Myasthenia gravis

MG is the archetypal postsynaptic NMJ disorder and is characterised by fluctuating skeletal muscle weakness. It is the most common NMJ disorder and is approximately four times as prevalent as chronic inflammatory demyelinating polyradiculoneuropathy.4 It is caused by autoantibodies targeting components of the postsynaptic NMJ. The diagnosis of MG or myasthenic syndrome should be considered in every patient presenting with weakness without sensory symptoms.

A history of fatigue is often unhelpful and not specific for the diagnosis of MG; many patients with weakness from any cause will report worsening symptoms at the end of the day. It is the presence of fatiguable signs that suggests MG. Ptosis, often asymmetric, is the most common presenting symptom in MG, occurring in 50%–70% of patients. Fifty percent of patients with pure ocular MG will develop generalised symptoms within 2 years of onset; roughly 15% remain pure ocular long-term.5 The ocular features, while prominent early, may fade or become symmetric over time. Most patients with MG have fatiguable weakness of ocular, bulbar, limb or respiratory muscles. Weakness of facial and neck muscles commonly occurs and should always be evaluated. Table 1 lists useful clinical signs described in MG.

For ocular presentations, pain, proptosis, pupillary involvement and optic nerve dysfunction are red flags pointing away from a diagnosis of MG. For generalised presentations, pain, significant muscle wasting and marked limb asymmetry are red flags. Deep tendon reflexes are typically normal in MG but are often absent or reduced in LEMS and some congenital myasthenia syndrome subtypes.

Serological evaluation for MG involves testing for AChR antibodies, which are present in roughly 85% of generalised cases and 50% of ocular cases.5 MuSK antibodies are present in 5%–10% of cases and should be tested in all AChR-seronegative patients. AChR and MuSK antibodies may very rarely coexist in the same patient. Compared with AChR-MG patients, MuSK-MG patients often have more axial and respiratory muscle weakness, fewer ocular manifestations, fewer fluctuations in weakness, less response (or paradoxical worsening) with pyridostigmine, and may have early deterioration.6 Anti-LRP4 and anti-agrin antibodies are uncommon, and may occur in isolation or in combination with AChR or MuSK antibodies.7 Approximately 10% of MG patients are seronegative, some of whom have antibodies to clustered AChR identifiable only on cell-based assay.8 Other patients with ‘seronegative MG’ will have a myasthenia mimic. Thymus imaging with CT or MRI is an important step in the diagnostic work-up for MG patients. Thymoma is present in 10%–20% of cases and is more common in those aged 30–50 years, while thymic hyperplasia typically occurs in younger patients.9

Pharmacological tests use acetylcholinesterase inhibitors such as edrophonium chloride (Tensilon), neostigmine and pyridostigmine, to demonstrate temporary improvement in muscle weakness. Tensilon is less widely used nowadays due to limited availability and potentially serious cardiac complications. Pyridostigmine is commonly given as a therapeutic trial in MG; importantly, patients with MG mimics may report subjective improvements following pyridostigmine, and some people with MG do not respond, making false positive and negative responses to pyridostigmine common. Patients with MuSK-MG and some congenital myasthenia subtypes may in fact worsen with pyridostigmine.10

Lambert-Eaton myasthenic syndrome

LEMS is a presynaptic NMJ disorder.11 It is caused by pathogenic autoantibodies targeting P/Q-type voltage-gated calcium channels (VGCC) on the presynaptic terminal. Over 90% of patients with LEMS have anti-VGCC antibodies. Roughly half of all patients with LEMS have an associated small-cell lung carcinoma, and so the condition warrants a thorough, and sometimes repeated, investigation for malignancy.

LEMS is clinically characterised by proximal lower limb-predominant weakness, autonomic symptoms, and areflexia. Proximal leg weakness leading to a waddling gait is characteristic of LEMS and often leads to initial misdiagnosis of myopathy or lumbar canal stenosis. Leg fatigue and difficulty initiating walking may be mistaken for an extrapyramidal disorder.12 Unlike in myasthenia, people with LEMS do not develop extraocular or bulbar weakness in the absence of generalised weakness. Common autonomic symptoms include dry mouth, constipation and erectile dysfunction. A characteristic feature is postexercise facilitation: transient improvement in weakness or re-appearance of absent/decreased reflexes following 10 s exercise of the tested muscle. Almost all people with LEMS show decrement at low-frequency (2–5 Hz) repetitive nerve stimulation (see the Electrophysiological evaluation section), and therefore it is commonly misdiagnosed as seronegative MG on electrophysiological grounds.

