The key to an earlier diagnosis of Myasthenia Gravis is awareness

MG is a rare neuromuscular autoimmune disorder, that can cause extreme fatigue and profound muscle weakness, however, since the symptoms can fluctuate throughout the day, week by week, or month by month, a delayed diagnosis by several years occurs far too often and the consequences for these patients are traumatic; including the physical, financial and emotional burdens. Earlier diagnosis and treatment allow patients better outcomes and improved quality of life. As an Orthoptist living with MG, I would like to take this opportunity to increase awareness of the subtle eye signs that can help diagnose MG.

Common Symptoms

Some common symptoms of MG are ptosis, blurry vision, diplopia and eye movement restrictions, extremely weak neck, arms, hands, and/or legs, profound tiredness and exhaustion, difficulty with mobility and movement, frequent sudden falls, trouble smiling, difficulty chewing, difficulty breathing or swallowing. When these latter 'bulbar' muscles are affected, the patient is at risk of a myasthenic crisis and respiratory failure.

Diagnosis Delays

The fluctuating and variable nature of MG contributes to the difficulty in diagnosis in many patients, however, diagnosis of MG can be quite easy when obvious classical signs are present at the time of clinical assessment. When mild signs or unusual symptoms are only present during the clinical consultation a high degree of awareness and specific testing are required to diagnose. Unfortunately, an MG diagnosis in such patients is often delayed by many months or even years. (Lisak R 1994).

MG and the Eye

The extraocular muscles (EOMs) are especially prone to be affected by MG (Ansari and Nadeem 2016), however, at onset, only 50% of MG patients have obvious mg eye signs (MGES), (Chisari, Sciacca et al. 2023). Ocular Myasthenia Gravis (OMG) is diagnosed when only the EOMs including orbicularis oculi, levator palpebrae, four recti and two oblique muscles in each eye are affected. OMG is reported as becoming MG within 2 years in 80% of patients (Hake and Kaminski 2011), so early diagnosis is crucial as even a patient with OMG has the risk of Myasthenic Crisis and Respiratory Failure occurring as it transforms into generalised MG (Habib, Sacks et al. 2024).

Limitations of antibody testing and nerve studies

There is a misconception that all MG patients will demonstrate obvious signs like prominent ptosis during an examination or even in selfies. This is where the eye care professional plays a vital role in providing evidence to help lead to an earlier diagnosis in MG patients. The eye signs in some MG patients can be difficult to diagnose as they may be subtle - even ptosis in some MG patients may not appear as ptosis!

After subtle MG eye signs are observed a neurological assessment including antibodies and electrodiagnostic testing can be undertaken. However, many MG patients remain undiagnosed, as lack of obvious clinical signs at the time of consultation results in no diagnostic tests being ordered. Careful ophthalmic assessment is essential, as antibody and electrodiagnostic testing can have false negative results. Approximately 10% of MG (Lazaridis and Tzartos 2020) and 50% of OMG patients are seronegative. Electrodiagnostic testing also has limitations in accuracy in some patients and requires accurate specialised testing facilities that are not always available (Yoganathan, Stevenson et al. 2022, Vinciguerra, Bevilacqua et al. 2023).

There is no such thing as a typical Myasthenia Gravis patient!

Ocular signs in MG are commonly misdiagnosed as another condition or missed entirely. MG is known as the “Great Imitator” with ocular motility findings presenting with signs consistent with other neurological diseases like Parkinson’s Disease, Amyotrophic Lateral Sclerosis, Bell's Palsy and Multiple Sclerosis. Antibody testing in MG patients is negative 15-20% of the time and electrophysiological studies can also be falsely negative at times, so clinical assessment is vital, especially in seronegative patients.

Distinguishing between ‘fatigue’ and ‘fatigability’ is crucial in MG diagnosis. ‘Fatigue’ is a subjective description of excessive tiredness or exhaustion that often interferes with activities of daily living (ADL). Whereas ‘Fatigability’ is an objective reduction in the strength of muscle groups after a specific action.

MG Eye Signs

The eye muscles are known to be the most susceptible to MG, however, signs may be subtle. Ophthalmic testing for MG involves inducing fatigue and testing the function of the extra ocular muscles, levator palpebrae and orbicularis couli. Testing for MG eye signs involves tests to disclose ptosis, lid retraction, restriction of ocular movement, distinct saccadic signs, Cogan’s Lid Twitch, and orbicularis oculi weakness.

Fatigability explains why MG ocular motility signs can at times be fleeting. MG is known as a condition where muscle function weakens with use and improves with rest, however, the duration of improvement after rest is also variable. A good example of this is the sleep test where the improvement in ocular motility and/or ptosis may be brief. Another example is when MG signs improve rapidly but briefly, with a blink/closing of eyes or change in fixation during ophthalmic assessment.

MG Eye Signs are variable, fluctuating and unpredictable. Awareness of the Rarer MG eye signs can help with earlier diagnosis, especially in seronegative patients.

Below is a summary list of some of the lesser-known eye signs.

Ptosis

·?Ptosis can be highly variable and often remains unnoticed when mild, and when ptosis is bilateral, it is often asymmetrical, (Lisak, 1994).

