgical operations.3,4 Thymomas are associated with a more fulminant course of MG Methods and are present in one third of patients who expe- rience MC.5 A significant number of MCs also Ethics occur in the context of surgical procedures, par- The protocol was designed following the recom- ticularly thymectomy, and often require pro- mendations for clinical research standards of the longed postoperative intubation.6–8 Estimates of Myasthenia Gravis Foundation of America mortality in MC are as high as 6–10%.9 The res- (MGFA).27 In accordance with the Declaration piratory failure that characterizes MC is the most of Helsinki, this study was carried out following common cause of death. the protocol approved by the Hospital Universitari Vall d’Hebron Institutional Review Thymectomy, alone or combined with immune- Board on 25 May 2012, with registration num- suppressive and anticholinesterase therapies, is ber MG2012PREP. All participants signed an currently accepted as the standard treatment for informed consent agreement following extensive MG.10–14 Co-adjuvant therapies with plasma explanation of the aims of the study. The study exchange (PLEX) or intravenous immunoglobu- was registered in the European Clinical Trials lin (IVIg) are effective disease-stabilizing regimens Database [EudraCT identifier: 2012-001544]. to reduce the risk of postoperative respiratory complications and the need for prolonged, assisted ventilation leading to extended hospitalization.15 Design and setting Small-scale clinical studies have shown signifi- Our study was a single-centre, prospective, rand- cant improvements in respiratory function and omized, double-blind, placebo-controlled trial muscle strength in thymectomized patients after involving parallel treatment with IVIg or placebo PLEX.16–19 Complications associated with the use preoperatively in consecutive patients diagnosed of a large-bore central venous catheter or the with MG scheduled for elective surgical proce- occurrence of large volume shifts during the pro- dures, including thymectomy under general anaes- cedure are limiting factors of PLEX. thesia between February 2013 and December 2016. The primary objective of the study was to IVIg represents a short-term immunomodulating assess the effectiveness of preoperative preparation alternative in patients who are poor candidates for with IVIg to prevent postoperative MC. Secondary PLEX, and has been demonstrated to be benefi- objectives were the effectiveness of IVIg in reduc- cial in controlling MC. A small randomized con- ing the length of hospital stays and inducing trolled trial of IVIg 1.2 and 2.0 g/kg over 2–5 days changes in the quantitative myasthenia gravis compared with PLEX in MG patients with exac- (QMG) score for disease severity. erbations or crisis showed comparable efficacy between the two treatment groups.20 Other stud- ies also failed to show significant differences in Patients the efficacy of PLEX and IVIg in patients during The patients were males and females acute exacerbations of MG.21–23 However, aged > 18 years, with generalized MG at the time 2 journals.sagepub.com/home/tan J Gamez, M Salvadó, et al. of screening27 needing elective surgical proce- 7 days before the procedure. The first dose was dures requiring general anaesthesia, including administered at least 12 days beforehand, with thymectomy. The eligible individuals belonged to the benefit of IVIg peaking around 15 days, just the cohort of MG patients monitored in our unit when surgery took place.28–31 Patients assigned and new patients who met criteria for thymec- to the placebo group received intravenous saline tomy. Exclusion criteria were as follows: hyper- solution for the same time period and under the sensitivity to homologous immunoglobulins; same conditions. The medications were pro- serum IgA levels < 5% below the lower limit of vided by the pharmacy department in photopro- normal values; presence of severe diseases, such tective bags and opaque tubes to mask the vials as heart failure, cardiomyopathy, severe