Recurrent respiratory failure with myasthenia gravis‐like immune‐mediated necrotizing myopathy

Immune-mediated necrotizing myopathy (IMNM) is a type of inflammatory myopathy subdivided into three major subtypes: anti-signal recognition particle (anti-SRP) IMNM, anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) IMNM, and seronegative IMNM, which accounts for 10%–20% of cases. Patients usually present with subacute symmetrical muscle weakness, usually involving the proximal and pharyngeal muscles with significantly elevated creatinine kinase levels. Associated symptoms include myalgia, fatigue, and weight loss.1, 2 Anti-SRP IMNM usually presents with a more fulminant course, with early dysphagia and possible respiratory failure, while this is rarer in anti-HMGCR and seronegative IMNM. Notably, seronegative IMNM is linked to malignancy, resulting in decreased survival.3 We present a case of a 34-year-old man with an unusual clinical manifestation of seronegative IMNM, namely acute respiratory failure. The patient reported no chronic medical conditions and had never taken statins. Three months before admission, the patient started having generalized weakness, unintentional 9.07 kg weight loss, and ptosis. Two months later, the weakness progressed, affecting his lower extremities, causing difficulty swallowing, chewing, dysarthria, and tongue numbness. He was admitted to an outside facility with rhabdomyolysis and intubated due to respiratory failure. Predominant proximal muscle weakness along with fatiguability was noted. There, electromyography showed increased insertional activity in the upper limbs as well as fibrillation potentials, positive sharp waves suggestive of inflammatory myopathies, and also decremental response on repetitive nerve stimulation of the right facial nerve and left ulnar nerve suggestive of possible neuromuscular junction disorder. A brain magnetic resonance imaging showed abnormal white matter changes, and a muscle biopsy of the left thigh was performed but had not resulted when he was evaluated by neurology. He was suspected of having myasthenia gravis versus polymyositis, thus was empirically treated with prednisone 60 mg daily, pyridostigmine 60 mg daily, and mycophenolate mofetil 1000 mg daily at discharge. Two weeks later, he was found unresponsive and was transferred to our facility for a higher-level care where he was found to be in hypercapnic respiratory failure and intubated. He was hypotensive but afebrile. Full neurologic examinations were not feasible as he was sedated and intubated. Initial investigations showed leukocytosis with neutrophilia (24.9 K/μL, 85.7% neutrophils) and mildly elevated procalcitonin (0.11 ng/mL) and erythrocyte sedimentation rate (28 mm/h). Creatinine kinase (3601 IU/L, normal range 26–308 IU/L), and liver enzymes were markedly elevated. The viral hepatitis panel, human immunodeficiency virus and syphilis screening, antinuclear antibody, and thyroid function tests were normal. Computerized tomography of the head and neck with angiography as well as computerized tomography of the chest, abdomen, and pelvis demonstrated lower lobe airspace opacities with centrilobular nodules suggestive of pneumonia, but no signs of malignancy or cerebrovascular diseases. The patient was treated empirically with piperacillin-tazobactam and norepinephrine for septic shock and aggressive fluids for rhabdomyolysis. A stress dose of hydrocortisone was started for a possible adrenal crisis due to chronic steroid use. Neurology was consulted for a suspected myasthenia crisis and he was treated empirically with intravenous immunoglobulin (IVIG) 0.4 g/kg while awaiting further diagnostic results. Clinical improvement was observed on the second day of IVIG infusion; he was extubated to noninvasive mechanical ventilation and later a nasal cannula. A more extensive physical examination was only significant for generalized proximal muscle weakness (Medical Research Council Grades 4) with distal muscle groups all Grade 4+/5 and a general decrease in deep tendon reflex. Blood cultures were negative, and piperacillin-tazobactam was discontinued after completing 5 days of treatment. The muscle biopsy retrieved from outside reported necrotizing myopathy with focal mild inflammations and positive human leukocyte antigen I immunohistochemistry study, with no endomysial fibrosis and only mild perivascular inflammation, favoring IMNM. Special investigations (Supporting Information: Table S1) revealed a negative myositis profile, including 3-hydroxy-3-methylglutaryl-coenzyme A antibodies, anti-SRP antibodies, anti-Jo antibodies, and a negative myasthenia gravis panel. The patient was diagnosed with seronegative IMNM. IVIG was extended to 7-day course as his strength, but not his bulbar weakness recovered after 5 days of treatment. Subsequently, hydrocortisone was switched to previous dose of prednisolone, mycophenolate mofetil was escalated to 2 g daily, pyridostigmine was discontinued as myasthenia gravis had been ruled out, and he was transferred back to his facility. At 2-month follow-up, he remained on the same medication regimen. Creatinine kinase had trended down to 957 IU/L and erythrocyte sedimentation rate had normalized (3 mm/h). This case presented a distinct clinical manifestation of acute respiratory failure seronegative IMNM, without interstitial lung disease. This is likely a secondary diaphragmatic weakness. Only a few cases of seronegative IMNM presenting with respiratory failure have been reported. A case reported intermittent ptosis with respiratory failure in a seronegative IMNM patient, which may lead to a misdiagnosis of myasthenia gravis. There have also been cases where myasthenia gravis presented with rhabdomyolysis-like symptoms, further adding to the confusion.4 Studies on the pathophysiology of seronegative IMNM are limited. One explanation for seronegativity is that other as-of-yet undiscovered antibodies may cause the pathology.2 Antimitochondrial M2 and anti-aminoacyl tRNA synthetase antibodies were also reported to be associated with IMNM.1 Due to the rarity of seronegative IMNM, the diagnosis required supportive histopathology of muscle biopsy and the exclusion of other diagnoses, especially drug-induced myopathies. No definite guidelines existed for the treatment of IMNM. Medical therapy reduces the disease activity of IMNM without a direct impact on muscle regeneration.5 A systemic corticosteroid and immunosuppressant should be initiated within the first month of clinical presentation of IMNM, especially in the presence of swallowing dysfunction; corticosteroid monotherapy is usually insufficient.2 Although our patient was initially treated with IVIG for a presumed myasthenia crisis, the treatment is also indicated for severe IMNM. In short, IMNM can present with respiratory failure due to respiratory muscle weakness, mimicking more common conditions such as myasthenia gravis, or dermatomyositis. Atypical clinical findings of those conditions, especially combined with inconsistent electromyography or serologic findings, should prompt consideration of other diagnoses. A muscle biopsy can be a helpful tool for arriving at the final diagnosis. Nattanicha Chaisrimaneepan: Resources, writing original draft, review and editing. Gwyn Srifuengfung: Writing original draft, review, and editing. None. The authors declare no conflicts of interest. Verbal and written consent was obtained from the patient for the publication of this case. The data used in this article are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.