Myasthenia Gravis (MG) is a chronic antibody-mediated autoimmune disease that affects the neuromuscular junction. It leads to fluctuating fatigable muscle weakness. The most common presenting manifestations are ocular symptoms with double vision and ptosis. Other symptoms can include bulbar, limb weakness and in 15% of cases respiratory failure as a myasthenic crisis [1,2]. It often affects patients of all ages with a peak in younger women and older men. Immune-mediated inflammatory and necrotizing myopathies are a complex group of entities that have clinical, laboratory and histologic evidence of muscle involvement by inflammation and/or necrosis in varying patterns and distribution. Many different classification systems and nomenclatures are used; however, laboratory evaluation for myositis-specific and myositis-associated antibodies is essential for the appropriate diagnosis of any underlying diseases. Muscle involvement by inflammatory or necrotizing immune myopathy in patients with underlying MG is quite rare; it is most commonly seen in the setting of a thymoma [2]. We present a case who presented with severe neuromuscular junction failure with muscle end plate necrosis.

Case Report

A 45-year-old woman with a past medical history of Crohn’s disease and a benign thymoma presented to the hospital with rapidly progressive weakness, double vision, slurred speech and difficulty swallowing for 3 weeks. Initially, her symptoms started with swelling of her thighs and arms with arm and leg weakness. She described difficulty swallowing and breathing for one week before admission. She was previously diagnosed with a benign thymoma for which she underwent thymectomy 9 years prior. She was not on any medication at the time of presentation; however, she had been on multiple different tumor necrosis factor inhibitors (anti-TNF) for Crohn’s disease in the past several years. Her family history was negative for neuromuscular disorders. Clinical examination revealed bifacial weakness, neck flexion weakness and upper extremity proximal weakness (3/5). She also had distal weakness and was unable to use her first dorsal interosseous or abductor pollicis brevis. Lower extremity examination showed proximally (3/5) and distally (4+/5). Sensory examination was intact with absent reflexes in upper and lower extremities except ankles was 1+. Initial investigations seen in Table 1 and 2.

Table 1: laboratory results

Table 2: Myositis Panel

Otherwise, normal full blood count, renal function, Anti-VGCC and anti-LRP4 antibodies were negative. Thyroid function and vitamin B12 levels were within the normal range. Protein electrophoresis was normal. Anti-ganglioside panel was negative. Table 2 for the complete myositis panel.

Cerebrospinal fluid (CSF) analysis was unremarkable for protein, glucose, white and red blood cells and West Nile virus immunoglobulin G antibody. Nerve Conduction Studies (NCS) revealed only motor nerve abnormality (Figure 1). 

Figure 1(a-d): Nerve Conduction Studies, (a) The left median motor nerve showed no response at the wrist (upper trace) and no response at the elbow (lower trace), (b) The left ulnar motor nerve showed no response at the wrist (upper trace), no response at the elbow (middle and lower trace), (c) Left peroneal motor nerve recording from the extensor digitorum brevis (EDB) motor nerve showed no response at the ankle (upper trace), no response at the fibular head (middle trace) and no response at the popliteal fossa (lower trace) and (d) The left tibial motor nerve showed reduced amplitude

Electromyography (EMG) revealed widespread rapid recruitment with active denervation and myopathic potential and also reduced amplitude of motor nerves which indicated evidence of a motor syndrome.

Based on the presence of anticholinesterase antibodies and the EMG findings, a diagnosis of myasthenia gravis was made. The patient was started on intravenous immunoglobulin at a dose of 2 g/kg for a total of 5 days. She was also started on Mestinon 60 mg four times daily and prednisone 40 mg daily. with marked improvement in her distal weakness.

A right triceps skeletal muscle biopsy was performed. The muscle biopsy showed prominent myofiber necrosis, regeneration, atrophy and fibrosis. There was variable involvement of the muscle fascicles, with some showing only mild-moderate changes while others were very severely affected, with near complete replacement of the fascicles by fibrosis. There is a patchy moderate Perivascular Perimysial and Endomysial lymphoplasmacytic and histiocytic inflammatory infiltrate as well as Perimysial widening. The inflammatory infiltrate was predominantly comprised of CD3-positive T lymphocytes (CD4>CD8) and histiocytes, with several perivascular CD20-positive B-lymphocytes. Endomysial T cells were also present, mostly surrounding small vessels as well as scattered throughout. Lymphocytic invasion of non-necrotic myocytes was not seen. Overall, the findings were most consistent with an inflammatory and necrotizing myopathy (Figure 2).

Figure 2(a-f): Histopathology of muscle biopsy, (a) Hematoxylin and eosin (H&E)-stained frozen muscle sections demonstrate an active and chronic necrotizing and inflammatory process with Perimysial and Endomysial fibrosis, perivascular and Endomysial inflammation (100x, scale bar 100mm), (b) Gomori trichrome stain highlights extensive fibrosis (100x, scale bar 100mm), (c) Higher-power H&E shows perivascular inflammation (200x, scale bar 50mm), (d-f) Immunohistochemistry for inflammatory markers illustrate lymphocytic infiltrate, brown staining (all 200x, scale bar 50 mm): (d) CD20 shows perivascular B-cells, (e) CD4-positive T helper cells predominate around vessels and in endomysium and (f) Scattered CD8-positive cytotoxic T cells are also present but fewer in number

The patient had a CT chest with no evidence of anterior mediastinal mass to suggest residual or recurrent thymoma. The patient was then transferred to a long-term care facility to continue physical rehabilitation. Her weakness has improved and she is now able to walk without assistance.

