Myasthenia gravis: do not forget the patient perspective

Abstract

•Myasthenia gravis patients have a significant disease burden in addition to muscle weakness.•Fatigue is prominent in a subgroup of patients with myasthenia gravis.•Patient-reported data illustrate limitations in daily activities and quality of life in myasthenia gravis.•Comorbidities and treatment side-effects should be evaluated in all patients with myasthenia gravis.•Optimal and specialized care for myasthenia gravis should be evaluated with a local, national and global perspective. Patients with a chronic disease often have worries about the future and experience impairment in daily functions and quality of life. Symptoms such as fatigue, pain, insomnia, and depression are common, often secondary to the primary disease manifestation. Doctors tend to focus on the specific disease-related symptoms and signs, ongoing disease activity and improvement or deterioration of relevant biomarkers. Myasthenia gravis (MG) is a chronic disease with weakness in some but not all skeletal muscles as the single primary symptom [[1]Gilhus N.E. Verschuuren J.J. Myasthenia gravis: subgroup classification and therapeutic strategies.Lancet Neurol. 2015; 14: 1023-1036Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar]. Antibodies to acetylcholine receptors (AChR), muscle-specific kinase (MuSK), or lipoprotein-related peptide (LRP4) in the postsynaptic muscle membrane are specific for MG and induce the muscle weakness [[2]Gilhus N.E. Tzartos S. Evoli A. Palaces J. Burns T.M. Verschuuren J. Myasthenia gravis.Nature Rev Dis Primers. 2019; 5: 30Crossref PubMed Scopus (76) Google Scholar]. In 10-20% of MG patients, no such serum antibodies are detected by standard assays. AChR, MuSK and LRP4 antibodies bind selectively to skeletal muscle and have the sole action of impairing neuromuscular transmission, thus reducing skeletal muscle function. However, patients often describe fatigue as more important than weakness for daily function. MG treatment aims at restoring the function of neuromuscular transmission [[3]Gilhus N.E. Myasthenia and the neuromuscular junction.Curr Opin Neurol. 2012; 25: 523-529Crossref PubMed Scopus (49) Google Scholar]. This can be done symptomatically by increasing acetylcholine availability through inhibition of acetylcholine esterase, or by suppression of the immune response against the postsynaptic muscle membrane. Supportive and additional therapies aiming at the total patient incapacities are often neglected. Most MG patients do well. In a long-term study, 75% had remission or only mild symptoms, and only 3% had lasting severe disease [[4]Andersen J.B. Gilhus N.E. Sanders D.B. Factors affecting outcome in myasthenia gravis.Muscle Nerve. 2016; 54: 1041-1049Crossref PubMed Scopus (29) Google Scholar]. There is hardly any increased mortality due to MG [5Owe J.F. Daltveit A.K. Gilhus N.E. Causes of death among patients with myasthenia gravis in Norway between 1951 and 2001.J Neurol Neurosurg Psychiat. 2006; 77: 203-207Crossref PubMed Scopus (41) Google Scholar, 6Hansen J.S. Danielsen D.H. Somnier F.E. Frøslev T. Jakobsen J. Johnsen S.P. et al.Mortality in myasthenia gravis: a nationwide population-based follow-up study in Denmark.Muscle Nerve. 2016; 53: 73-77Crossref PubMed Scopus (18) Google Scholar, 7Westerberg E. Punga A.R. Mortality rates and causes of death in Swedish myasthenia gravis patients.Neuromusc Dis. 2020; 30: 815-824Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. However, only around 20 % obtain a complete stable remission [[8]Mantegazza R. Antozzi C. When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies.Ther Adv Neurol Dis. 2018; 11: 1-11Crossref Scopus (55) Google Scholar], and 15-25% do not respond satisfactorily to first and second-line treatments [[8]Mantegazza R. Antozzi C. When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies.Ther Adv Neurol Dis. 2018; 11: 1-11Crossref Scopus (55) Google Scholar]. In a retrospective, Chinese study of 2154 patients, 9% had at least one MG crisis with the use of respiratory support [[9]Huang X. Liu W.B. Men L.N. Feng H.Y. Li Y. Luo C.M. et al.Clinical features of myasthenia gravis in southern China: a retrospective review of 2,154 cases over 22 years.Neurol Sci. 2013; 34: 911-917Crossref PubMed Scopus (40) Google Scholar]. MG implies considerable costs for the individual as well as for the society [[10]Landfeldt E. Pogoryelova O. Sejersen T. Zethraeus N. Breiner A. Lochmuller H. Economic costs of myasthenia gravis: a systematic review.Pharmacoeconom. 