Toxins

A large array of naturally existing toxins can cause NMJ dysfunction. The most well-known is botulinum neurotoxin produced by Clostridium botulinum. Botulinum neurotoxin cleaves SNARE proteins resulting in reversible blockade of the NMJ by preventing presynaptic vesicle release.13 Weakness from therapeutic use of botulinum neurotoxin may occur due to both local effects and systemic spread, and its effects can last weeks to months.

The typical clinical features of botulism are descending flaccid paralysis with ptosis and diplopia, bulbar dysfunction, limb and respiratory muscle weakness, prominent autonomic symptoms such as pupillary involvement and dry mouth, and rapid onset, without sensory impairment or altered sensorium.13

Other toxic causes of NMJ dysfunction include snake envenomation (β-bungarotoxin), black widow spider bites (α-latrotoxin), tick paralysis and organophosphate poisoning.14 Various medications can cause NMJ dysfunction, including aminoglycosides, macrolides, beta-blockers and magnesium sulfate.10 Immune checkpoint inhibitor therapy for cancer may cause de novo MG or exacerbate pre-existing disease and can be associated with the highly morbid triple-M syndrome (myositis, myocarditis, MG).15 Finally, excessive pyridostigmine use (>450–600 mg/day) can exacerbate muscle weakness and cause cholinergic crisis.

Congenital myasthenic syndromes

The CMS are a heterogenous group of over 30 genetic disorders caused by mutations affecting NMJ components. Weakness and other clinical features of CMS are wide-ranging depending on the affected gene and can vary between people with the same genetic mutation.16 Associated features can include muscle atrophy, facial dysmorphism, scoliosis, limb deformities (arthrogryposis), and rarely, epilepsy and cognitive impairment. Age of onset is not only congenital, and a growing number of adults are diagnosed with CMS. The diagnosis should be particularly considered in seronegative MG patients with abnormal repetitive nerve stimulation or single-fibre electromyography (EMG) who have not responded to immunotherapy. It is also useful to consider CMS in undiagnosed myopathies, particularly those with congenital onset, which may have overlapping features with CMS such as feeding difficulties, facial weakness, respiratory muscle weakness, and absent or reduced reflexes. Electrophysiology may give important clues for specific types of CMS (see case 5). The diagnosis is confirmed by genetic testing. Therapeutic options for CMS include pyridostigmine, 3,4-diaminopyridine, oral salbutamol/albuterol, ephedrine and fluoxetine, depending on the genotype.17

Aponeurotic ptosis (levator dehiscence) and other degenerative conditions

Aponeurotic ptosis is the most common cause of acquired ptosis.20 It occurs due to dehiscence of the levator aponeurosis from the superior tarsal plate and may be unilateral or bilateral. Risk factors include older age, eyelid trauma, surgery and contact lens use. Like MG, patients may report worsening of ptosis in the evening due to fatigue of Müller’s muscle. Key distinguishing features for aponeurotic ptosis are raised upper eyelid skin crease with increased margin-to-crease distance on downgaze, persistence of ptosis on downgaze and good levator excursion despite ptosis (figure 3).

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Figure 3

Top row: left upper eyelid ptosis in primary gaze. Relevant eyelid measurements: A=marginal reflex distance 1 (MRD1), B=palpebral fissure height. Bottom row: persistence of left upper eyelid ptosis in downgaze, consistent with left levator dehiscence. C=margin-to-crease distance (MCD), which is typically measured in downgaze. This is increased in levator dehiscence. A crease is not visible in all people. Figure created by Dr Sarah El-Wahsh.

Sagging eye syndrome is an increasingly recognised condition in the elderly that causes intermittent diplopia and may accompany aponeurotic ptosis.21 It occurs due to inferomedial migration of lateral rectus as a result of degeneration of supportive connective tissues, resulting in esotropia and vertical misalignment. Patients present with intermittent or progressive diplopia on distance vision (eg, while driving or watching television) but not on near vision.