Repeat NCS/EMG after 2 months still showed electrophysiological evidence of active denervation and myopathic potential in proximal and distal muscles with reduced amplitude of motor nerves (Figure 3).

Figure 3(a-d): Nerve Conduction Studies, (a) Right median motor nerve showed reduced amplitude at the wrist (upper trace) and reduced amplitude at the elbow (lower trace), (b) Right ulnar motor nerve showed reduced amplitude at the wrist (upper trace) and reduced amplitude at the elbow (middle and lower trace), (c) Right peroneal motor nerve recording from Extensor Digitorum Brevis (EDB) motor nerve showed no response at the ankle (upper trace), no response at the fibular head (middle trace) and no response at the popliteal fossa (lower trace) and (d) Right tibial motor nerve showed normal amplitude at the ankle (upper trace) and normal amplitude at the knee (lower trace)

Myasthenia gravis is an autoimmune disorder caused by autoantibodies against the nicotinic acetylcholine receptor that is present in the postsynaptic membrane located in the neuromuscular junction. Myasthenic Crisis is usually caused by triggering infection or inadequate treatment leading to exacerbation of myasthenic symptoms resulting in respiratory failure. It can be very difficult to distinguish between myasthenia and myositis in an acute setting given rapidly progressive symptoms [3,4]. Although rare, myasthenia gravis can have an overlapping myositis disorder. Typically, myositis has clinical signs of dermatomyositis or polymyositis [5]. The key features of myasthenia gravis are fluctuating weakness and fatigue-specific muscle groups. Often, myopathies have been described before in the literature. Overlap syndrome which is associated with myasthenia gravis and myositis is typically seropositive [4-6]. To our knowledge, this is the first case that presented clinical, serological and electrophysiological evidence of myasthenia gravis concurrent with necrotizing myositis with seronegative Idiopathic Necrotizing Autoimmune Myopathy (INAM). The clinical presentations of myositis and myasthenia were similar in symptoms but there were differences noted in clinical exams and investigations done. Together with high titer AChR, electrophysiological evidence of post-synaptic neuromuscular junction deficit of EMG, elevated CK and muscle biopsy suggests diagnoses of both seropositive myasthenia gravis and seronegative necrotizing myositis. The progressive muscle weakness with elevated CK along with an incomplete response to immunomodulatory therapies and pyridostigmine encouraged us to search for other explanations for her weakness and muscle swelling.

The muscle biopsy results validated our suspicion that we are dealing with not only myasthenia but with necrotizing myositis as well as emphasized the importance of muscle biopsy in the diagnosis of myopathy in atypical cases. The presence of myofiber necrosis in the biopsy the criteria for the diagnosis of clinically defined necrotizing myositis. The patient had an overwhelming autoimmune reaction against muscle AChR that lead to an inflammatory and necrotizing reaction against muscle fiber. Another possibility is whether in our case we are dealing with two different overlapping autoimmune diseases that were incidentally presented together.

Seronegative necrotizing myopathy is an uncommon presentation with seropositive myasthenia, it could be classified as part of the necrotizing myositis spectrum. As a such presentation, the response to treatment and long-term prognosis remains incompletely defined and the evidence base for best-practice treatment is lacking. The case described here highlights that myasthenia gravis act as an autoimmune disorder that triggers to induce a complex autoimmune disease leading to muscle necrosis with another possibility of it being myasthenia with overlapping necrotizing myositis picture. Further research studies are warranted.

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2. Conti-Fine, B.M. et al. “Myasthenia Gravis: Past, Present, and Future.” Journal of Clinical Investigation, vol. 116, 2006, pp. 2843-2854. https://doi.org/10.1172/JCI29894.

3. Thanvi, B.R. “Update on Myasthenia Gravis.” Postgraduate Medical Journal, vol. 80, 2004, pp. 690-700. https:// doi.org/10.1136/pgmj.2004.018903.

4. Allenbach, Y. et al. “Immune-Mediated Necrotizing Myopathy: Clinical Features and Pathogenesis.” Nature Reviews Rheumatology, vol. 16, 2020, pp. 689-701. https:// doi.org/10.1038/s41584-020-00515-9.

5. Paik, J.J. et al. “The Co-Existence of Myasthenia Gravis in Patients with Myositis: A Case Series.” Seminars in Arthritis and Rheumatism, 2013. https://doi.org/10.1016/j. semarthrit.2013.12.005.

6. Kanazawa, M. et al. “Clinical Features of Patients with Myasthenia Gravis Associated with Autoimmune Diseases.” European Journal of Neurology, vol. 14, 2007, pp. 1403-1404. https://doi.org/10.1111/j.1468-1331.2007. 01978.x.