coronary of immunoglobulin and placebo. The treatments heart disease, severe hypertension, and stages IV were administered under the supervision of one or V chronic kidney disease; history of thrombotic of the investigators (JG) in a day hospital setting. episodes (pulmonary embolism, acute myocardial Concurrent treatment with rituximab, alemtu- infarction, deep venous thrombosis, ischaemic zumab, plasmapheresis, tumour necrosis factor stroke, known hypercoagulable state); history of alpha (TNF-α) and other immunoglobulin was haemolysis, aseptic meningitis or severe recurrent not allowed. headache after intravenous infusion of immuno- globulins; pregnancy; and breastfeeding women. Assessments The diagnosis of MG was established by history The patients were evaluated at baseline, that is, at and clinical signs and symptoms. The following most, 15 days before the surgical procedure, and tests were performed to confirm the clinical diag- then every day until the 14th postoperative day. nosis: single-fibre electromyography (SF-EMG) Patients with MG were assessed until discharge and repetitive nerve stimulation, edrophonium test from the hospital. Measurements included vital (Tensilon®, Roche Laboratories, Hoffmann-La signs, laboratory tests (blood tests, biochemical Roche Inc., Nutley, NJ), and serum acetylcholine profile, and serum anti-AChR antibodies), pul- receptor (AChR) antibodies (AChR-Ab; RIA kit, monary function tests (EasyOne™ spirometer, RSR Ltd., Cardiff, UK). For patients negative for ndd Medizintechnik AG, Zurich, Switzerland), AChR-Abs, we tested for antimuscle-specific QMG score, MG quality-of-life questionnaire kinase (anti-MuSK) antibodies (MuSK-Ab; RSR (MGQoL), concomitant treatments/procedures, Ltd.). The preoperative diagnosis of thymoma was and adverse events (AEs). The QMG score is a based on clinical symptoms, conventional radio- scale ranging from 0 to 39, with higher scores for graphs, and chest computed tomographic (CT) each of 13 items indicating the most severe weak- scans. Thymectomy was indicated in generalized ness. The MGQoL consists of 15 items scored on forms of anti-AChR-positive MG, in patients a 5-point Likert scale (from 0 to 4), with higher under 55-years old, and in all patients with thy- scores indicating a lower QoL. moma, regardless of age. The following variables were recorded for all patients: demographics (sex, age); body mass Study procedures index (BMI); age at onset of MG; duration of After informed consent, the eligible patients MG; MGFA class at clinical onset; history of thy- scheduled for elective thymectomy (extended moma; previous MC and surgical procedures trans-sternal thymectomy) and other surgical with general anaesthesia; preoperative bulbar procedures under general anaesthesia were ran- symptoms and bulbar score; anti-AChR antibody domized to preoperative preparation with IVIg levels; forced vital capacity (FVC); forced expira- or placebo (see CONSORT flow chart in Figure tory volume in 1 s (FEV1); peak expiratory flow 1). A computer-generated list of random num- (PEF); QMG score; MGQoL score; preoperative bers was used to allocate the patients to the dose of pyridostigmine; steroids and other immu- treatment or placebo group. Patients in the nosuppressants (azathioprine, tacrolimus, treatment group received five doses of IVIg mycophenolate mofetil); duration of surgery; (0.4 g/kg/day; Privigen®, CLS Behring AG, Bern, blood transfusion requirement; duration of stay Switzerland) for 5 consecutive days before sur- in the post-surgery recovery room; length of hos- gery, with the final dose administered at least pital stay; and AEs. journals.sagepub.com/home/tan 3 Therapeutic Advances in Neurological Disorders 12 Figure 1. CONSORT diagram. Of the 49 patients recruited for the study, 2 withdrew informed consent. A total of 47 patients were subsequently randomized; 25 assigned to the IVIg group and 22 to the placebo group. IVIg, intravenous immunoglobulin. Endpoints when the distribution of data departed from nor- The primary endpoint of