Resumption of acetylcholinesterase inhibitors and immunosuppressants in the perioperative management of myasthenia gravis

Clinical vignette

Mary, a 64-year-old woman with myasthenia gravis, underwent elective upper gastrointestinal surgery. Her myasthenia gravis symptoms were effectively controlled with pyridostigmine 60 mg administered every 4 hours (total daily dose 360 mg), prednisolone 15 mg once daily, and azathioprine 100 mg once daily. Mary was also living with obesity and experiencing chronic back pain. Following surgery, she was admitted to a high-dependency unit due to her comorbidities and the complexity of the procedure. She was expected to remain nil by mouth for 24 hours postoperatively as per surgical protocol. How should her pharmacological therapy for myasthenia gravis have been managed, and when should it have been resumed in the perioperative period?

Pathophysiology and diagnosis of myasthenia gravis

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction, caused by antibodies directed against receptors at the post-synaptic membrane, causing disruption of transmission. Most patients produce antibodies against the nicotinic acetylcholine receptor (AChR), although antibodies to muscle-specific kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (Lrp4) may also be present [1]. These autoantibodies activate complement, leading to a reduction of functional receptors by approximately 30% or more compared with normal levels. This receptor loss impairs neuromuscular transmission and causes muscle weakness that typically worsens with sustained activity over the course of the day [2].

Clinically, this autoimmune disease presents with fluctuating, fatigable muscle weakness, often beginning with ocular symptoms such as ptosis and diplopia, before progressing to bulbar, limb and respiratory muscles [1, 2]. Myasthenic crisis, a serious complication characterised by severe respiratory or bulbar weakness, occurs in approximately 20% of patients and is often precipitated by infection, surgery or interruption of therapy, with most cases requiring intubation and mechanical ventilation [3, 4].

Diagnosis combines clinical assessment with serological testing for AChR, MuSK and Lrp4 antibodies, electrophysiological studies showing decremental response to repetitive nerve stimulation, and thoracic imaging to test for thymoma [1, 2].

Therapeutic management of myasthenia gravis

Treatment of myasthenia gravis is multimodal and tailored to disease severity and progression.

Symptomatic therapy relies on acetylcholinesterase inhibitors, such as pyridostigmine, which inhibit the breakdown of acetylcholine at the neuromuscular junction, thereby prolonging its action and improving neuromuscular transmission. Typical dosing ranges from 180 to 450 mg daily in divided doses, with the onset of effect seen within 30 minutes. Excessive dosing can lead to cholinergic side effects and, rarely, cholinergic crisis and management by a specialist is most appropriate [2].

Cholinergic crisis presents with miosis, hypersalivation, bradycardia, diarrhoea, sweating and paradoxical weakness, resembling organophosphate poisoning [1, 4]. Management involves temporarily withholding cholinesterase inhibitors, while severe manifestations may require intravenous (IV) atropine or glycopyrrolate, and intubation if respiratory function is compromised [1, 2].

Corticosteroids, most commonly prednisolone, form the cornerstone of long-term immunomodulatory therapy in patients with myasthenia gravis [2, 4]. Non-steroidal immunosuppressants are frequently added as steroid-sparing agents, with azathioprine being the most commonly used agent. Non-steroidal immunosuppressive therapy may be escalated to mycophenolate mofetil, methotrexate, ciclosporin and rituximab for refractory cases [1, 2].

Rapid immunomodulation with IV immunoglobulin (IVIg) or plasma exchange (PLEX) may be used in acute exacerbations, myasthenic crisis, or for perioperative bridging in high-risk patients [1]. PLEX lowers anti-AChR antibody levels, resulting in improved muscle strength within several days, but the effect is generally transient, while clinical improvement from IV immunoglobulin may persist for several months [2].

Thymectomy is indicated in patients with thymoma and may also be considered in younger anti-AChR antibody-positive patients without thymoma to improve long-term outcomes and reduce steroid dependence [1, 2].

Risks in the perioperative period

The perioperative setting poses significant risks for patients with myasthenia gravis. Surgical stress, anaesthetic agents, infection, interruption of therapy, hypothermia and hyperthermia, electrolyte disturbances and interacting drugs (e.g. certain antibiotics, magnesium) may destabilise neuromuscular transmission. Additional factors around the time of surgery, including inadequate analgesia, sleep deprivation and emotional stress, may precipitate deterioration [3].

