|CASE BASED REVIEW
|Ahead of print publication
Myasthenia overlap – Report of two cases and review of literature
Manesh Manoj, Rasmi Ranjan Sahoo, Kasturi Hazarika, Prashant Bafna, Anupam Wakhlu
Department of Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||19-Nov-2020|
|Date of Acceptance||20-Nov-2020|
|Date of Web Publication||18-Nov-2021|
Department of Rheumatology, King George's Medical University, Lucknow - 226 020, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
The presence of more than one autoimmune disease in a patient can complicate not only the diagnosis but also pose a therapeutic challenge to the treating physician. Myasthenia gravis (MG) is a rare disorder which may overlap with a number of other autoimmune conditions. It is important to recognize its co-presence since the management of the accompanying autoimmune condition may need to be tailored accordingly. In this article, we describe two cases with MG overlap, one with primary Sjogren's syndrome and the other with Takayasu arteritis. Herein, we review the literature and clinical approach and management of such patients.
Keywords: Myasthenic crisis, overlap, proximal myopathy, Sjogren's syndrome, Takayasu arteritis
| Introduction|| |
Autoimmune diseases affect approximately 3%–5% of the world's population. Some of these diseases may overlap or co-exist with each other. The co-existence of more than one autoimmune disease in the same patient poses a diagnostic challenge, as one disease may be masked or even overlooked initially. This, in turn, poses therapeutic challenges to the treating physician and may result in disastrous consequences. Myasthenia gravis (MG) is a rare autoimmune disorder characterized by fluctuating fatigability of muscles, which has been seen to complicate the presentation of other immunological diseases. Autoimmune thyroid disease has been previously described to be most commonly associated, but a number of other diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis, and idiopathic inflammatory myositis have also been described. The co-existence of MG complicates the evaluation of symptoms such as muscle weakness and may significantly alter the initial management of the case, requiring a balanced approach. MG is classically considered to be the neurologist's domain, but every rheumatologist must be aware and prepared to evaluate, diagnose, and treat the condition. In this review, we discuss two cases of MG, one associated with primary Sjogren's syndrome (pSS) and the other with Takayasu arteritis (TA).
| Case Reports|| |
A 60-year old female was admitted with a history of difficulty in walking for the past 2 years, generalized body pain, arthralgias, and was bed bound for the past 3 months. She also complained of dry mouth for the past 2 years, severe enough to cause difficulty in deglutition. She presented with 4−/5 proximal muscle weakness of all four limbs with mild distal weakness. Initial investigations revealed severe hypokalemia (2.1 mEq/L). An appropriate correction was initiated. Considering SS with distal renal tubular acidosis, an arterial blood gas was sent, which revealed normal anion gap metabolic acidosis. Urine examination revealed alkaline urine with nephritic range proteinuria and no active sediments. Hence, possible tubulointerstitial nephritis was considered. The next day, she rapidly developed severe weakness (1/5) of all four limbs including distal muscles and bulbar weakness, despite improving hypokalemia. A detailed re-evaluation of the history revealed that she had a history of occasional drooping of eyes and fatigue toward evening for the past several years, which she attributed to melancholy. Hence, MG was suspected. A positive therapeutic response to neostigmine strengthened the suspicion. Myasthenia autoantibody profile was positive for AChR antibodies. Anti-nuclear antibody (ANA) was 4+ fine speckled and extractable nuclear antigens (ENA) revealed SSA, SSB, and Ro52+++. Her viral markers (HIV, HbsAg, and anti-HCV) were negative. A computed tomography (CT) of the thorax ruled out thymoma. The patient was initially managed with intravenous immune globulin (IVIG) (2 g/kg over 2 days), low-dose steroids initially, and pyridostigmine. Steroids were gradually increased, potassium supplementation optimized with potassium citrate, acidosis corrected, dose of pyridostigmine optimized, and second-line immunosuppression with mycophenolate mofetil (MMF) initiated. Renal biopsy was declined by the patient. Gradual systematic physiotherapy was initiated. The patient was mobile with support at discharge at 1.5 months.
