Dr. Akshay Nair, N12639, Dr. Nita AmitShah
Introduction:
Myasthenia gravis (MG) is a potentially serious, but treatable autoimmune disease affecting the neuromuscular junction (NMJ) of the skeletal muscle. Ocular myasthenia gravis (OMG) can mimic isolated cranial nerve palsies, gaze palsies, internuclear ophthalmoplegia, blepharospasm, and even a stroke.
The NMJ is the site of chemical communication between a nerve fiber and a muscle where motor nerve impulses are transmitted to the muscle cell. An action potential initiates neuromuscular transmission and results in the release of ACh molecules at the NMJ, which then diffuse across the synapse, bind to receptors on the striated muscle and depolarize the postsynaptic membrane, resulting in muscle contraction.
There are many diagnostic and clinical tests that are used to diagnose myasthenia. However, each of these have varying sensitivities and specificities. Often times, a barrage of investigations is advised and the patient has to undergo all of them to finally conclusively diagnose OMG. Therefore this study was conceptualized to assess the diagnostic yield of different investigations in patients with ocular myasthenia gravis who presented with unilateral ptosis.
Antiacetylcholine receptor antibodies (AChRAbs) have been demonstrated in up to 99% of patients with generalized myasthenia and 40-77% of patients with OMG. AChRAbs decrease the number of available AChRs by receptor blockade, complement‑mediated membrane damage, and accelerated degradation of the receptors.[1] This results in defective transmission at the NMJ and subsequent muscle weakness.
Variable ptosis is one of the most common manifestations of OMG. Ptosis occurs primarily due to the involvement of the levator palpebrae superioris (LPS) complex. It may be unilateral or bilateral– in bilateral cases, it is often asymmetrical. Ptosis may increase after prolonged up gaze – referred to as the “lid fatigability test.” Another clinical sign described is the Cogan’s lid twitch, a quick overshooting upward movement followed by a downdrift of the upper lid after the patient performs a saccade back to primary position from looking down for at least 15 seconds.
Methods:
In our study we retrospectively reviewed the records of 37 consecutive patients of ocular myasthenia gravis who were subsequently treated for myasthenia gravis. Those included in the study were:
Adult patients
- Presenting only as unilateral ptosis
- Distinct history of variability in ptosis with or without prior episode of diplopia
- Absence of systemic symptoms
- No prior treatment for myasthenia
- Positive response to treatment was taken as the gold standard.
All patients underwent four diagnostic tests – ice test, Single fibre EMG, neostigmine test and anti-acetylcholine receptor antibody assessment.
Results:
The results were as follows: The mean age of the patients was 46.7 years. The mean duration of complaints was 13.3 months. Ice test was seen positively in 94.6% of the patients (34/37). SFEMG was found to be positive in 59.5% (22/37) of the patients. Neostigmine test was noted to be positive in 56/8% (21/37) of the patients and a positive AChR-Ab assay was noted in 45.9% (17/37) of the patients. On analyzing the positives and co-relating with the history, it was found that neostigmine test (p=0.008) and AChR-Ab (p=0.007) were more likely to be positive in those with history of ptosis ≥1 year. However, SFEMG had significantly higher rate of positivity in those aged ≥45 (p=0.04) and also those with a prior history of diplopia (p=0.02). Ice test had the highest positivity among all patients.
Discussion:
The ice test is a simple, but effective clinical test that can be used to confirm the diagnosis of MG. An icepack is placed over the patient’s closed eyelids for a period of 2 min (for ptosis) to 5 min (for ophthalmoparesis)
Elevated AChRAb titers confirm the diagnosis of MG. However, a normal titer does not exclude the disease. The presence of an elevated AChRAb titer helps to distinguish acquired MG from a congenital myasthenic syndrome since the latter is persistently seronegative. AChRAb testing also provides a baseline for future comparisons and response to immunomodulatory treatment.[1] The absolute antibody titer correlates poorly with the severity of the disease from the patient to patient, but in individual patients, changes in disease severity do tend to be associated with changes in antibody titer.
In SFEMG, the nerve to be studied is electrically stimulated 6-10 times at 2 or 3 Hz (slow rate) with a supramaximal stimulus and the compound muscle action potential (CMAP) is recorded with surface electrodes. In MG, as the number of individual muscle fiber action potentials reduce, the CMAP also reduces in both amplitude and area with a resulting decremental response.[2] In MG, a characteristic decrement (>10%) in muscle action potential amplitude is typically seen by the fourth or fifth response in a series of low-frequency RNS, whereas the amplitude remains the same in normal individuals.[3] This decremental response is seen in only 33% of patients with purely OMG.
Peeler et al studied the clinical utility of acetylcholine receptor antibody testing in ocular myasthenia gravis. They reported that among the 223 participants, AChR antibody testing results were positive in 158 participants (70.9%). In an adjusted model, increased age at diagnosis (odds ratio [OR], 1.03; 95% CI, 1.01-1.04; P = .007) and progression to generalized myasthenia gravis (OR, 2.92; 95% CI, 1.18-7.26; P = .02) were significantly associated with positive antibody test results. They also reported that women were less likely to have a positive antibody test result (OR, 0.36; 95% CI, 0.19-0.68; P = .002). Patients who developed symptoms of generalized myasthenia gravis had a significantly higher mean (SD) antibody level than those who did not develop symptoms of generalized myasthenia gravis. They were able to demonstrate that demonstrate a higher sensitivity of AChR antibody testing than previously reported in the largest cohort of patients with OMG available to date. Older age, male sex, and progression to generalized myasthenia gravis were significantly associated with a positive antibody test result.[4]
Similarly, Morren et al studied the diagnostic accuracy of single fiber electromyography for myasthenia gravis in patients followed longitudinally. They found that in their cohort of 348 patients who underwent SFEMG, myasthenia gravis was ultimately diagnosed in 31% (19% ocular, 12% generalized). A sensitivity of 78% was seen for MG regardless of subtype, 73% for ocular MG, and 85% for generalized MG. A specificity of 91% was obtained for MG of either ocular or generalized subtype. They concluded that the diagnostic accuracy of SFEMG using this methodology minimizing incorporation bias is more reliable than that usually described in previous studies. There is utility in increasing diagnostic yield when SFEMG results are combined with clinical data and those from other diagnostic tests, particularly serology.[5]
We summarize that among the screening tests, the bedside ice test has the highest sensitivity. However, our study does not include false positives, therefore the specificity of the ice test could not be assessed in this study. Furthermore, duration of history, age & history of diplopia are factors that may be considered while deciding investigations in order to maximize diagnostic yield. In patients with a history of variable ptosis for over one year, neostigmine test and AChRAb were likely to yield a positive result and in older patients (over 45 years of age), SFEMG appears to be the investigation of choice to maximize diagnostic yield. The same holds true for patients who have had one or more episodes of transient diplopia in the past.
References:
- Grigg J. Extraocular muscles: Relationship of structure and function to disease. Aust N Z J Ophthalmol 1999;27:369‑
- Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis 2007;2:44.
- Ozdemir C, Young RR. The results to be expected from electrical testing in the diagnosis of myasthenia gravis. Ann N Y Acad Sci 1976;274:203‑
- Peeler et al. Clinical Utility of Acetylcholine Receptor Antibody Testing in Ocular Myasthenia Gravis. JAMA Neurol. 2015;72(10):1170-4.
- Morren JA, Levin KH, Shields RW. Diagnostic Accuracy of Single Fiber EMG for Myasthenia Gravis in Patients Followed Longitudinally. J Clin Neurophysiol. 2016 Mar 31. [Epub ahead of print]
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