Autoimmune myasthenia gravis (MG) is caused by autoantibodies targeting the neuromuscular junction at the postsynaptic level, causing impaired muscle cell depolarization. Clinically, this manifests as fluctuating voluntary muscle weakness and fatigability, characterized by developing or worsening weakness in the context of activity Gilhus et al. (2019). Weakness exacerbated by repeated muscle work and ameliorated by rest is the hallmark of MG; in fact, patients can report important fluctuations of symptoms between the morning and the end of the day. Of note, weakness and fatigability may also appear in muscle groups not directly involved in the task being performed, such as swallowing difficulties emerging after prolonged conversation. Muscle fatigability should be distinguished from fatigue, which is defined as excessive mental and physical exhaustion Funke et al. (2024). Another common distinction from myasthenic weakness is generalized asthenia which typically does not associate with loss of muscle strength during activity but is prominent also at rest Grob et al. (1981).

Specific patterns of weakness coupled with anamnestic evidence of symptom fluctuations should prompt the clinician to actively search for fatigability in the neurologic examination and request the pertinent diagnostic exams for MG. However, it is important to bear in mind that patients with mild disease may have a completely normal clinical examination, facing the risk of being misdiagnosed with functional conditions Gilhus et al. (2019). This highlights the importance of knowing and considering MG in the differential diagnosis of other neurologic conditions, including taking a focused and detailed history aimed at uncovering subtle clues of neuromuscular junction involvement. Although weakness in MG can potentially involve any voluntary muscle, it is known to preferentially affect specific muscle groups, such as the extraocular muscles Grob et al. (1981). Specific clinical features of MG can be summarized by the region involved: Meriggioli and Sanders (2009) ocular symptoms, such as ptosis and diplopia; cranial symptoms comprising facial involvement, mainly weakness in eyelid closure and to a lesser extent in the lower face with masticatory weakness; bulbar symptoms which include dysarthria, dysphagia and dysphonia; limb symptoms, commonly proximal and symmetric; axial symptoms, mainly neck flexion or extension; and respiratory symptoms, from exertional dyspnea to respiratory failure. An important distinction can be made between isolated extraocular involvement and diffuse disease, which are respectively called ocular MG (OMG) and generalized MG (GMG). As will be elaborated in the next section, a high proportion of patients who present with ocular symptoms will develop generalized disease, usually reaching maximum severity within two years of onset Grob et al., 1981, Grob et al., 2008.

Autoimmune MG is a not a single disease entity, and several subgroups with distinct prognostic and therapeutic implications have been described based on antibody profile, age of onset, disease distribution and thymic abnormalities. Gilhus and Verschuuren (2015) Specific antibody-subgroups have also been associated with characteristic clinical presentations. For example, prominent bulbar involvement is characteristic of MG associated to anti-muscle specific kinase (MuSK) antibodies Evoli et al. (2003), Zhou et al. (2004) This subgroup can also present with involvement of peculiar muscles groups, such as the axial muscles, (Sanders and Juel, 2008, Sanders et al., 2003, Zhou et al., 2004) or muscle atrophy associated to myopathic changes, which are unusual features of other antibody-subtypes of MG (see Section 6 of this chapter) Sanders and Juel (2008), Martignago et al. (2009), Ishii et al. (2005). Anti-acetylcholine receptor (AChR) antibody associated MG, which is the most common form of MG, can present with either ocular or generalized disease phenotypes. It is important in this subgroup to assess the presence of thymic pathology because of its association with thymoma and, conversely, actively search for symptoms and signs of MG in patients presenting with thymoma as it develops in about one third of cases Gilhus and Verschuuren (2015). Thymoma associated MG (TAMG) is usually associated with a more severe phenotype compared to other anti-AChR subtypes at onset, although long term prognosis does not seem to differ Meriggioli and Sanders (2009), Bril et al. (1998). Lastly, MG associated to anti-lipoprotein-related protein 4 (LRP4) antibodies and seronegative MG (SNMG) have variable clinical presentation, with a prevalence of ocular or mild generalized forms depending on the clinical series Li et al. (2023), Rivner et al. (2020), Martinez-Harms et al. (2024), Zisimopoulou et al. (2014). Table 1 outlines the mayor serological, demographical, and clinical characteristics of different MG subtypes, while Fig. 1 provides a graphical summary of the possible presentations of MG in relation to the principal antibody subtypes.

The following sections will cover in detail the chief symptoms of MG by region involved. A section will be dedicated to myasthenic crisis specifically. Lastly, we will focus on atypical features and presentations of MG to which the clinician must pay attention.