A 35-year-old female was admitted with a history of absence of pulses of the left upper limb, detected 8 months back, and generalized weakness for the past 3 months. She also had difficulty in swallowing with nasal twang of voice and nasal regurgitation for 15 days. A detailed history revealed increased fatigue toward the later part of the day for 2 years. The absence of pulses was detected as part of her evaluation for fatigue. The right upper limb blood pressure (BP) was elevated compared to the other three limbs. A CT aortogram revealed diffuse narrowing of the infrarenal aorta including bilateral external iliac arteries and narrowing of the left subclavian artery and proximal part of the left axillary artery and features suggestive of abdominal aortic dissection [Figure 1]a and [Figure 1]b. No thymoma was visible. On admission, she had severe neck weakness and 4−/5 proximal muscle weakness of all four limbs. Initially, inflammatory myositis was also considered, but the presence of a history of drooping of eyelids towards the later part of the day and dramatic response to a neostigmine challenge test confirmed the diagnosis of MG. This was further confirmed by a repetitive nerve stimulation test once the patient became ambulatory. Her inflammatory markers were elevated and viral markers (HIV, HbsAg, and anti-HCV) were negative. Given aortic dissection, it was decided to achieve a target BP of 130/80 or below in her right upper limb, and hence, she was started on a beta-blocker. The patient was initially treated with IVIG, given her severe neck and pharyngeal muscle weakness, at a dose of 1 g/kg/day (financial constraints) and she was also started on low-dose steroids with a plan to titrate upward. Pyridostigmine was initiated and increased gradually. However, the patient developed bradycardia, owing to both beta-blocker and pyridostigmine, and hence, a calcium channel blocker was substituted. Myasthenia-associated autoantibodies could not be performed due to financial constraints. MMF was considered the choice of second-line immunosuppression for co-existent MG, but owing to financial constraints in the long term, she was started on azathioprine., She was ambulatory and doing well at discharge.
|Figure 1: Computed tomography aortogram showing significant narrowing of the infrarenal abdominal aorta (arrow) with multiple collateral formation (arrowheads) (a). The left subclavian and proximal axillary arteries were non-visualized (arrow) with evidence of extensive distal collaterals (arrowhead) (b)|
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| Discussion|| |
The diagnosis of classical MG from the clinical history is usually straightforward. However, as exemplified by these two cases, with the co-existence of other autoimmune diseases, muscle weakness could have very well been attributed to hypokalemia or inflammatory myositis, muscle ischemia, or to simple disuse. Symptoms of minimal drooping of eyes and episodic weakness may be too trivial for the patient to mention or the physician to inquire and hence may not find a mention in the history. The temporal profile of events and correlation with other clinical and laboratory parameters are also very significant in making such distinctions.
MG has been previously reported to be associated with SS in a number of case reports.,,,, However, only a few have sufficient information to reliably confirm a diagnosis of pSS., Most of these patients had an associated thymoma, which was absent in both of our patients. Thymoma has also been seen to be associated with cases of pSS without associated features of MG. Studies by Lindahl et al. previously revealed lymphocytic infiltration of minor salivary glands in patients with MG without any other features of SS. Hence, a salivary gland biopsy in isolation may not always be reliable enough in these patients. There has been no reported occurrence of TA with MG in literature so far.
MG usually is divided into early or late onset, depending on whether it initially appears before or after the age of 50 years, respectively. Early-onset myasthenia (EOM) is more commonly associated with autoimmune diseases. Another important consideration in these patients is the need for DVT prophylaxis, especially during periods of severe muscle weakness. Some studies have shown late-onset myasthenia (LOM) to be associated with antiphospholipid antibodies. In our series, one patient had EOM and the other had LOM. MG associated with other autoimmune diseases tends to have an indolent, slowly progressive course, is usually generalized, and is seen more often in females. Myasthenic crisis is usually rare. However, both our patients presented in a state of impending myasthenic crisis.
In patients with impending or manifest myasthenic crisis, mild bulbar weakness with proximal muscle weakness may be the only symptom, and a high index of suspicion is warranted to differentiate from inflammatory myositis. Signs of respiratory distress (soft speech, use of accessory muscles of respiration, and abdominal breathing) may not be evident always due to severe muscle weakness and should not be considered the only indicator for disease worsening.
At the bedside (also due to nonavailability of edrophonium), a simple and reliable screening test may be done using neostigmine injection. Three ampoules of injection neostigmine (total dose of 1.5 mg) are mixed with two ampoules of injection atropine (1.2 mg) and then diluted to 10 ml with 0.9% N saline. One to two ml of this solution given intravenously, with continuous cardiac monitoring, may reveal a drastic improvement in muscle strength (within 1–2 min with a peak in 15–30 min) which can aid in diagnosis. The classically described ice pack test has not been validated and testing for autoantibodies (acetylcholine receptor antibody, muscle-specific kinase (MuSK), anti-striated muscle antibody, anti-LRP-4 antibody) can corroborate the diagnosis but requires time and finances. Repetitive nerve stimulation test and single fiber electromyography also require specialized equipment and personnel and may not be always available.