2020; 38: 715-728Crossref PubMed Scopus (3) Google Scholar]. Patient reports, either as a score in formal outcome measures or as complaints during ordinary consultations, illustrate how other aspects than actual muscle strength is important in their self-evaluation of current health status. Fatigue is prominent in some patients, and does not necessarily correlate to muscle strength [[11]Ruiter A.M. Verschuuren J. Tannemaat M.R. Fatigue in patients with myasthenia gravis. A systematic review of the literature.Neuromusc Dis. 2020; 30: 631-639Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. This fatigue can peripheral (due to muscle microdamage and activity) and central (with a brain component) [[11]Ruiter A.M. Verschuuren J. Tannemaat M.R. Fatigue in patients with myasthenia gravis. A systematic review of the literature.Neuromusc Dis. 2020; 30: 631-639Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Daily functions, working capacity and quality of life are not determined by arm strength or ptosis alone. Patient-reported tools for MG include MG-ADL, MG Impairment Index and MG-QOL15 [[2]Gilhus N.E. Tzartos S. Evoli A. Palaces J. Burns T.M. Verschuuren J. Myasthenia gravis.Nature Rev Dis Primers. 2019; 5: 30Crossref PubMed Scopus (76) Google Scholar,[12]Barnett C. Herbelin L. Dimachkie M.M. Barohn R.J. Measuring clinical treatment response in myasthenia gravis.Neurol Clin. 2018; 36: 339-353Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar,[13]Burns T.M. Sadjadi R. Utsugisawa K. Gwathmey K.G. Joshi A. Jones S. et al.International clinimetric evaluation of MG-QoL15, resulting in slight revision and subesequent evaluation of the MG-QoL15R.Muscle Nerve. 2016; 54: 1015-1022Crossref PubMed Scopus (37) Google Scholar The scores reflect patient satisfaction, adaptability and health status, but does not necessarily correlate to severity or deterioration of MG muscle weakness [[14]Menon D. Barnett C. Bril V. Comparison of the single simple question and the patient acceptable symptom state in myasthenia gravis.Eur J Neurol. 2020; 27: 2286-2291Crossref PubMed Scopus (2) Google Scholar]. The aim of this review is to focus on MG aspects that in our experience are very important for the patient, but less so for the treating neurologists. The authors of this opinion paper, consisting of expert neurologists and patients suggested as representatives by their MG organizations from three European countries, have through a consensus process selected such aspects. Consensus was reached through several digital meetings where high priority aspects from all authors were accepted, without any further formal process. The first author searched Web of Science for the key words myasthenia gravis and each aspect combined, and selected the most relevant papers. The co-authors supplemented with relevant papers. The patient's perspective combines their present health situation with prognosis, treatment effects and side-effects, benefits versus risks of procedures and treatments, therapies in addition to pharmacological drugs, comorbidity, and availability of best treatment and expertise. Controlled studies are sparse, exact knowledge is limited, and the authors’ personal experience has been included. Discussing all relevant aspects should make it easier to adapt to living with MG. This is especially important for newly diagnosed patients who usually have a lot of questions and concerns. When evidence-based information is available, it should be presented for the patients. Patient-reported data and registry data both illustrate that MG patients often experience impaired daily functions even when their muscle weakness is only mild to moderate. This can be due to specific limitations, such as diplopia impairing driving. More often it is explained by the numerous demanding tasks for modern people at work and in leisure time. An additional health factor such as mild MG may lead to severe consequences for daily functions. This can reflect a competitive labour market, expectations in family life, or comorbidity. In a North American registry study of 1140 MG patients, a large proportion had a significant disease burden measured by activities of daily living and quality of life [[15]Cutter G. Xin H.C. Aban I. Burns T.M. Allman P.H. Farzaneh-Far R. et al.Cross-sectional analysis of the myasthenia gravis patient registry: Disability and treatment.Muscle Nerve. 