A multicenter analysis of 250 cases

Objective To determine demographic characteristics, clinical features, treatment regimens, and outcome of myasthenic crisis (MC) requiring mechanical ventilation (MV). Methods Analysis of patients who presented with MC between 2006 and 2015 in a German multicenter retrospective study. Results We identified 250 cases in 12 participating centers. Median age at crisis was 72 years. Median duration of MV was 12 days. Prolonged ventilation (>15 days) depended on age (p = 0.0001), late-onset myasthenia gravis (MG), a high Myasthenia Gravis Foundation of America Class before crisis (p = 0.0001 for IVb, odds ratio [OR] = infinite), number of comorbidities (>3 comorbidities: p = 0.002, OR 2.99), pneumonia (p = 0.0001,OR 3.13), and resuscitation (p = 0.0008, OR 9.15). MV at discharge from hospital was necessary in 20.5% of survivors. Patients with early-onsetMG (p = 0.0001, OR 0.21), thymus hyperplasia (p= 0.002, OR0), and successful noninvasive ventilation trial were more likely to be ventilated for less than 15 days. Noninvasive ventilation in 92 cases was sufficient in 38%, which was accompanied by a significantly shorter duration of ventilation (p = 0.001) and intensive care unit (ICU) stay (p = 0.01). IV immunoglobulins, plasma exchange, and immunoadsorption were more likely to be combined sequentially if the duration of MV and the stay in an ICU extended (p = 0.0503, OR 2.05). Patients who received plasma exchange or immunoadsorption as first-line therapy needed invasive ventilation significantly less often (p = 0.003). In-hospital mortality was 12%, which was significantly associated with the number of comorbidities (>3) and complications such as acute respiratory distress syndrome and resuscitation. Main cause of death was multiorgan failure, mostly due to sepsis. Conclusion Mortality and duration of MC remained comparable to previous reports despite higher age and a high disease burden in our study. Prevention and treatment of complications and specialized neurointensive care are the cornerstones in order to improve outcome. MORE ONLINE CME Course NPub.org/cmelist *On behalf of the Initiative of German Neurointensive Trial Engagement (IGNITE). From theDepartment of Neurology (B.N., K.A., A.V.), UniversityMedical Center Regensburg; NeuroCure Clinical Research Center (P.M., S.K., A.M.) andDepartments of Neurology and Experimental Neurology (P.M., A.M.), Charité–Universitätsmedizin Berlin; Berlin Institute of Health (P.M., S.K., A.M.); Department of Neurology (S.S., J.B.), HeidelbergUniversity Hospital; Department ofNeurology (J.B.), KlinikumKassel; Department ofMathematics and Computer Science (U.N.), Philipps-Universität Marburg; Department of Neurology (H.B.H., S.T.G.), University Hospital Erlangen; Department of Neurology (A.T., A.S.), HELIOS Klinikum Erfurt; Department of Neurology (J.D., C.R.), DRK-Kliniken Nordhessen, Kassel; Department of Neurology (H.S., E.S.), University Hospital, Technische Universität Dresden; Department of Neurology (H.S.), Klinikum Augsburg; Department of Neurology (E.S.), Städtisches Klinikum Dresden; Department of Neurology (H.F.), University of Freiburg; Department of Neurology (C.F.), St. Josef‐Hospital, Ruhr‐University Bochum; Department of Neurology (A.A.), KlinikenMaria Hilf GmbHMönchengladbach; Hans Berger Department of Neurology (J.Z.), Jena University Hospital; Department of Neurology (C.D., H.R.S.), University of Cologne; and Department of Neurology (C.D.), LVR-Klinik Bonn, Germany. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. Coinvestigators are listed in appendix 2 at the end of the article. Copyright © 2019 American Academy of Neurology e299 Copyright © 2019 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Within the first 2 years after the diagnosis of myasthenia gravis (MG), approximately 15%–20% of patients with MG develop a potentially life-threatening myasthenic crisis (MC) with requirement of mechanical ventilation (MV) and extended intensive care management. Until the early 1960s, mortality of MC was >40%. Today, reports on mortality are heterogeneous and usually range between 5% and 12% but higher rates up to 22% also have been reported. Data on therapy regimens, outcome, and mortality in MC are based mainly on small monocentric cohorts or on nationwide registries. The first group is less representative due to the single-center character with a small study population (13–53 patients); the second group exclusively addressed epidemiologic issues and outcome but lacked clinical data. In addition, data might have been biased because of different definitions of crisis including or excluding Myasthenia Gravis Foundation of America (MGFA) Class IV. In consequence, reliable data for MC requiring MV (MGFA Class V) from large-enough cohorts hardly exist. There are reports that demographic characteristics in MG—such as an increasing prevalence of