the study was the occur- mality. Analysis of variance and analysis of covar- rence of MC in both arms. The secondary end- iance were used to assess differences in QMG points were the length of hospital stay and changes scores and other outcome measures. To deter- in QMG score. mine variables associated with the primary end- point, defined as the presence of MC, variables were fitted in a logistic regression model using the Statistical analysis Firth penalized likelihood method,32 with the pre- Categorical variables are expressed as frequencies operative QMG score, duration of MG, preoper- and percentages, and continuous variables as ative FVC, and operative time as independent mean and standard deviation (SD). The distribu- variables. The Statistical Package for the Social tion of variables in the two study groups was com- Sciences (SPSS) programme (SPSS Inc., pared with the chi-square test or Fisher’s exact Chicago, IL, USA) version 16 was used for the test for categorical data, and the Student’s t test analysis of data. Statistical significance was set at or the Wilcoxon test for quantitative variables p < 0.05. 4 journals.sagepub.com/home/tan J Gamez, M Salvadó, et al. Results included prednisone in 31 cases, tacrolimus in 26, azathioprine in 4, and mycophenolate mofetil Baseline characteristics in 2. Six patients received pyridostigmine only A total of 49 patients were recruited for the study, and two patients tacrolimus only. The remaining but 2 of them withdrew informed consent. A total patients were treated with double or triple combi- of 47 patients were therefore randomized; 25 nations of pyridostigmine and immunosuppres- were assigned to the IVIg group and 22 to the sant drugs. placebo group. There were 19 men and 28 women, with a mean age of 58.6 years, mean BMI of 27.8 kg/m2. The mean disease interval between Perioperative data clinical onset and randomization was 6.2 years. Thymectomy was the most common surgical pro- The distribution of the patients according to cedure, and was performed in 16 (34.0%) MGFA class at clinical onset was 2 patients with patients. Differences in preoperative variables class I, 17 with class IIa, 3 with class IIb, 14 with between patients treated with IVIg (n = 9) or pla- class IIIa, 9 with class IIIb and 2 with class IVb. cebo (n = 7) in the subset of 16 thymectomized The two patients with an ocular form at clinical patients were not observed (Table 2). Details of onset had progressed to generalized forms at the the procedures are shown in Table 3. The mean time of study inclusion. Of the 47 patients, 45 duration of surgery was 120.7 min in the overall were anti-AChR-positive and 2 anti-MuSK-posi- study population and 159.1 min in patients tive. None was seronegative for anti-AChR and undergoing thymectomy (Table 4). Only one anti-MuSK (double seronegative). The mean thymectomized patient in the IVIg group required anti-AChR level was 12.9 nmol/l. FVC was 84.4% perioperative blood transfusion. Differences in and FEV1 90.1% of predicted values. None of the postoperative AEs per preparation regimen were patients was in complete clinical remission and all not observed. Surgical complications were of them belonged to the minimal manifestations recorded in two patients in the IVIg group and in category of the MGFA Post-Intervention Status three patients treated with placebo. (MGFA-PIS) classification. A total of 5 patients (IVIg 4, placebo 1) were classified as the MM-1 In relation to the primary endpoint, one patient (Minimal manifestations class 1) category, 2 randomized to the placebo group presented with (IVIg 2) as the MM-2 category and 40 (IVIg 19, MC, which required non-invasive ventilation (but placebo 21) as the MM-3 category. A total of 45 no reintubation) for 6 days. This 63-year-old patients had anti-AChR antibodies (IVIg 21, pla- woman had been diagnosed with MG 8 months cebo 24) and 2 patients had anti-MuSK antibod- previously and presented with a MC 3 months ies (IVIg 1, placebo 1), without differences before surgery. Her BMI was 41.9 