2019; 60: 707-715Crossref PubMed Scopus (15) Google Scholar]. This burden was not clearly related to muscle strength or ongoing treatment. Younger patients and women reported more limitations and a poorer disease-specific quality of life. The authors suggested that more active immunosuppressive drug treatment might have improved daily functions in this cohort. In a population study from two European countries (Norway and The Netherlands) health-related quality of life was reduced in MG patients with generalized symptoms, whereas those with ocular symptoms only or in remission scored similar to healthy controls [[16]Boldingh M.I. Dekker L. Maniaol A.H. Brunborg C. Lipka A.F. Niks E.H. et al.An up-date on health-related quality of life in myasthenia gravis -results from population based cohorts.Health Qual Life Outcomes. 2015; 13: 115Crossref PubMed Scopus (37) Google Scholar]. Female gender, but not age, was a determinant for lower quality of life. Physical activity, job, socio-economic factors, psychological well-being , and comorbidity were determinants for quality of life and daily functions. Quality of life in MG had not improved compared to studies from previous decades despite more effective immunosuppressive treatment. A Chinese cross-sectional study of 1815 MG patients found a distinct reduction in activities of daily living [[17]Dong D. Chong M.K.C. Wu Y.S. Kaminski H. Cutter G. Xu X. et al.Gender differences in quality of life among patients with myasthenia gravis in China.Health Qual Life Outcomes. 2020; 18: 296Crossref PubMed Scopus (2) Google Scholar]. This reduction correlated with quality of life, but less so with muscle strength. Main factors associated with daily living impairment were comorbidities, female sex, and unemployment. Younger patients with MG reported more symptoms and lower health-related quality of life. An active lifestyle counteracted reduced functions, whereas social support did not influence the results. Side-effects of MG drug treatment may have an impact on daily functions [[18]Bacci E.D. Coyne K.S. Poon J.L. Harris L. Boscoe A.N. Understanding side effects of therapy for myasthenia gravis and their impact on daily life.BMC Neurol. 2019; 19: 335Crossref PubMed Scopus (8) Google Scholar]. MG patients often need to ration their daily activities. This means that they may be unable to combine full-time jobs and perform tasks at home. Frost et al found that MG patients had almost six times higher odds of no labour market participation and long-term sick leave compared with the general Danish population [[19]Frost A. Svendsen M.L. Rahbek J. Stapelfeldt C.M. Nielsen C.V. Lund T. Labour market participation and sick leave among patients diagnosed with myasthenia gravis in Denmark 1997-2011: a Danish nationwide cohort study.BMC Neurol. 2016; 16: 224Crossref PubMed Scopus (8) Google Scholar]. Females were more affected. Immunosuppressive drug treatment, a proxy for MG severity, was negatively associated with labour-market participation. MG patients with refractory disease worked fewer hours than those with a well-controlled MG [[20]Harris L. Aban I.B. Xin H.C. Cutter G. Employment in refractory myasthenia gravis: A Myasthenia Gravis Foundation of America Registry analysis.Muscle Nerve. 2019; 60: 700-706Crossref PubMed Scopus (3) Google Scholar]. However, disease severity did not influence short-term absence from work in this study. Among 165 Australian MG patients, 40% had stopped work due to MG, and 20% had changed their occupation [[21]Blum S. Lee D. Gillis D. McEniery D.F. Reddel S. McCombe P. Clinical features and impact of myasthenia gravis disease in Australian patients.J Clin Neurosci. 