Heavy eye syndrome is a related condition that occurs in people with high myopia, presenting with slowly progressive diplopia and reducing range of fusion. Floppy eyelid syndrome is characterised by upper eyelid laxity leading to easily evertible lids and is strongly associated with obstructive sleep apnoea.22

Red flags: raised upper eyelid skin crease, increased margin-to-crease distance on downgaze, persistence of ptosis on downgaze, history of eyelid trauma (including frequent eye rubbing) or contact lens-wearing, diplopia on distance but not near vision in the elderly, severe myopia, laxity of upper eyelids in people with obstructive sleep apnoea.

Thyroid-associated orbitopathy

Thyroid-associated orbitopathy is an autoimmune inflammatory condition occurring in up to 40% of people with Graves’ disease, but can also occur in hypothyroid and euthyroid states.23 Presenting symptoms include painful red eye, lacrimation and diplopia. The characteristic and most common sign in thyroid-associated orbitopathy is eyelid retraction (>90% of cases), defined as upper eyelid margin at or above the superior limbus in primary gaze, without frontalis activation. Other clinical features include exophthalmos, restrictive ophthalmoparesis, and optic neuropathy. Orbital imaging often shows bilateral extraocular muscle belly enlargement with sparing of tendinous insertions, preferentially involving inferior and medial recti (figure 4). In severe cases, superior and lateral recti are involved. Dual pathology is common, as MG is 50 times more prevalent in patients with thyroid-associated orbitopathy.

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Figure 4

MR scan of orbits in thyroid-associated orbitopathy. (A) T1 VIBE fat-suppressed postgadolinium axial scan showing enlargement and enhancement of the medial recti bilaterally with myotendinous sparing (red arrows). There is less pronounced enlargement and enhancement of the lateral recti (yellow arrows). Also, note the asymmetric proptosis (green arrows). (B) T1 coronal image showing disproportionate enlargement of bilateral medial recti (red arrowheads) and inferior recti (green arrowheads) with fatty replacement, most marked in the right inferior rectus.

Red flags: eyelid retraction, exophthalmos, chemosis, ocular pain, dysthyroid state, extraocular muscle enlargement on imaging (inferior>medial>superior recti) sparing the tendinous insertions.

Orbital inflammatory disorders

Orbital myositis and associated orbital inflammatory disorders may affect unilateral or bilateral extraocular muscles.24 These conditions are characterised by acute painful diplopia due to extraocular muscle paresis and/or restriction and may be associated with chemosis, exophthalmos and eyelid swelling. Orbital myositis may be idiopathic or secondary to an autoimmune (sarcoidosis, IgG4-related disease), infective (herpes zoster ophthalmicus, Lyme disease), drug-related (immune checkpoint inhibitor-toxicity) or paraneoplastic process. The MR scan of orbits typically shows enhancing fusiform enlargement of the affected muscle belly involving the tendinous insertion.

Red flags: orbital pain, exophthalmos, MR scan showing enlarged extraocular muscles involving tendons.

Chronic progressive external ophthalmoplegia and mitochondrial cytopathies

Chronic progressive external ophthalmoplegia is a mitochondrial disorder presenting with bilateral, symmetrical, painless, progressive, pupil-sparing ptosis and ophthalmoparesis, typically with onset in the third and fourth decades of life.25 Patients often do not have diplopia and are unaware of their ptosis due to its slowly progressive nature. The condition may occur in isolation or with systemic mitochondrial syndromes. Single-fibre EMG is typically abnormal and may erroneously lead to MG diagnosis. MR scan of the orbits may show an underappreciated symmetrical atrophy of the extra-ocular muscles. The diagnosis is confirmed by genetic testing.

Red flags: slowly progressive symmetric ptosis and/or ophthalmoparesis, multi-system involvement

Oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy is an autosomal dominant adult-onset disease characterised by insidious onset of ptosis and dysphagia due to selective involvement of eyelid and pharyngeal muscles.26 With advancing disease, other symptoms may develop including ophthalmoparesis and weakness of tongue, limb girdle, and facial muscles. Oculopharyngeal muscular dystrophy is caused by a GCN trinucleotide repeat expansion in exon 1 of the poly(A) binding protein nuclear 1 (PABPN1) gene. Normal alleles have 10 repeats; the disease severity is greater and onset is earlier in those with increasing repeat numbers from 11 to 18, and if both copies are abnormal.

