Guideline for the management of myasthenic syndromes

Abstract

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

Keywords: Lambert-Eaton myasthenic syndrome; congenital myasthenic syndromes; disease-modifying treatment; myasthenia gravis; myasthenic syndromes; treatment guideline.

Figure 1.

Scheme for the disease-modifying therapy of MG (therapy scheme). #: A (highly) active generalized MG (including ‘therapy refractory’ MG) may be defined as (a). moderate/high MGFA score (⩾MGFA IIb) and/or at least two recessive severe exacerbations/myasthenic crises requiring therapeutic intervention (IVIG, PLEX, and IA) within 1 year after first diagnosis and despite adequate disease-modifying and symptomatic treatment or (b). persistent symptoms relevant to daily living (⩾MGFA IIa) and one severe exacerbation/myasthenic crisis within the last 12 months despite adequate disease-modifying and symptomatic treatment or (c). persistent symptoms relevant to daily living (⩾MGFA IIa) present in MG of mild/moderate disease course despite adequate disease-modifying and symptomatic treatment for more than 2 years. Note: Disease severity is assessed according to MGFA classification. However, the MGFA status used here only takes into account the severity at the time of clinical assessment and not the highest score ever assessed in the course of disease. &: Seronegative and LRP4 antibody-positive MG are generally treated like AChR-Ab-positive MG. In italics: Off-label therapies (a). Steroids are not indicated as long-term therapy (at least above Cushing’s threshold, e.g. for prednisolone 7.5 mg/day); steroid-sparing strategies should be applied at an early stage. (b). Consider age (usually 18–65 years) and disease duration (usually <5 years); obligatory in case of suspected thymoma. (c). Off-label use of MMF is reimbursable as second choice therapy in Germany. (d). Eculizumab is on-label for the treatment of refractory AChR-Ab-positive gMG, ravulizumab is approved as add-on therapy for AChR-Ab-positive gMG. (e). Efgartigimod is approved as an add-on therapy for AChR-Ab-positive gMG. (f). IVIG is refundable when used as an off-label treatment for severe myasthenic exacerbations; SCIG can be used instead of IVIG in exceptional cases, but reimbursement is not regulated for this indication in Germany. (g). Cave: Steroid dip. (h). Justifiable as expanded access/compassionated use. Source: Own illustration. Ab, antibody; AChR, acetylcholine receptor; gMG, generalized MG; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; LRP4, lipoprotein-related protein 4; MMF, mycophenolate mofetil; SCIG, subcutaneous Ig.