Trauma-induced myasthenia gravis: coincidence or causal relationship?

Abstract

We report a case of a 55-year-old man presenting with diplopia, masticatory weakness and dysarthria several weeks post multitrauma. The clinical suspicion of myasthenia gravis (MG) was supported with positive acetylcholine receptor antibodies and abnormal repetitive stimulation study. He responded well to pyridostigmine, intravenous immunoglobulin and oral prednisolone. In this report, we describe the timing and progression of MG in our patient, and review the literature pertaining to the relationship between trauma and MG. The search for definitive evidence of causation may be impractical, but should not delay the recognition and management of a treatable condition.

Background

Myasthenia gravis (MG) is a well-recognised autoimmune condition that occurs due to IgG1 antibodies forming against acetylcholine receptors (AChRs), leading to reduced activation of these receptors which play an important role in neuromuscular transmission. Majority of patients with MG (85%) were found to have AChR antibodies, while many of the remaining patients were found positive for antibodies to muscle-specific tyrosine kinase (MuSK).¹ MG is a predominantly humoral-mediated disease, but T cells and in particular T-helper (Th) 1 and 17 cells play important roles. Since T cells originate in the thymus, it is likely a critical organ in the pathogenesis.²

Trauma is recognised as a potential trigger of autoimmune conditions such as MG as it is known to activate a cascade of immune responses.³ The relationship between trauma and MG will be explored in this report through a recent case we encountered. Given an interventional study such as a randomised controlled trial is impractical to assess this relationship, clinicians rely on observational studies and case reports. Our report aimed to describe this possible association and the importance of early recognition of a treatable condition.

Case presentation

Our patient is a 55-year-old man diagnosed with MG 3 months after a motor vehicle accident (MVA). He suffered the MVA in January 2019 which resulted in several rib and spinal fractures, tension pneumothorax and post-traumatic amnesia in the context of possible opiate-induced delirium. He first noted intermittent diplopia 6 weeks after his MVA, and then over the next few weeks he noticed weakness in mastication and dysarthria. Delirium and stroke had initially been considered by his treating clinician, which were later excluded. It took approximately 3 months from the onset of symptoms to him being referred and reviewed in our general neurology clinic.

He had no medical history or family history of significance, particularly no history of autoimmune conditions. He was premorbidly high functioning.

On examination when he first presented to neurology clinic, he had diplopia on lateral gaze, worst on the right, as well as weakness of eyelid closure. He did not have any limb weakness or fatigability.

Investigation results were consistent with MG, which are described in detail below. He was diagnosed as ocular and bulbar MG. The symptoms were controlled with pyridostigmine alone.

He re-presented about 8 months later with flare of his previous symptoms, as well as new symptoms of fatigable ptosis and neck weakness.

Investigations

Acetylcholine receptor (AChR) antibodies were strongly positive (titre >8 nmol/L, normal range <0.4 nmol/L), and muscle-specific receptor tyrosine kinase (MuSK) antibodies were negative.

Repetitive nerve stimulation showed significant decrements in right nasalis (see figure 1). CT thorax did not show any evidence of a thymoma.

Figure 1.

Repetitive stimulation study recording over right nasalis. Stimulation rate 3 Hz. (A) (Baseline) Amplitude 4 to 1 decrement 18.1%; (B) (post exercise at 0:00) amplitude 4 to 1 decrement 9.7%; (C) (post exercise at 0:30) amplitude 4 to 1 decrement 22.2%; (D) (post exercise at 1:00) amplitude 4 to 1 decrement 21.8%.

Other investigations, including full blood count, electrolytes, renal function, liver function tests and brain imaging, were all unremarkable.

Treatment

After his initial presentation and diagnosis, the patient was commenced on pyridostigmine 60 mg three times a day. Steroids were not started at the time given concern for bone recovery in the context of recent multiple fractures. His symptoms were adequately controlled by pyridostigmine alone for 8 months.

He was admitted to hospital in April 2020 after flare of MG symptoms. Intravenous immunoglobulin and oral prednisolone were started with good control of symptoms. There is a plan for discussion of commencement of azathioprine as steroid-sparing agent at the next clinic visit.