Oculopharyngeal distal myopathy is rare but clinically more distinct. It presents with similar oculopharyngeal weakness but with forearm and distal leg weakness. The facial weakness of facioscapulohumeral muscular dystrophy may also be included in the differential diagnosis for MG.

Red flags: progressive oculo-bulbar symptoms, tongue and skeletal muscle wasting, positive family history.

Myotonic dystrophy

Myotonic dystrophy type 1 (DM1) may be confused with MG due to the shared clinical feature of ptosis and facial weakness. However, DM1 is a multi-system disease with many distinguishing characteristics: clinical and electrophysiological myotonia, temporal muscle wasting, distal muscle weakness, premature cataracts and frontal balding in men.27 DM1 is inherited in an autosomal dominant fashion and demonstrates maternal anticipation. It is caused by a trinucleotide repeat expansion in the myotonic dystrophy protein kinase gene.

Red flags: clinical and electrophysiological myotonia, temporal muscle wasting, distal limb weakness, premature cataracts, positive family history.

Congenital disorders of eye movement

Several congenital disorders of eye movement may be mistaken for ocular MG. These include congenital fibrosis of extraocular muscles, Duane syndrome (absent/dysplastic abducens motor neurones) and Brown syndrome (abnormal superior oblique tendon–trochlea complex resulting in inability to elevate the adducted eye).28 People with congenital fibrosis of extraocular muscles may have ptosis and often adopt abnormal head positions to compensate for their ophthalmoplegia. Key distinguishing features include life-long and non-progressive ophthalmoplegia, typically without reported diplopia, and sometimes with monocular amblyopia if not patched in childhood; childhood photographs can help. There may be a family history and some cases are associated with other congenital anomalies (eg, intellectual disability, developmental limb abnormalities).

Decompensation of a long-standing phoria (ie, the tendency of eyes to deviate when fusion is broken) may cause intermittent diplopia and be mistaken for ocular MG.29 Phorias may decompensate in mid-life due to progressive loss of fusion with ageing or during an intercurrent illness. Clues to a decompensated phoria include a history of childhood strabismus, history of eye patching or surgery in childhood, anomalous head position, monocular amblyopia in the unfavoured eye, no duction deficit (ie, normal range of eye movements when testing each eye separately) and comitance (ie, deviation of the eyes remains constant with changes in direction of gaze).

Red flags: congenital/life-long ophthalmoplegia, no fluctuation or progression, childhood strabismus/patching, amblyopia.

Acute and chronic motor neuropathies (eg, Guillain-Barré syndrome, motor neurone disease)

Guillain-Barré syndrome variants may mimic NMJ disorders.30 Miller Fisher syndrome is one of the most important differentials for early ocular MG—the classic pattern is of weakness of eye abduction and elevation. There may be pupillary abnormalities and ptosis. Important clues include the presence of ataxia, areflexia and a history of preceding gastrointestinal or respiratory illness. Most patients have anti-GQ1b antibodies. Single-fibre EMG is typically abnormal and may lead to misdiagnosis of abrupt-onset MG.

Motor neurone disease is generally distinguishable from MG but may be optimistically mistaken for the latter if there is a reported history of fluctuation, subjective response to therapy, or if repetitive nerve stimulation or single-fibre EMG abnormalities are overinterpreted in isolation. Conversely, bulbar-onset MuSK-MG often has fibrillation potentials in affected muscles on EMG and may be misdiagnosed as motor neurone disease.

Red flags: preceding infection, progressive rather than fluctuating weakness, ataxia, sensory disturbance, areflexia (without postexercise facilitation), hyperreflexia, widespread denervation on EMG.

Ocular motor cranial neuropathies

Oculomotor (CNIII), trochlear (CNIV) and abducens (CNVI) nerve lesions produce ophthalmoparesis and ptosis (CNIII) which can be mistaken for ocular MG.31 Motor deficits in cranial neuropathies typically persist rather than fluctuate, and in the case of oculomotor nerve lesions, the pupil may be involved.

Oculomotor synkinesis due to aberrant re-innervation following nerve injury may closely mimic ocular MG, as it can produce variable eyelid movements such as upper eyelid elevation on downward gaze. Synkinetic changes in pupil size may also occur with eye movements. The key distinguishing feature is that abnormal synkinetic movements are reproducible.