elderly—have changed, but little is known if this is applicable for MC as well and how it affects therapy and outcome of MC since age and comorbidity are main predictors for survival. Moreover, it is not known whether noninvasive ventilation (NIV), proposed by few monocentric trials, is applied inMC to a noteworthy degree in real-world practice. This study was performed in order to analyze clinical characteristics, treatment, and potential factors affecting outcome and mortality of MC requiring MV in a representative neurocritical care population. Methods Study design and patient selection Twelve German Departments of Neurology with specialized neurointensive care units (NICUs) or neurologically associated interdisciplinary intensive care units (ICUs) took part in the study, 4 of which were certified myasthenia centers (thus being specialized in the treatment of MG and fulfilling certain quality standards by the Deutsche Myasthenie Gesellschaft–DMG/German Myasthenia Society). All consecutive patients were retrospectively analyzed if they had MC and required MV. For identification, all patients discharged with the diagnosis of MG according to the ICD-10 (G70.0-70.3) who were treated and ventilated in an ICU between 2006 and 2015 were reviewed. MC was defined as an exacerbation of myasthenic symptoms with bulbar or general weakness requiring MV. Diagnosis of MG had to be established according to national guidelines clinically and confirmed by specific tests (antibody testing or repetitive stimulation or improvement after cholinergic medication). Patients with cholinergic crisis, LambertEaton syndrome, and myasthenic syndromes other than MG (such as congenital MG) were excluded as well as those who required MV due to reasons other than MG (e.g., heart failure or after surgery) and if MV was initiated within 4 weeks after thymectomy to exclude patients with postthymectomy crisis. Episodes of MC were counted separately if patients were discharged in their prehospital status and if new triggers for the next crisis could be determined. Standard protocol approvals, registrations, and patient consents Local ethics committees and institutional review boards of the participating centers approved the study based on the central vote of the ethics committee at University of Regensburg (no. 15-101-0259). Patient consent was not necessary after ethic committee approval since solely retrospective data were obtained and patients were anonymized. Data acquisition We obtained data on baseline demographics, clinical features, medication, and comorbidities by reviewing medical charts and institutional databases. MGFA class in the last visit before MC, the most likely factors that precipitated the crisis (multiple answers possible), antibody status, and history of thymoma, and thymectomy were recorded. Data collection regarding treatment regimens included IV immunoglobulin (IVIg), plasma exchange (PE), immunoadsorption (IA), and IV pyridostigmine or neostigmine. MV was categorized as NIV, invasive ventilation, and invasive ventilation after NIV (NIV + invasive ventilation). Data regarding clinical course of MC included duration of ICU stay and days in hospital, duration of MV, predefined complications, in-hospital mortality, and site of referral/discharge. We obtained follow-up data on mortality and outcome from institutional databases after discharge as available. Glossary AChR-Ab = acetylcholine receptor antibody; CPR = cardiopulmonary resuscitation; IA = immunoadsorption; ICD-10 = International Classification of Diseases–10; ICU = intensive care unit; IVIg = IV immunoglobulin; LOS-h = length of stay in hospital; LOS-ICU = length of stay in intensive care unit; MANOVA = multivariate analysis of variance; MC = myasthenic crisis; MG = myasthenia gravis; MGFA = Myasthenia Gravis Foundation of America; MLE = maximum likelihood estimate; MMF =mycophenolate mofetil;MTX =methotrexate;MuSK-Ab =muscle-specific tyrosine kinase antibody;MV =mechanical ventilation; NICU = neurointensive care unit; NIV = noninvasive ventilation; OR = odds ratio; PE = plasma exchange. e300 Neurology | Volume 94, Number 3 | January 21, 2020 Neurology.org/N Copyright © 2019 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Statistics GraphPad Prism 5 (GraphPad Software, La Jolla, CA) as well as R (The R Foundation for Statistical Computing, Vienna, Austria) was used for statistical analysis. Depending on distribution, data were presented as mean (SD) or median (interquartile range); group comparison was tested with either Student t test or Fisher exact test with odds ratios (ORs), respectively. The significance level was set to α = 0.05 both-sided. For the calculation of OR, the conditional maximum likelihood estimate (MLE) was used, rather than the unconditional MLE. Duration of ventilation was dichotomized (>15 days vs <15 days). To detect significant differences among group means of metric d