kg/m2. The between the study groups. Twenty-six patients chest CT identified the presence of a thymoma. had previously undergone surgery with general She presented clinical signs of MC 2 h after leav- anaesthesia, half of which were thymectomies. A ing the operating room and undergoing extuba- total of 10 patients (5 in each arm) had previously tion. A control CT confirmed bilateral pleural presented MCs. Of these 10 patients with history effusion, left basal atelectasis, left phrenic nerve of previous MC, 1 patient presented a crisis after palsy, anaemia, cardiac arrhythmia (atrial fibrilla- thymectomy and 1 after abdominal surgery; in tion), progressive decompensation of her diabe- the remaining 8 patients, triggers were respiratory tes, high blood pressure values and renal infection in 4, mastoiditis in 1, use of benzodiaz- insufficiency. The patient was discharged home epines in 1, poor medication adherence in 1 and 28 days after surgery. The patient was randomized spontaneous in 1. As shown in Table 1, statisti- to the placebo group. MC was not recorded in cally significant differences in the distribution of any of the other study patients. preoperative variables between the study groups were not found, except for a lower level of anti- In relation to the secondary endpoints, no statisti- AChR antibodies in the placebo group as com- cally significant differences were found for the pared with the IVIg group (p = 0.045). length of stay in the recovery room after surgery or the total length of hospital stay between patients In relation to preoperative treatment, 45 patients treated with IVIg and those treated with placebo received anticholinesterase drugs as symptomatic (Table 4). As shown in Figure 2, the length of treatment. Treatment with immunosuppressants hospital stay was similar in patients treated with journals.sagepub.com/home/tan 5 Therapeutic Advances in Neurological Disorders 12 Table 1. Preoperative characteristics of the study population. Variables All patients Study groups p (n = 47) value IVIg (n = 25) Placebo (n = 22) Sex, n (%): 0.718 Men 19 (40.4) 9 (36) 10 (45.4) Women 28 (59.6) 16 (64) 12 (54.5) Age, years 58.6 (16.2) 61.1 (15.3) 55.7 (17.0) 0.357 BMI, kg/m2 27.8 (4.8) 27.4 (4.7) 28.2 (5.0) 0.898 Age at clinical onset, years 52.4 (18.6) 54.3 (17.5) 50.2 (20.0) 0.609 Duration of MG, years 6.2 (8.0) 6.8 (7.9) 5.5 (8.3) 0.639 MGFA class at clinical onset 0.090 I 2 0 2 IIA 17 11 6 IIB 3 3 0 IIIA 14 8 6 IIIB 9 3 6 IVB 2 0 2 MGFA-PIS category 0.200 MM-1 5 4 1 MM-2 2 2 0 MM-3 40 19 21 Patients with prior history of: Thymoma 13 (27.7) 6 (24) 7 (31.8) 0.786 Surgery with general anaesthesia 26 (55.3) 13 (52) 13 (59.1) 0.846 Myasthenic crisis 10 (21.3) 5 (20) 5 (22.7) 1.000 Bulbar symptoms, n (%) 14 (29.8) 6 (24) 8 (36.4) 0.545 Bulbar score 0.3 (0.7) 0.1 (0.3) 0.4 (1.0) 0.296 Anti-AChR level, nmol/l 12.9 (8.3) 14.4 (8.0) 11.3 (8.5) 0.045 Pulmonary function tests: FVC, % 84.4 (14.9) 85.1 (15.4) 83.7 (14.6) 0.912 FEV1, % predicted 90.1 (17.9) 91.0 (18.9) 89.0 (17.0) 0.886 Peak flow 396.4 (142.1) 359.2 (135.9) 438.6 (140.2) 0.796 QMG score 6.3 (3.7) 6.1 (3.8) 6.6 (3.5) 0.653 (Continued) 6 journals.sagepub.com/home/tan J Gamez, M Salvadó, et al. Table 1. (Continued) Variables All patients Study groups p (n = 47) value IVIg (n = 25) Placebo (n = 22) MGQoL score 13.7 (14.7) 11.6 (13.6) 16.0 (15.8) 0.472 Pyridostigmine treatment, n (%) 42 (89.4) 21 (84.0) 21 (95.5) 0.352 Pyridostigmine, mg 178.1 (35.4) 180.0 (30.0) 175.7 (43.9) 1.000 Immunosuppressants, mg/day: Prednisone (n = 47) 11.8 (20.6) 13.5 (21.7) 9.9 (19.5) 0.600 Azathioprine (n = 4) 62.5 (25.0) 62.5 (25.0) 0 0.112 Tacrolimus (n = 26) 3.5 (1.3) 3.2 (1.2) 3.9 (1.4) 0.229 Mycophenolate mofetil (n = 2) 1250 (1061) 500 2000 1.000 Data as mean ± SD unless otherwise stated. AChR, acetylcholine receptor; BMI, body mass index; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; IVIg, intravenous immunoglobulin; MG, myasthenia gravis; MGFA-PIS, Myasthenia Gravis Foundation of America Post- Intervention Status; MGQoL, MG quality-of-life