Ocular neuromyotonia is a rare cause of intermittent diplopia characterised by recurrent, brief tonic spasms of extraocular muscles lasting seconds to minutes.32 Episodes may occur spontaneously or after holding eccentric gaze. Ocular neuromyotonia typically occurs in the setting of cranial irradiation or nerve compression. In superior oblique myokymia, very brief, repetitive torsional movements of the eye cause paroxysms of vertical diplopia.

Red flags: reproducible ocular dysmotility, pupillary involvement, brief recurrent tonic spasms of extraocular muscles, paroxysmal vertical diplopia with torsional eye movements.

Blepharospasm and hemifacial spasm

Blepharospasm is a focal dystonia characterised by stereotyped synchronous spasms of the orbicularis oculi muscles.33 Spasms may produce sustained narrowing or closure of the eyelids, mimicking ptosis. Associated features may include dystonia in other body regions, tremor, sleep and cognitive disturbance. There have been a few case reports of blepharospasm associated with MG.

Hemifacial spasm, by contrast, is a peripheral nerve hyperexcitability disorder characterised by involuntary, unilateral (rarely bilateral), intermittent, irregular, tonic and/or clonic contractions of muscles innerved by the ipsilateral facial nerve.34 Intermittent involuntary eye closure is a common complaint, and may be mistaken for fatigable ptosis. Physical examination often identifies typical contractions of hemifacial muscles. Joseph Babinski, known for his description of the abnormal plantar response, described another phenomenon seen in hemifacial spasm: simultaneous eyebrow elevation and eyelid closure due to co-contraction of frontalis and orbicularis oculi muscles. This ‘other Babinski sign’ is a common and highly specific examination finding in hemifacial spasm and not seen in blepharospasm, facial tics, or voluntary contraction.35

Red flags: short-lived spasm or tonic contraction of eyelids, dystonia or tremor in other body regions, unilateral facial contractions, the ‘other Babinski sign’.

Brainstem disorders (eg, demyelination, stroke)

Central disorders of eye movement may be mistaken for NMJ dysfunction due to variable ptosis, diplopia and ophthalmoparesis. Abrupt onset of reproducible deficits should raise suspicion for a vascular or demyelinating cause. Subacute onset of ptosis and diplopia with spontaneous regression, initially mistaken for response to pyridostigmine, may occur in primary CNS lymphoma of the brainstem.36 Ocular MG may be clinically indistinguishable from internuclear ophthalmoplegia (pseudo-internuclear ophthalmoplegia) due to slow adducting saccades.37 A lesion of the central caudal subnucleus of the oculomotor nerve, a single midline structure in the dorsal midbrain, produces bilateral ptosis.38 Assessment for additional signs of fatiguable weakness is key for clinical differentiation from MG.

Red flags: abrupt onset of symptoms without progression or variability, lack of other clinical features of NMJ dysfunction.

Head drop

Head drop is a common and well-recognised clinical feature of MG. However, head drop can rarely be the sole initial manifestation of MG, particularly in MuSK-positive MG, leading to confusion with other differentials such as motor neurone disease, Parkinson’s disease and myositis.39 Fluctuating neck weakness that improves after rest should raise suspicion for MG. Importantly, decrement on repetitive nerve stimulation is not specific to NMJ disorders, and may occur in other conditions with impaired NMJ transmission, such as motor neurone disease.40

Clues: neck weakness with fluctuation or improvement after rest.

Distal weakness

Distal muscle weakness at onset is rare in MG, presenting as symmetrical or asymmetrical weakness of intrinsic hand muscles, triceps brachii, or ankle dorsiflexors leading to foot drop.41 The described cases had no sensory symptoms or muscle wasting, and their weakness fluctuated. Routine nerve conduction studies and needle EMG were useful in excluding more common neuromuscular disorders such as entrapment neuropathies. Over time, many of the reported patients with initial distal weakness developed generalised myasthenic features, underscoring the importance of follow-up. Distal weakness is a feature of some CMS subtypes, such as those due to agrin mutation, and can be mistaken for a distal myopathy.42 Finger and wrist extensor weakness is characteristic of slow-channel CMS.43

Clues: fluctuating distal weakness without muscle atrophy or sensory disturbance.