2015; 22: 1164-1169Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. MG can therefore lead to lower income, lower pensions, and to challenges regarding various types of insurance. MG patients often experience a reduced social network. Muscle weakness and fatigue may cause them to abstain from social gatherings. Some MG patients feel inadequate regarding family responsibilities, and even experience break-ups or divorces because of the disease. Many patients feel a loss from no longer being able to live the life they were used to. Social support is important for most MG patients [[16]Boldingh M.I. Dekker L. Maniaol A.H. Brunborg C. Lipka A.F. Niks E.H. et al.An up-date on health-related quality of life in myasthenia gravis -results from population based cohorts.Health Qual Life Outcomes. 2015; 13: 115Crossref PubMed Scopus (37) Google Scholar,[17]Dong D. Chong M.K.C. Wu Y.S. Kaminski H. Cutter G. Xu X. et al.Gender differences in quality of life among patients with myasthenia gravis in China.Health Qual Life Outcomes. 2020; 18: 296Crossref PubMed Scopus (2) Google Scholar. The variability of symptoms during the day can represent an additional challenge for MG patients. When they are seen by their doctor or their employer, they may appear healthy and symptom-free, with no obvious functional limitations and no need for treatment and extra support. Later in the day this could change considerably. Muscle weakness is used to assess disease severity, and the effect of treatments. However, for some patients, other symptoms are more important. Even with moderate or minimal muscle weakness and no obvious comorbidity, some MG patients feel weak and tired. Nearly one third of consecutive MG patients responded “no” when asked whether they were satisfied overall with their current MG status [[14]Menon D. Barnett C. Bril V. Comparison of the single simple question and the patient acceptable symptom state in myasthenia gravis.Eur J Neurol. 2020; 27: 2286-2291Crossref PubMed Scopus (2) Google Scholar]. Patients dissatisfied with their MG state had worse disease severity score, more fatigue, and were more likely to be women and unemployed [[22]Mendoza M. Tran C. Bril V. Katzberg H.D. Barnett C. Patient-acceptable symptom states in myasthenia gravis.Neurology. 2020; 95: E1617-E1618Crossref PubMed Scopus (7) Google Scholar]. Fatigue has in some patients a greater impact on daily living than muscle weakness [[23]Barnett C. Bril V. Kapral M. Kulkarni A. Davis A.M. A conceptual framework for evaluating Impairments in myasthenia gravis.Plos One. 2014; 9: e98089Crossref PubMed Scopus (17) Google Scholar]. This includes lack of energy, tiredness, and exhaustion, reported in 40-80% of MG patients, a much higher figure than in controls [[11]Ruiter A.M. Verschuuren J. Tannemaat M.R. Fatigue in patients with myasthenia gravis. A systematic review of the literature.Neuromusc Dis. 2020; 30: 631-639Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,24Tran C. Bril V. Katzberg H.D. Barnett C. Fatigue is a relevant outcome in patients with myasthenia gravis.Muscle Nerve. 2018; 58: 197-203Crossref PubMed Scopus (17) Google Scholar, 25Hoffmann S. Ramm J. Grittner U. Kohler S. Siedler J. Meisel A. Fatigue in myasthenia gravis: risk factors and impact on quality of life.Brain Behavior. 2016; 6: e00538Crossref PubMed Scopus (31) Google Scholar, 26Elsais A. Wyller V.B. Loge J.H. Kerty E. Fatigue in myasthenia gravis: is it more than muscular weakness?.BMC Neurol. 2013; 13: 132Crossref PubMed Scopus (32) Google Scholar. Fatigue is more frequent in female MG [[11]Ruiter A.M. Verschuuren J. Tannemaat M.R. Fatigue in patients with myasthenia gravis. A systematic review of the literature.Neuromusc Dis. 2020; 30: 631-639Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar], and correlates with daily activities, quality of life, but less so with muscle weakness [[25]Hoffmann S. Ramm J. Grittner U. Kohler S. Siedler J. Meisel A. Fatigue in myasthenia gravis: risk factors and impact on quality of life.Brain Behavior. 2016; 6: e00538Crossref PubMed Scopus (31) Google Scholar]. Presence of MuSK antibodies correlated strongly with fatigue [[25]Hoffmann S. Ramm J. Grittner U. Kohler S. Siedler J. Meisel A. Fatigue in myasthenia gravis: risk factors and impact on quality of life.Brain Behavior. 