questionnaire; MM, minimal manifestations; MM-1, the patient continues to receive some form of immunosuppression but no cholinesterase inhibitors or other symptomatic therapy; MM-2, the patient has received only low-dose cholinesterase inhibitors (,120 mg pyridostigmine/day) for at least 1 year; MM-3, the patient has received cholinesterase inhibitors or other symptomatic therapy and some form of immunosuppression during the past year; QMG, quantitative myasthenia gravis score; SD, standard deviation. IVIg and those treated with placebo in the overall severe enough to require intubation and mechani- study population and in the subset of patients cal ventilation is approximately 20–30%.33 A sig- undergoing thymectomy. Similar findings were nificant number of these MCs occur in the context observed regarding the length of stay in the post- of surgical procedures, particularly thymecto- surgical recovery room (Figure 3). mies, and often lead to prolonged postoperative intubation and prolongation in the intensive care The mean QMG score before surgery was unit and extended hospitalization. A number of 6.3 points (SD ± 3.7). There was a deterioration risk factors for MC have been reported, including of the QMG score on the first day after surgery of chronic MG (more than 6 years), pre-existing res- less than 2 points (mean 7.9, SD ± 4.0), returning piratory disease, large doses of pyridostigmine, to baseline values on the postoperative day 4. severe bulbar weakness, thymoma, major postop- Changes in the QMG score in the two study erative complications, and marginal preoperative groups were similar (Figure 4). Intergroup differ- vital capacity.8,34–36 Furthermore, weaning ences in the QMG score over the 14 days of the patients with MC from mechanical ventilation is study compared with baseline were not statisti- often difficult, and the ideal time for extubation is cally significant. uncertain. It has been shown that older age, male sex, history of previous crisis, development of Finally, in the logistic regression model, none of pulmonary complications, in particular atelecta- the variables analysed (preoperative QMG score, sis, and intubation for more than 10 days are asso- duration of MG, preoperative FVC and operative ciated with extubation failure.6,37 Moreover, time) were predictors of MC in either the overall extubation failure leads to poorer outcomes.38 study population or in the subset of thymecto- mized patients. The first-line therapies for the treatment of MC are IVIg and PLEX.39,40 Although there is some evidence to suggest PLEX may be more effective Discussion than IVIg in the treatment of MC,41 other studies The lifetime prevalence of acute episodes of res- have found these treatments to be equally effec- piratory muscle weakness in MG patients that are tive.20,42 In addition, PLEX has been used to journals.sagepub.com/home/tan 7 Therapeutic Advances in Neurological Disorders 12 Table 2. Preoperative characteristics of patients undergoing thymectomy. Variables All patients Study groups p (n = 16) value IVIg (n = 9) Placebo (n = 7) Sex, n (%) 0.358 Men 7 (43.7) 5 (55.6) 2 (28.6) Women 9 (56.2) 4 (44.4) 5 (71.4) Age, years 53.9 (13.4) 52.7 (10.4) 55.5 (17.3) 0.681 BMI, kg/m2 27.1 (6.0) 25.4 (4.6) 29.4 (7.1) 0.596 Age at clinical onset, years 53.1 (13.6) 51.9 (10.7) 54.5 (17.5) 0.681 Duration of MG, years 0.8 (0.6) 0.8 (0.6) 0.8 (0.5) 0.918 MGFA class at clinical onset, no.: 0.090 I 0 0 0 IIA 6 4 2 IIB 1 1 0 IIIA 5 3 2 IIIB 3 2 1 IVB 1 0 1 Patients with prior history of: Thymoma 9 (56.2) 5 (55.5) 4 (57.1) 1.000 Surgery with general anaesthesia 5 (31.2) 4 (44.4) 1 (14.3) 0.308 Myasthenic crisis 4 (25) 1 (11.1) 3 (42.9) 0.261 Bulbar symptoms, n (%) 5 (31.2) 2 (22.2) 3 (42.9) 0.596 Bulbar score 0.4 (1.0) 0.2 (0.4) 0.7 (1.5) 0.727 Anti-AChR level, nmol/l 15.5 (8.1) 16.3 (7.4) 14.4 (8.5) 0.440 Pulmonary function tests: FVC, % 86.4 (14.8) 84.3 (17.1) 89.1 (11.8) 0.408 FEV1, % predicted 92.7 (16.1) 90.1 (17.4) 96.1 (14.8) 0.681 Peak flow 433.7 (110.4) 438.6 (127.2) 430.0 (103.3) 0.832 