Limb-girdle muscle weakness

Pure limb-girdle weakness without oculo-bulbar involvement is an atypical presentation of autoimmune MG.44 Conversely, LEMS typically presents as limb-girdle weakness. Several types of CMS, particularly those associated with tubular aggregates on muscle biopsy, can present in adulthood with limb-girdle weakness.45 Adult-onset CMS should be considered in all patients with undiagnosed limb-girdle phenotypes. Abnormal repetitive nerve stimulation may sometimes be the first or only clue to an NMJ disorder in limb-girdle presentations.

Clues: limb-girdle weakness plus autonomic symptoms (LEMS), postexercise facilitation of muscle strength and reflexes (LEMS), tubular aggregates on muscle biopsy (CMS), abnormal repetitive nerve stimulation (MG, LEMS, CMS).

Case 5

A 60-year-old man had non-progressive proximal limb weakness since childhood. As a child, he had experienced fluctuations in walking distance requiring frequent breaks and reliance on a wheelchair. He had nocturnal hypoventilation requiring non-invasive ventilation. Following extensive investigations, he was diagnosed with non-5q spinal muscular atrophy. Many decades later, he was re-referred to neurology. Nerve conduction studies identified a distinctive repetitive CMAP following nerve stimulation (figure 5). Repetitive nerve stimulation showed abnormal decrement in the ulnar nerve. Whole exome sequencing identified biallelic variants in the COLQ gene (c.718G>T(:)1026C>G), confirming a diagnosis of congenital myasthenic syndrome. He responded well to oral salbutamol, with significant improvement in gait and exercise capacity.

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Figure 5

(A) Stimulation of the median nerve (recording from abductor pollicis brevis) at the wrist and elbow produced a repetitive compound muscle action potential (red arrowhead) in a patient with COLQ congenital myasthenic syndromes. (B) Normal median compound muscle action potential morphology in a healthy individual for comparison.

Central ocular motor signs and reduced visual acuity

Ocular MG can masquerade as any central ocular motor disorder such as internuclear ophthalmoplegia or one-and-a-half syndrome due to selective weakness of extraocular muscles. Nystagmus can occur due to corrective saccades of drifting extraocular muscles or due to dissociated nystagmus, mimicking an internuclear ophthalmoplegia. There is often fatiguable ptosis; this and other signs of ocular MG almost invariably arise during the course of the disease.

Contrary to conventional teaching, ocular MG may rarely be associated with afferent visual abnormalities. Reduced near visual acuity may result from impaired accommodation from ciliary muscle fatigue. Reduced distance visual acuity (‘pseudo-myopia’) may occur in one or both eyes due to accommodation excess despite impaired vergence as a result of medial rectus weakness.46 However, reduced visual acuity is very uncommon in MG and should prompt a search for other causes of vision loss. Nevertheless, the above mechanisms should be considered in the absence of another identifiable cause.

Clues: central ocular motor signs with fatiguable ptosis, reduced visual acuity in the setting of ophthalmoparesis.

Dual pathologies

MG may coexist with other central or peripheral neurological disorders. Examples in the literature include coexistent MG and motor neurone disease, Parkinson’s disease, oculo-pharyngeal muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, mitochondrial myopathy, and even CMS. Unusual new symptoms such as ptosis in motor neurone disease or fluctuating weakness in a patient with another confirmed neurological diagnosis should warrant evaluation for NMJ dysfunction. The mechanism leading to MG in other neuromuscular disorders is not fully understood but may relate to immune sensitisation towards self-antigens in damaged muscle fibres. In our experience, myasthenic symptoms may be disproportionately severe in muscles affected by a second pathology. For example, superimposed MG may lead to worsening focal limb weakness in pre-existing cervical or lumbar radiculopathy or disproportionate respiratory muscle weakness in patients with post-operative phrenic nerve injury.

Clues: new atypical or fluctuating weakness in a patient with another neurological disorder.

Closing remarks

The diagnosis of an NMJ disorder can be challenging due to the many mimics and atypical presentations. Neurologists must be aware of the diagnostic use and limitations of physical signs and pertinent investigations to avoid missing or misdiagnosing NMJ disorders. Ultimately, it is the combined interpretation of the clinical presentation, physical examination, antibody testing, imaging, electrophysiology, and treatment response, that leads to a secure diagnosis. NMJ disorders are a highly debilitating yet often rewarding group of neurological conditions to diagnose and treat. They warrant a high index of suspicion to ensure timely and accurate diagnosis.