· Don't only test for fatigability in upgaze! ?Scottish Neurologist John Simpson was the first to describe increased ptosis on sustained upgaze and the most commonly used test. In the 'Simpson Test' the patient is asked to maintain upgaze for 2-3 minutes testing for fatigue-induced ptosis. Lateral gaze has previously been reported to provoke ptosis (Oosterhuis 1982) and a recent study has now recommended testing for fatigability of ptosis using multiple directions of gaze, holding the gaze for 60 seconds during at least two follow-up visits (de Meel, Raadsheer et al. 2019).

·?Ptosis has been known to switch from one eye to the other or be fleeting, lasting only a few seconds (Oosterhuis 1982, Lisak,1994.)

·?In some patients, a Ptosis is not always obvious to the examiner or the patient, as it may appear more as a narrow palpebral fissure. It may appear as a narrow palpebral fissure in one eye with upper lid retraction in the contralateral eye. Some patients who don't notice ptosis may only report blurriness caused by lid obstruction. (Puklin, Sacks et al. 1976)

Lid Retraction

Lid Retraction is not commonly thought of as an MG sign, however, it has been noted that there are 3 types of eyelid retraction associated with MG (Puklin, Sacks et al. 1976)

i)??? Transient retraction of the upper eyelids that is often uncovered by prolonged upgaze of 5-10 seconds or lateral gaze.

ii)??? The unilateral retraction associated with ptosis of the contralateral eyelid is often prolonged and can be explained to be due to Hering’s law of equal innervation, where central adaptive compensation for unilateral ptosis may lead to hyper-retraction of a less affected lid.

iii)??? Cogan’s Lid Twitch, which is the fleeting lid twitch sign evident after looking down and then to the primary position. (Cogan 1965; Hake & Kaminski, 2011)

Retraction of the upper eyelids in myasthenia gravis is an important sign to consider and is often confused with that of lid retraction in Thyroid Eye Disease (Puklin, Sacks et al. 1976).

Saccades

·?Saccades in the MG patient are often normal or overacting even in an extraocular muscle that is restricted, which is considered pathognomonic of MG.

·There may be fatigue during saccades that results in disconjugate eye movement and associated nystagmus movements in some MG patients, which adds to the difficulty in differentiating complex eye movements from other neurological conditions like Internuclear Ophthalmoplegia (INO). (Hake and Kaminski, 2011). Saccadic Fatigue has been found to be an early indicator of MG diagnosis (Nguyen, Chae et al. 2024)

· Another saccadic-related movement characteristic of MG is quiver movements which are essentially twitching of eyes on a change of gaze direction. These are small amplitude hypermetric saccades that overshoot the target when attempting voluntary refixation. (Yee, Cogan et al. 1976)

Ocular Motility

MG may present with obvious variable ocular motility restrictions that can mimic a variety of conditions, as the "Great Imitator" the list of possible OM findings is endless, however, the key is to look for variability, fatigability and fluctuating signs.

· A recent study has demonstrated the importance of holding the gaze to induce fatigability for at least 60 seconds and testing multiple directions of gaze during at least two follow-up visits (de Meel, Raadsheer et al. 2019)

·?Some MG patients may complain of diplopia with apparent normal ocular motility (Hake and Kaminski, 2011). Other MG symptoms include dizziness, unsteadiness or blurring of vision without diplopia (Hake and Kaminski, 2011)

Orbicularis Oculi

·?Weakness of eye closure may be characterised by fatigue of the eyelids during attempted sustained closure.

·?A less known sign of weakness of the orbicularis oculi is when there may be a retraction of the lower eyelid or paralytic ectropion associated with fatigue (Miller, Walsh et al. 2005)

Accommodative Excess - Blurry vision and headaches

Myasthenia Gravis should be considered in the differential diagnosis in patients complaining of blurry vision and headaches where accommodative spasm and pseudo myopia are being considered. Overstimulation of the parasympathetic nervous system (PNS) has been documented to be associated with muscle fatigue. (Hilora, 2023)

Triggers for MG other than activity and stress

Glare

Glare is also known to be a trigger of eye signs and symptoms in MG patients, a fact that should help with diagnosis. Sunglasses are essential to reduce eye symptoms.

Medication

It's important to be aware that many medications can induce or trigger MG, (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038781/)

Eye signs and symptoms often present early, so the orthoptist and other eye care professionals need to be aware of the subtle rarer eye signs to help with earlier diagnosis. With greater awareness, we may find that MG is not as rare as we currently believe it to be.

Delayed diagnosis of MG by several years occurs far too often and the consequences for these patients are traumatic; including the physical, financial and emotional burdens. Earlier diagnosis and treatment allow patients better outcomes and improved quality of life.

Suzann Beaupark

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Disclaimer - This article is intended to be for educational purposes mainly directed at Health Professionals. However, it is also an important resource for everyone to be aware of the signs and symptoms of MG. It outlines many subtle eye signs and general symptoms that have been documented as signs and symptoms of Myasthenia Gravis (MG) in many patients. MG is known to be The Great Imitator and thus some signs and symptoms overlap with other conditions. This article does not constitute medical advice for an individual and does not replace consultation with a Neurologist, Ophthalmologist or other relevant health care specialist.

References

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