These triggers can lead to bulbar and respiratory weakness, ineffective cough and dysphagia. Subtle signs – nasal speech, slurred articulation, inability to clear secretions or new-onset dysphagia – should raise immediate concern. Myasthenic crisis may present as difficulty in weaning from the ventilator or as gradually worsening respiratory distress following surgery [3].

Patients who are deteriorating must be identified and require close monitoring to assess serial respiratory rate, forced vital capacity and arterial blood gases, to identify evolving type 2 respiratory failure. Management includes additional cholinesterase inhibitors and escalation of immunotherapy with IVIg or PLEX, along with corticosteroids. Many patients, however, may require tracheal intubation and invasive mechanical ventilation [1, 3, 4].

Given this vulnerability, patients with myasthenia gravis undergoing major surgery should be managed postoperatively in a high-dependency or intensive-care setting with particular vigilance in the first days post procedure [1].

Management of pharmacological therapy in the perioperative period

The perioperative management of medications is crucial, as even brief interruptions in therapy can destabilise disease control and precipitate a crisis. The three principal drug classes requiring careful consideration are anticholinesterase inhibitors, corticosteroids and non-steroidal immunosuppressants.

Anticholinesterase inhibitors

Historically, anticholinesterase drugs, such as pyridostigmine, were withheld on the morning of surgery due to concerns about interactions with neuromuscular blocking agents. However, the current evidence does not support improved outcomes on the duration of neuromuscular blockade or mechanical ventilation [5]. In contrast, withholding pyridostigmine has been shown to increase the risk of respiratory complications requiring an intraoperative use of neostigmine [2, 6]. Therefore, pyridostigmine should be continued perioperatively [2, 5, 6].

Missed doses during long procedures may manifest as postoperative weakness, so perioperative bridging should be considered [1]. The regimen should be resumed as soon as possible postoperatively, especially in patients with generalised or severe disease [7]. When enteral administration is not feasible (e.g. nil by mouth), parenteral substitution should be provided: pyridostigmine 60 mg orally is roughly equivalent to 2 mg IV (approximately one-thirtieth of the oral dose), and one-tenth of the oral dose when given intramuscularly [1, 6]. Neostigmine can be used as an alternative parenteral agent [1, 7, 8]. The oral regimen should be resumed promptly once feasible [8].

Corticosteroids

Corticosteroids should be continued without interruption throughout the perioperative period. Abrupt withdrawal risks both the exacerbation of myasthenic symptoms and adrenal insufficiency [1]. Patients who are taking long-term corticosteroid therapy at doses equivalent to or greater than 5 mg prednisolone per day require additional perioperative cover – most commonly IV hydrocortisone – to compensate for suppressed endogenous cortisol production [9]. Parenteral substitution should be provided while patients are nil by mouth, and the usual maintenance dose resumed as soon as oral intake is re-established [1, 6, 10].

Non-steroidal immunosuppressants

Agents such as azathioprine have long half-lives, and perioperative interruptions for a few days are unlikely to impact their disease control. These drugs may be withheld temporarily while the patient is nil by mouth, but should be restarted promptly once oral intake has been resumed. Prolonged interruption should generally be avoided in order to maintain immunosuppressive efficacy [1, 6, 10].

Conclusion

In the postoperative setting, timely resumption of therapy for myasthenia gravis is essential to prevent complications and minimise the risk of myasthenic crisis. Anticholinesterase therapy and corticosteroids should be continued perioperatively, with parenteral bridging of anticholinesterase therapy if oral administration is not possible [1]. Perioperative steroid cover should be provided for patients who are taking long-term corticosteroids to prevent adrenal crisis. Non-steroidal immunosuppressants may be held temporarily but should be resumed promptly once enteral intake is feasible [1, 3].

In Mary’s case, pyridostigmine was substituted with IV administration during the 24 hours she remained nil by mouth. Her prednisolone was substituted with IV hydrocortisone until enteral intake was re-established. Azathioprine was held, but restarted once she resumed oral intake. Despite an uneventful immediate postoperative course, she remained in the high-dependency unit for 48 hours after surgery to optimise physiological homeostasis by maintaining normothermia, normal electrolytes, adequate analgesia, mobilisation and chest physiotherapy, while being closely monitored for early signs of deterioration.

The perioperative period is a time of heightened risk for patients with myasthenia gravis [3]. Early recognition of clinical deterioration, combined with proactive and tailored medication management, is essential to prevent complications and support optimal outcomes [1]. This narrative review focuses on postoperative pharmacological management and does not address all aspects of perioperative care relevant for patients with myasthenia gravis.

Declarations and conflicts of interest