2016; 6: e00538Crossref PubMed Scopus (31) Google Scholar]. When using a neuromuscular fatigue scale with eight patient-reported items in 257 MG patients from a single Canadian centre, the authors found a correlation between fatigue and MG severity, and with fatigue reduction after effective immunomodulatory treatment [[24]Tran C. Bril V. Katzberg H.D. Barnett C. Fatigue is a relevant outcome in patients with myasthenia gravis.Muscle Nerve. 2018; 58: 197-203Crossref PubMed Scopus (17) Google Scholar]. Seemingly conflicting results probably reflect that fatigue covers a range of meanings and symptoms that have various pathogenesis and is measured by different methods. Chronic fatigue may complicate and interfere with outcome parameters in formal treatment trials and perhaps explain negative results. Personalities do not differ in MG patients and controls, and frequency of long-term psychiatric disturbances corresponds to the general population [[27]Doering S. Henze T. Schussler G. Coping with myasthenia gravis and implications for psychotherapy.Arch Neurol. 1993; 50: 617-620Crossref PubMed Scopus (22) Google Scholar], although affective comorbidities can appear [[28]Law C. Flaherty C.V. Bandyopadhyay S. A review of psychiatric comorbidity in myasthenia gravis.Cureus. 2020; 12: e9184PubMed Google Scholar]. Depression occurs in 10-30% of MG patients [29Gavrilov Y.V. Alekseeva T.M. Kreis O.A. Valko P.O. Weber K.P. Valko Y. Depression in myasthenia gravis: a heterogeneous and intriguing entity.J Neurol. 2020; 267: 1802-1811Crossref PubMed Scopus (3) Google Scholar, 30Suzuki Y. Utsugisawa K. Suzuki S. Nagane Y. Masuda M. Kabasawa C. et al.Factors associated with depressive state in patients with myasthenia gravis: a multicentre cross-sectional study.BMJ Open. 2011; 1e000313Crossref PubMed Scopus (40) Google Scholar, 31Aysal F. Karamustafalioglu O. Ozcelik B. Yilmaz M. Karamustafalioglu N. Yumrukcal H. et al.The relationship of symptoms of anxiety and depression with disease severity and treatment modality in myasthenia gravis: a cross-sectional study.Noropsik Ars-Arch Neuropsych. 2013; 50: 295-300Crossref Scopus (12) Google Scholar]. This represents a double risk compared with matched non-MG controls [[32]Chu H.T. Tseng C.C. Liang C.S. Yeh T.C. Hu L.Y. Yang A.C. et al.Risk of depressive disorders following myasthenia gravis: a nationwide population-based retrospective cohort study.Front Psychiatry. 2019; 10: 481Crossref PubMed Scopus (3) Google Scholar]. Depression in MG correlated strongly with fatigue, and with corticosteroid treatment. MG patients are more frequently than controls treated with drugs for psychiatric disorders [[33]Andersen J.B. Owe J.F. Engeland A. Gilhus N.E. Total drug treatment and comorbidity in myasthenia gravis: a population-based cohort study.Eur J Neurol. 2014; 21: 948-955Crossref PubMed Scopus (23) Google Scholar].Depression in MG can be seen as a response to a chronic disease with physical disabilities and fatigue, and is not a primary symptom associated with the disease.Table 1Key points for clinical assessment of MG patients in addition to muscle strength evaluation, drug compliance and treatment side effects.•Daily functions that are limited, with best and worst to capture variability•Precipitating worsening (infection, long days, menstruation), and how they can be better managed•Non-myasthenic causes of symptoms, comorbidity•Mood and anxiety•Family planning and written advise on planning pregnancy and effects of drugs, from puberty•Function at work or educational establishment and adaptations t reduce fatigue; rest times, shorter days, mid-weekday off, working from home.•Job limitations and whether entitled to financial help or extra support•Social function and limitations•Exercise and fitness•Smoking•Weight management and diet•Burden on support network (family, partner, children) Open table in a new tab Pain is not regarded as a symptom associated with MG. However, in a few small studies, body pain was reported more frequently in MG than in controls [[34]Padua L. Evoli A. Aprile I. Caliandro P. D'Amico P. Rabini A. et al.Quality of life in patients with myasthenia gravis.Muscle Nerve. 