QMG score 6.1 (3.0) 5.2 (2.4) 7.1 (3.5) 0.363 MGQoL score 18.5 (17.3) 17.3 (18.7) 20.0 (16.7) 0.633 Pyridostigmine treatment, n (%) 12 (75%) 7 (77.8) 5 (71.4) 1.000 Pyridostigmine, mg/day 178.1 (35.4) 180 (30) 175.7 (43.9) 1.000 Immunosuppressants, mg/day: Prednisone (n = 15) 22.2 (24.7) 21.1 (20.3) 23.6 (31.2) 0.957 Azathioprine (n = 1) 50 50 0 Tacrolimus (n = 10) 3.4 (1.3) 3.2 (0.8) 3.6 (1.7) 1.000 Data as mean ± SD unless otherwise stated. AChR, acetylcholine receptor; BMI, body mass index; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; IVIg, intravenous immunoglobulin; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; MGQoL, MG quality-of-life questionnaire; QMG, quantitative myasthenia gravis score; SD, standard deviation. 8 journals.sagepub.com/home/tan J Gamez, M Salvadó, et al. Table 3. Type of surgical procedures. Surgery Number of patients (%) All patients 47 (100) Thymectomy 16 (34.0) Combined gastroscopy and colonoscopy 9 (19.1) Abdominal procedures 7 (14.9)   Laparoscopic cholecystectomy 5   Adrenalectomy 1   Bariatric surgery 1 Cardiothoracic procedures 5 (10.6)    Cardiac radiofrequency ablation 2    Mitral valve replacement 1   Thoracoscopic lobectomy 1    Metastatic pleural resection 1 Hysterectomy 4 (8.5) Maxillofacial procedures 4 (8.5)   Mastoidectomy 2   Parotidectomy 2 Bladder tumour resection 1 (2.1) Total hip replacement 1 (2.1) Table 4. Perioperative data in all patients and in those undergoing thymectomy. Variables Overall study population Thymectomy surgical procedures All patients IVIg Placebo All patients IVIg Placebo (n = 47) (n = 25) (n = 22) (n = 16) (n = 9) (n = 7) Operation time, min 120.7 (68.0) 122.9 (68.7) 118.2 (68.8) 159.1 (52.1) 166.7 (59.1) 149.3 (43.9) p = 0.749 p = 0.832 Blood transfusion, n (%) 1 (2.1) 1 (4.2) 0 1 (6.2) 1 (11.1) 0 p = 1.000 p = 0.601 Time in recovery room, h 22.6 (42.2) 19.9 (28.9) 25.8 (54.1) 42.6 (65.8) 32.9 (40.1) 55.2 (91.5) p = 0.733 p = 0.536 Length of hospital stay, days 3.7 (3.7) 3.2 (2.7) 4.2 (4.5) 5.4 (4.9) 4.8 (3.3) 6.3 (6.5) p = 0.586 p = 0.782 Data as mean ± SD unless otherwise stated. IVIg, intravenous immunoglobulin; SD, standard deviation. journals.sagepub.com/home/tan 9 Therapeutic Advances in Neurological Disorders 12 Figure 2. Effect of preoperative preparation with IVIg Figure 3. Effect of preoperative preparation with IVIg or placebo on hospital stay. or placebo on stay in the postsurgical recovery room. Effect of preoperative preparation with IVIg or placebo on Effect of preoperative preparation with IVIg or placebo on the length of hospital stay in the overall study population of the length of stay in the postsurgical recovery room in the 47 patients (a) and in the subset of 16 patients undergoing overall study population of 47 patients (a) and in the subset thymectomy (b). of 16 patients undergoing thymectomy (b). IVIg, intravenous immunoglobulin. IVIg, intravenous immunoglobulin. prepare patients for thymectomy and has been (cardiothoracic and abdominal surgery), as well as shown to improve postoperative outcomes.18 low-risk interventions (gynaecological, urological, Isolated reports have described cases of IVIg as orthopaedic and endoscopic procedures) have been also being able to prevent MC.23,43 However, evaluated. Our study was designed following the there have been no randomized controlled and recommendations for clinical research standards27 double-blind trials to examine the effectiveness of and the international consensus guidance for the preoperative treatment with IVIg in preventing management of MG of the MGFA.44 Only one MC in surgical MG patients. Although they were case of MC occurred in this study, in a patient obtained in a limited number of patients, the assigned to the placebo group, and none of the results reported here are therefore new and clini- patients treated preoperatively with IVIg developed cally relevant. MC. Given the baseline characteristics of the study population, it therefore seems that in MG subjects This is the first prospective study to evaluate the with