There are different etiologies for neuromuscular junction disorders (NMJD) discussed in the literature whereby myasthenia gravis (MG), belonging to the autoimmune category, is the most common form. Other causes are congenital or toxic (eg, botulism).

1. Myasthenia Gravis

MG is a disease that interferes with the transmission of acetylcholine at the neuromuscular junction, leading to proximal muscle weakness and fatigue. In the majority of cases, it is caused by the binding of circulating autoantibodies to postsynaptic nicotinic Ach receptors. This in turn prevents acetylcholine, the neurotransmitter that is responsible for muscle contraction at the motor end plate, from connecting to its receptor. There is a generalized, an ocular, and a paraneoplastic variant of MG. The abovementioned autoantibodies can be found in about 80% of those with the generalized form of MG. In about 10% of patients with MG, a thymoma can be detected, which goes along with anti-titin antibodies.

1. The lead symptom of MG is general fatigue associated with progressive proximal muscle weakness, especially upon activity and improving with rest. There is a typical progression during the day, with a peak weakness during the evening hours. Facial, oropharyngeal, ocular, and neck muscles are as susceptible as skeletal muscles. Ocular involvement with diplopia and ptosis is frequently the initial sign. Further symptoms include dysarthria and dysphagia with severe cases affecting the respiratory muscles as well. Myasthenic crisis is a life-threatening condition with respiratory failure and aspiration that develops usually over days, rarely acutely. It is caused by infections, errors in the intake of medication, and insufficient immunosuppression. Intensive care support and plasma exchange or IVIG are vital in these cases. Despite these measures, the mortality can be still as high as 5%.
2. A cholinergic crisis can present clinically in a similar fashion to the myasthenic crisis with flaccid paralysis; however, the underlying pathophysiology, and thus the therapy, is very different. Treatment with excess doses of cholinesterase inhibitors can lead to a cholinergic crisis by the nonresponsiveness of ACh receptors to abundant acetylcholine. Applying edrophonium (an ACh-esterase inhibitor) can distinguish both forms of crises by worsening the cholinergic crisis and by improving the symptoms of a myasthenic crisis. There is no specific treatment for cholinergic crisis other than discontinuing the responsible agents and applying supportive measures like intubation and mechanical ventilation. Atropine, a blocking agent at the muscarinergic ACh receptor, has only a limited impact on the muscle weakness component, which is triggered through nicotinic acetylcholine receptors. Several medications can exacerbate symptoms of MG (Table 30.2).
3. A thorough history and a physical examination, especially with a focus on the muscle groups, are essential. If MG is suspected with symptoms that can be objectified (important!), pharmacologic testing with neostigmine, edrophonium, or pyridostigmine with atropine at the bedside should be carried out to look for improvement of muscle strength, which occurs rapidly after the administration of the abovementioned drugs. Careful documentation of the affected muscles is mandatory. A nonpharmacologic but unspecific test is the “ice-on-eyes” test that leads to an improvement of symptoms by decreasing the activity of ACh esterase due to low temperature. Additional neurophysiologic testing with 3-Hz repetitive nerve stimulation (accessory or facial nerve) with evidence of a decrement of more than 10% further underscores the diagnosis. Laboratory testing should include anti-ACh-receptor antibodies (high yield in generalized and paraneoplastic MG forms), anti-MuSK (muscle-specific-kinase) antibodies (in 40%-70% positive in ACh receptor antibody “seronegative” MG), and anti-titin antibodies (frequently associated with thymoma), besides general labs to assess complex comorbidities (eg, diabetes, autoimmune thyroid disease) and for the guidance of immune therapy. The autoantibody status is merely used for classification and has essentially no impact on management. Further studies should include imaging (chest CT or MRI) to rule out a thymoma.
4. Patients with suspected MG in the ICU should be stabilized first from the respiratory and, if necessary, cardiovascular standpoints. This might implicate intubation and mechanical ventilation. Symptomatic treatment is achieved with acetylcholine esterase inhibitors such as pyridostigmine or neostigmine. Frequently intravenous administration is required in severe MG exacerbations, but attention should be paid to their rather high side-effect profile (eg, bronchial secretions). Glucocorticoids have good efficacy on muscle weakness in MG with frequent initial deterioration of symptoms. The average onset of action, however, is 4 to 8 weeks in 70% to 80% of the cases. Thus, they are combined with other immunosuppressants, for example, azathioprine or cyclosporine A; an escalation therapy would include more potent immunomodulators like mycophenolate, cyclophosphamide, or methotrexate. Challenging courses might require off-label applications of agents like tacrolimus or monoclonal antibodies like rituximab or alemtuzumab. In refractory cases or in a myasthenic crisis, IVIG therapy or plasma exchange should be considered. Thymectomy should be considered after clinical stabilization in all patients with evidence of thymoma and also in patients aged 15 to 50 years with generalized MG, without detected thymomas.
2. Lambert-Eaton Myasthenic Syndrome

A more uncommon disorder of neuromuscular junction transmission is Lambert-Eaton myasthenic syndrome (LEMS), which is also an autoimmune disorder. Most often it presents with progressive proximal muscle weakness, especially in the lower extremities, autonomic dysfunction, and areflexia. Different than myasthenia gravis, strength may temporarily improve with exertion due to buildup of acetylcholine. The pathophysiology of LEMS is based on antibodies directed against presynaptic voltage-gated calcium channels (VGCC), and there is a strong association with malignancy, especially with small-cell lung cancer (SCLC). Treatment is focused on the underlying cause (removal of the tumor). Immune-directed therapy with steroids and plasma exchange is applied as well.

3. Botulism

Acute onset of symmetric descending weakness associated with bilateral cranial neuropathies (diplopia, nystagmus, ptosis, dysphagia, facial weakness) should raise red flags to consider botulism. Urinary retention and constipation can occur as well. Botulism is a rare potentially life-threatening disease caused by the toxin of the ubiquitously appearing gram-positive, spore-forming, obligate anaerobic bacterium Clostridium botulinum. There are different forms, namely, foodborne, infant, wound, adult enteric, and inhalational botulism. Foodborne botulism, for instance, is caused by the consumption of these pathogens in home-canned foods like vegetables or fruits. When botulism is suspected, the clinician ought to contact the State Health Department instantly to obtain antitoxin as the treatment of choice. Equine serum heptavalent botulism antitoxin is used for adults. Wound botulism requires antibiotics (penicillin G or metronidazole) after the administration of antitoxin.