2002; 25: 466-467Crossref PubMed Scopus (17) Google Scholar,[35]Tong O. Delfiner L. Herskovitz S. Pain, Headache, and other non-motor symptoms in myasthenia gravis.Curr Pain Headache Rep. 2018; 22: 39Crossref PubMed Scopus (4) Google Scholar. This is similar for most chronic disorders. Tension-type headache in MG is associated with diplopia and ptosis [[36]Nishimoto Y. Suzuki S. Utsugisawa K. et al.Headache in patients with myasthenia gravis (MG).Neurology. 2009; 72: A178Google Scholar]. Some of the immunosuppressive drugs used in MG can have headache as a side-effect [[35]Tong O. Delfiner L. Herskovitz S. Pain, Headache, and other non-motor symptoms in myasthenia gravis.Curr Pain Headache Rep. 2018; 22: 39Crossref PubMed Scopus (4) Google Scholar]. Opiates for severe pain can lead to a respiratory depression unwanted in MG. However, pain can also cause worsening of MG symptoms due to lack of rest and relaxation. Hearing loss might be a comorbidity of MG. Antibody-induced subacute hearing loss has been reported in a few patients with thymoma and MG [[37]Evoli A. Minicuci G.M. Vitaliani R. Battaglia A. Della Marca G. Lauriola L. et al.Paraneoplastic diseases associated with thymoma.J Neurol. 2007; 254: 756-762Crossref PubMed Scopus (73) Google Scholar,[38]Ralli M. Altissimi G. Di Stadio A. Mazzei F. Turchetta R. Cianfrone G. Relationship between hearing function and myasthenia gravis: A contemporary review.J Internat Med Res. 2017; 45: 1459-1465Crossref PubMed Scopus (13) Google Scholar. It has been suggested that AChR antibodies in some MG patients decrease the function of hair cells in the cochlea leading to impaired hearing [[38]Ralli M. Altissimi G. Di Stadio A. Mazzei F. Turchetta R. Cianfrone G. Relationship between hearing function and myasthenia gravis: A contemporary review.J Internat Med Res. 2017; 45: 1459-1465Crossref PubMed Scopus (13) Google Scholar,[39]Hamed S.A. Elattar A.M. Hamed E.A. Irreversible cochlear damage in myasthenia gravis - otoacoustic emission analysis.Acta Neurol Scand. 2006; 113: 46-54Crossref PubMed Scopus (8) Google Scholar. Potential and experienced side-effects of MG drugs can lead to symptoms and influence daily life. Most patients and neurologists are concerned about short-term and especially long-term side-effects of immunosuppressive drugs [[40]Hehir M.K. Punga A.R. Ciafaloni E. Myasthenia gravis patient and physician opinions about immunosuppressant reduction.Muscle Nerve. 2020; 61: 767-772Crossref PubMed Scopus (1) Google Scholar]. Those on corticosteroids are especially worried. Weight gain, mood change, gastric reflux, skin changes, fluid retention and osteoporosis represent relevant symptoms induced by corticosteroids [[18]Bacci E.D. Coyne K.S. Poon J.L. Harris L. Boscoe A.N. Understanding side effects of therapy for myasthenia gravis and their impact on daily life.BMC Neurol. 2019; 19: 335Crossref PubMed Scopus (8) Google Scholar]. At the same time, patients often fear a relapse with immunosuppressant dose reduction [[40]Hehir M.K. Punga A.R. Ciafaloni E. Myasthenia gravis patient and physician opinions about immunosuppressant reduction.Muscle Nerve. 2020; 61: 767-772Crossref PubMed Scopus (1) Google Scholar]. Optimal dose of acetylcholine inhibitors such as pyridostigmine is often a balance between effect and side-effects from the autonomic nervous system, such as diarrhea, gastric cramps, salivation, muscle cramps and flushing. Patients should be encouraged, to find the lowest possible dose that is clinically relevant, and to avoid overtreatment with possible negative effects. A critical review of other medications is important, as some MG patients have prescriptions that could potentially worsen symptoms [[41]Machado-Alba J.E. Calvo-Torres L.F. Gaviria-Mendoza A. Mejia-Velez C.A. Prescription profile of pyridostigmine use in a population of patients with myasthenia gravis.Muscle Nerve. 2017; 56: 1041-1046Crossref PubMed Scopus (6) Google Scholar]. Key points for the clinical assessment of MG patients in addition to muscle strength are listed in Table 1. The immunological reaction at the neuromuscular junction and in thymus should not interfere with cognitive function. AChR IgG antibodies cross the blood-brain barrier, but they do not bind to the AChR in the brain [[42]Whiting P.J. Cooper J. Lindstrom J.M. Antibodies in sera from patients with myasthenia gravis do not bind to nicotinic acetylcholine receptors from human brain.J Neuroimmunol. 