Outcome and follow-up

Our patient is currently 2 years since the original accident, and 8 months since hospitalisation and commencement of immunotherapy for flare of MG. In the last clinic appointment in June 2020, he had noted improvement in speech and swallowing. He will continue to be followed up with our neurology team.

Discussion

The primary purpose of this report is to highlight the delay in diagnosis that frequently occurs with MG, particularly in situations such as that experienced by our patient where the clinical setting obscures the diagnosis of this serious and treatable condition. We propose that awareness of an association or increased risk of MG after trauma could serve to minimise this delay.

While the onset of at least 50% of autoimmune diseases including MG have ‘unknown trigger factors’, trauma is often listed as a trigger. Physical and emotional stress are proven to have a negative impact on the immune function. In fact, several studies have reported that up to 80% of patients experienced emotional stress before the onset of their autoimmune disease.³ However, the mechanism in which trauma leads to autoimmunity remains unclear. Notably, there is a dearth of published data on trauma and MG.

Some observations provide clues to the possible pathogenesis. As evident by animal studies and studies of neonatal MG, the AChR antibodies of MG are proven to be pathogenic.^{4 5} There appears to be a safety threshold prior to overcoming the neuromuscular control. Certain triggers, such as trauma, may lead to a stronger autoimmune response which could increase the levels of AChR antibodies to allow this threshold to be breached. In fact, seropositive MG has been described in the literature even after minor trauma.^{6 7} The presumption is tissue microtrauma leads to a sudden increase in muscle permeability and thus increased exposure for receptors to antibody, resulting in impaired neuromuscular transmission. This is supported by studies that have consistently shown asymptomatic people and those with clinical resolution of MG continued to have high titres of AChR antibodies. It is therefore the exposure of AChR to the antibodies following trauma that may serve as a trigger for exacerbating the underlying immunopathology.^{6 7}

MG has also been reported after head injury and cardiac surgery, with the reported time interval from the trauma and onset of symptoms being days to weeks. The proposed mechanism of MG after cardiac surgery is related to the damage that occurs to thymic muscle cells which express AChR molecules.⁸ This, however, was not found in a follow-up study of 50 patients.⁹ This study was limited by patient numbers and the authors conclude that a connection between cardiac surgery and MG needs further evaluation, given the fact that thymic stroma expresses many self-antigens and a relationship is physiologically possible.⁹

Our patient belongs to the typical demographic profile of MG, which has a bimodal distribution with disease peaks in those 20–40 years of age as well as in those over 60 where it is more prevalent in men.^{10 11} However, the preceding trauma, in particular the direct chest injuries which likely resulted in inflammation of thymus and contributed to a proinflammatory and autoimmune state, is likely a further risk factor for him developing MG.

In summary, while it is not clear that the connection between trauma and MG is causative, there is enough evidence to warrant attention by neurologists to recognise this treatable condition early. Retrospective or prospective studies with large numbers of patients with MG could help further define the relationship and provide clarity regarding the mechanisms in play.

Patient’s perspective.

“If it is presumed that 'people' may have an 'underlying' or pre-disposition' to MG but do not know why they might, then this means that 'everyone' in the world should be considered to have the same disposition—which if so, makes the point irrelevant and it should be disregarded.—So If you have concluded that some people have a disposition to contract MG then presumably the medical profession must know the reason/cause (is it a genetic trait—in which case there would be family history [and I definitely have none, for MG or any other condition] or known/accepted and recognised triggers [websites suggest a comprehensive list of possible triggers, 80% of which I experienced during or following my accident]—I showed no signs of having a potential to contract MG prior to the accident. This is why you should be aware of all of my conditions.”

Learning points.

• Myasthenia gravis can develop after trauma or a traumatic event.

• Trauma is a known trigger for autoimmune diseases.

• The mechanism of trauma-induced autoimmunity is unclear, but is likely either directly from the related stress or indirectly from a predisposed state.

• Clinicians should be aware of this likely association which would prompt early referral to a neurologist, and early diagnosis and management.