preoperative QMG score < 8 and preopera- protective capacity of IVIg against postoperative tive FVC > 70%, no MC can be expected, regard- MC in patients with MG who are going to undergo less of age, MGFA class at onset, BMI, anti-AChR surgical procedures under general anaesthesia. In antibody level, and dosage of pyridostigmine or addition to thymectomy, this is also the first time other immunosuppressant drugs. On the other that other major and high-risk surgical procedures hand, we were unable to identify predictors of 10 journals.sagepub.com/home/tan J Gamez, M Salvadó, et al. other than thymectomy was also a distinctive fea- ture of the study. The main limitations of this study were that the MG patients at baseline were in good condition, with QMG scores and vital capacity close to nor- mal values. Before surgery, MG patients must achieve a postintervention status14 that is close to minimal manifestations or improvement. The fact that only one patient presented with MC means that statistical conclusions cannot be drawn, and logistic regression analysis with rare events also fails to provide a solution. Figure 4. Changes in mean QMG score. Changes in mean QMG score in the overall study population of 47 patients according to preoperative preparation with Taken together, our findings indicate that preop- IVIg or placebo. erative treatment with IVIg to prevent MC does IVIg, intravenous immunoglobulin; QMG, quantitative not appear to be justified in well-controlled MG myasthenia gravis. patients undergoing surgical procedures with general anaesthesia in high-volume MG centres. Plasmapheresis is also an effective treatment for postoperative MC, such as vital capacity < 80%, MC, but no controlled studies have been per- disease duration < 3 months, or the recently formed to compare IVIg and plasmapheresis.46,47 reported bulbar symptoms immediately before On the other hand, use of IVIg as a maintenance thymectomy45 in a study that developed a scoring therapy or as a steroid-sparing agent has been system to predict the possibility of postoperative studied to a limited extent.47 Better knowledge of MC. We also failed to identify other risk factors the main cells and pathways involved in the for MC shown in other studies, such as high BMI, immune network of MG have led to emerging high doses of pyridostigmine, anti-AChR titres, target-specific biologics with promising clinical thymoma, history of MC, dysphagia, bulbar relevance for treating early, acute and chronic symptoms, or intraoperative blood loss. MG and patients with refractory disease.47–49 Pretreatment with IVIg administered before thymectomy and other surgical procedures may Authors’ note consequently be omitted, based on our results for This paper was presented at the Clinical Trials the placebo and IVIg groups. It is possible that the Plenary Session of the 71st Annual Meeting of high cost of IVIg and potentially secondary effects the American Academy of Neurology, of high-dose IVIg are not justified, provided that Philadelphia, USA, 4–10 May 2019. MG patients have a preoperative QMG score < 8, good vital capacity, and the surgical procedure Funding takes place in hospitals with MG units and experi- The authors disclosed receipt of the following enced neurologists, anaesthetists, and surgeons financial support for the research, authorship, experienced in the medical and surgical care of and/or publication of this article: This work was MG patients. funded by a Fondo de Investigación Sanitaria (FIS-FEDER) (grants PI16-01673 and The number of thymectomies performed during PI19/00593) and an Interlaken Research Award the study period of 16 procedures is substantially Programme (2012-12094537). higher than in other studies of the outcome of thymectomy. In the MGTX study11 36 sites and Conflict of interest statement 6 years were required to recruit 66 patients treated The authors declare that there is no conflict of with thymectomy, with a ratio of 0.3 patients/cen- interest. tre/year. 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