1987; 16: 205-213Abstract Full Text PDF PubMed Scopus (40) Google Scholar]. Even though MG is a truly non-brain disorder, patients sometimes report reduced memory, lapses of concentration and cognitive difficulties. Four separate studies compared altogether 184 MG patients with controls [43Marra C. Marsili F. Quaranta D. Evoli A. Determinants of cognitive impairment in elderly myasthenia gravis patients.Muscle Nerve. 2009; 40: 952-959Crossref PubMed Scopus (9) Google Scholar, 44Sitek E.J. Bilinska M.M. Wieczorek D. Nyka W.M. Neuropsychological assessment in myasthenia gravis.Neurol Sci. 2009; 30: 9-14Crossref PubMed Scopus (24) Google Scholar, 45Feldmann R. Kiefer R. Wiegard U. Evers S. Weglage J. Intelligence, attention, and memory in patients with myasthenia gravis.Nervenarzt. 2005; 76: 960-966Crossref PubMed Scopus (5) Google Scholar, 46Paul R.H. Cohen R.A. Gilchrist J.M. Ratings of subjective mental fatigue relate to cognitive performance in patients with myasthenia gravis.J Clin Neurosci. 2002; 9: 243-246Abstract Full Text PDF PubMed Scopus (33) Google Scholar]. They found no evidence of neuropsychological impairment for verbal learning, attention, and memory. However, after completing the tests, the MG patients reported more mental and physical fatigue than the controls. Impaired performance in some tests was interpreted as secondary to muscle weakness. A meta-analysis of 300 tested MG patients and 179 controls concluded that the patients performed worse in several cognitive domains [[47]Mao Z.F. Yin J.J. Lu Z.Q. Hu X.Q. Association between myasthenia gravis and cognitive function: A systematic review and meta-analysis.Ann Indian Acad Neurol. 2015; 18: 131-137Crossref PubMed Scopus (10) Google Scholar]. Some MG patients report physical and cognitive fatigue with reduced cognitive ability and impaired social and physical functions. Such reports illustrate the patient perspective but do not necessarily imply a true cognitive impairment due to brain dysfunction [[35]Tong O. Delfiner L. Herskovitz S. Pain, Headache, and other non-motor symptoms in myasthenia gravis.Curr Pain Headache Rep. 2018; 22: 39Crossref PubMed Scopus (4) Google Scholar]. Preliminary patient reports and experimental data may indicate cerebral involvement in MuSK MG [[48]Sabres L. Evoli A. Punga A.R. Cognitive dysfunction in mice with passively induced MuSK antibody seropositive myasthenia gravis.J Neurol Sci. 2019; 399: 15-21Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar].MG should be regarded as a disease not affecting the brain, but it should be acknowledged that some MG patients have a reduced capacity for demanding cognitive tasks. Consequences of MG for family planning in young women were examined in 801 German MG patients [[49]Ohlraun S. Hoffmann S. Klehmet J. et al.Impact of myasthenia gravis on family planning: How do women with myasthenia gravis decide and why?.Muscle Nerve. 2015; 52: 371-379Crossref PubMed Scopus (11) Google Scholar]. Among the 307 patients who had not already completed their family planning before MG onset, more than half had abstained or intended to abstain from having children due to MG. However, at the same time 73% agreed to a statement that MG patients should not abstain from having children when the neurologist had no concerns. A low level of MG knowledge as well as previous intensive care treatment were associated with abstaining from giving birth. The most common concern was the possible influence of MG medication on the unborn child. This probably explains the infrequent use of MG medication in pregnancy [[50]Hoff J.M. Daltveit A.K. Gilhus N.E. Myasthenia gravis - Consequences for pregnancy, delivery, and the newborn.Neurology. 2003; 61: 1362-1366Crossref PubMed Scopus (105) Google Scholar], despite the fact that the most commonly used drugs such as pyridostigmine, prednisolone and azathioprine are regarded as safe for the developing child [[51]Norwood F. Dhanjal M. Hill M. James N. Jungbluth H. Kyle P. et al.Myasthenia in pregnancy: best practice guidelines from a UK multispecialty working group.J Neurol Neurosurg Psychiat. 2014; 85: 538-543Crossref PubMed Scopus (84) Google Scholar,[52]