Routine management of MG depends on the presentation of the patient and includes the use of rapidly acting therapies in impending and manifest myasthenic crisis (defined as the need for intubation or noninvasive ventilation) and long-term therapies. Rapid therapies include IVIG (1–2 g/kg) and plasmapheresis (five exchanges over a week). Long-term therapies include the use of anticholinesterase, usually pyridostigmine, in all cases, steroids at 1 mg/kg prednisolone equivalent in more severe cases and long-term immunosuppression, if required with AZA (up to 2 mg/kg), MMF (up to 2 g/day), cyclosporine (usually up to 5 mg/kg/day), tacrolimus (usually up to 3 mg/day), and rituximab (especially in anti-MuSK positive patients). A number of experimental therapies are also under investigation, the description of which is beyond the scope of this review.
One of the first-line drugs which can be used as a rapid therapy in MG presenting in crisis as well as an initial therapy in a number of other autoimmune conditions which may be associated with MG is IVIG. A dose of 2 g/kg over 2–5 days is recommended, though a few studies have suggested that 1 g/kg dose may be enough for MG, which could be considered in financially constrained patients. Furthermore, the fact that plasmapheresis requires specialized equipment and personnel may make IVIG a more attractive option in the acute crisis setting.
One major issue with severe MG complicating the presentation of another autoimmune disease is the initial dosing of steroids. In both the cases described above, the presence of probable interstitial nephritis with nephritic range proteinuria in the first case and the presence of TA in the second warranted the use of high-dose steroids up to 1 mg/kg prednisolone equivalent. However, the concurrent diagnosis of MG and the fact that these patients were managed in a nonintensive care unit ward setting precluded the use of high-dose steroids, as they may paradoxically worsen the weakness and precipitate myasthenic crisis in up to 50% of patients, some of whom may end up requiring mechanical ventilation (almost 10%). This may occur after 5–6 days of high-dose steroids and the need for mechanical ventilation may last for up to 1 week. Hence, steroids should be started at around 15 mg/day prednisolone equivalent with an aim to increase it at 5 mg increments every 4 or 5 days to a target of 1 mg/kg (not more than 80 mg/day). Patients with severe bulbar weakness will require nasogastric tube insertion and oral steroids may be substituted by IV dexamethasone in equivalent dosage. Steroid taper is usually decided according to the tapering protocol for the associated autoimmune disease, in other situations, such as those cases associated with conditions like RA or pSS (where high-dose steroids are usually not used), a slow taper with initial 10 mg every week till 40 mg/day then 10 mg every 2 weeks till 20 mg/day, followed by 5 mg every 2 weeks till 10 mg/day and more slowly beyond that may be followed.
Regarding long-term immunosuppression, usually, the associated autoimmune condition takes precedence in choosing which immunosuppressive agent to use, as mild MG may be controlled with the drugs used for the former with concomitant use of pyridostigmine. AZA or MMF is the usual first-line drug in these patients, although cyclosporine and tacrolimus are effective alternatives. Methotrexate has not been shown to be conclusively beneficial in MG and this is usually an issue in patients with associated RA. Tacrolimus is a good option for such patients. Rituximab has been shown to be useful in patients who are MuSK antibody positive, though majority of the patients with MG overlap are AchR positive. Cyclophosphamide has also been tried in refractory or relapsing cases. It has also been suggested that in patients with an overlap syndrome, the associated autoimmune condition tends to be milder, for example, in the case of SLE overlap with MG, where lupus nephritis is rare. A number of medications commonly used or co-prescribed in autoimmune and rheumatic diseases may have to be cautiously used or even avoided in patients with MG. An informative list of these drugs is available at http://myasthenia.org/HealthProfessionals/ClinicalOverviewofMG.aspx.
In conclusion, our cases exemplify that detailed attention to history, physical examination, and the temporal profile of events along with a high index of suspicion is important for the diagnosis of co-existing MG in patients of autoimmune diseases presenting with muscle weakness. The rheumatologist must pay special attention to bulbar and fluctuating muscle weakness. Once the diagnosis of co-existing MG has been made, careful attention must be paid to initiation and maintenance of immunosuppressive and other supportive therapy, especially if the patient is in impending myasthenic crisis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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