The Key to Early Diagnosis of Myasthenia Gravis is . . . . .

The Key to Early Diagnosis of Myasthenia Gravis is, “Awareness”!

June is Myasthenia Gravis Awareness Month, so as an Orthoptist involved in Myasthenia Gravis (MG) and Lambert Eaton Myasthenic Syndrome (LEMS) Research, I would like to take this opportunity to present a literature review highlighting the rare subtle signs that can help lead to earlier diagnosis of MG. 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 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, hence clinical assessment is vital, especially in these seronegative patients.?

Acquired Autoimmune Myasthenia Gravis (MG), (“myasthenia” is Greek for “weak muscle” and “gravis” is Latin for “Heavy or weighty”) is a potentially fatal, chronic neurological disease affecting the post-synaptic neuromuscular junction (NMJ). All races are affected and onset may occur at any age, with females under the age of 50 and males over the age of 60 being most commonly affected. 15% of MG patients have a Thymus Tumor that can potentially be malignant. MG may be Ocular MG (OMG) or Generalised MG (GMG), however, research shows that up to 80% of OMG may become GMG within 2 years of onset. (Hake & Kaminski, 2011). Therefore, even a patient who appears to have mild ocular symptoms is at risk of developing GMG and severe symptoms.

Lambert Eaton Myasthenic Syndrome (LEMS) is a similar condition that affects the pre-synaptic NMJ, however, there are differences in the pattern of weakness to MG and some autonomic symptoms are present. LEMS has a paraneoplastic basis about 40% of the time and autoimmune or congenital the remaining 60%. Men are affected more frequently than women with a ratio of 3:1. Antibody testing is positive only 80-90% of the time. Early diagnosis can be life-saving as it can lead to early cancer detection and/or early treatment to prevent respiratory failure. (Matsumoto H and Ugawa Y, 2016).?

In MG and LEMS the damage to NMJ results in fluctuating fatigue and weakness of the voluntary muscles affecting limbs, trunk, eye muscles, breathing and swallowing.?The weakness can range in severity from mild ocular muscle weakness to severe respiratory failure, with episodes that can be variable and unpredictable and often triggered by certain commonly used medications and anaesthetics. Many patients suffer significant disability with a significant number of patients reporting poor quality of life. A recent Australian study indicated that 65% of MG patients needed to stop working and 87% required Government support due to disability. (Blum et al, 2015). Treatment with pyridostigmine (Mestinon) and immunosuppression can help relieve symptoms and improve function in many patients.

In Australia the prevalence is estimated to be 117 per million and the incidence of 24.9. per million. (Gattellari et al, 2012). LEMS is much rarer with an incidence of 1 per million. There is not a lot of research available regarding LEMS, however LEMS and MG have been known to coexist (Oh, 2015) and often LEMS is initially diagnosed as MG, so I think that it is important to include LEMS when discussing MG Awareness.?

The treatment of Autoimmune LEMS has similarities to MG, however obtaining a LEMS diagnosis allows for appropriate investigations looking for an associated cancer. It is not possible to definitively differentiate between MG and LEMS from an Ophthalmic assessment, however, certain subtle signs may provide some degree of evidence. Antibody testing and electrophysiological testing can help with differentiation in some patients. (Sanders, 1995).?

In MG the equivalent degree of weakness in limb muscle is less symptomatic than in eye muscles, this is the reason why muscle weakness involving the extraocular muscles is often observed at an early stage of the development of MG. (Zhou et al, 2014). The eye muscles have also been shown to be the most susceptible muscle group to an autoimmune-mediated attack on the NMJ and therefore accurate ophthalmic examination is vital to aid in an early diagnosis. (Zhou et al, 2014).?

The commonly accepted current ophthalmic testing for MG and LEMS involves inducing fatigue and testing the function of Extraocular Muscles, Levator Palpebrae and Orbicularis Oculi. Testing for MG eye signs involves a variety of tests to disclose ptosis, lid retraction, restriction of ocular movement, distinct saccadic signs and orbicularis oculi weakness.?

MG may present with obvious variable ocular motility restrictions that can mimic a variety of conditions, however, variability is usually pathognomonic of MG. Diagnosis of MG can be quite easy when obvious classical signs are present, however, a high degree of awareness and specific testing is required to diagnose when mild signs or unusual symptoms are present. Unfortunately, an MG diagnosis in such patients is delayed by many months or even years. (Lisak R 1994, Ariatti 2013).?

Diplopia may also occur without obvious ocular misalignment in some MG patients while other patients may complain of dizziness, unsteadiness or blurring of vision without diplopia. It is important to induce appropriate adequate fatigue in such patients. Current testing involves inducing fatigue with sustained gaze in elevation and lateral gaze to disclose MG eye signs, most notably ptosis on sustained elevation and lid retraction on lateral gaze. This fatigue may also induce restriction of ocular motility or dizziness on attempted motility. 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 & Kaminski, 2011).

Ptosis can be highly variable and often remains unnoticed when mild. When ptosis is bilateral it is often asymmetrical and has been known to switch from one eye to the other or be fleeting, lasting only a few seconds. (Lisak,1994). Even though Ptosis is the most common sign that most eye professionals associate with MG, there are cases of MG that don't present with a ptosis, or that the retraction of the non-ptotic eyelid is more obvious. 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. This is especially evident in LEMS. Asking the patient about blurriness that may be related to the upper eyelid obstruction (Hake & Kaminski, 2011), especially associated with glare and/or fatigue, may help with diagnosis.??

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 et al,1976). (1) Transient retraction of the upper eyelids which is often uncovered by prolonged upgaze of 5-10 seconds or lateral gaze. (2) 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. (3) Cogan’s Lid Twitch, which is the fleeting lid twitch sign evident after looking down, 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 et al, 1976).?

Scottish Neurologist John Simpson was the first to describe increased ptosis on sustained upgaze, which is the most commonly used test today, (The Simpson Test) where the patient is asked to maintain upgaze for 2-3 minutes testing for fatigue-induced ptosis. Another author, Oosterhuis (1982) observed that sustained lateral gaze more easily provoked ptosis. Another sign, where there is Paradoxical lid elevation after sustained upgaze has been suggested to be a clinically useful sign in LEMS. (Breen, 1991).?

Weakness of the orbicularis oculi may be characterised by fatigue of the eyelids during attempted sustained closure. However, a less known sign is when there may be a retraction of the lower eyelid or paralytic ectropion. (Miller et al, 2007).??

The difficulty in diagnosing MG can be attributed to the variable nature of MG symptoms which are dependent on how fatigued the patient is at the time of testing. Signs can be fleeting and fatigue can improve rapidly at times with a blink/closing of eyes or change in fixation during ophthalmic assessment. Careful examination of these patients has the potential to save lives, improve the quality of life for patients and prevent unnecessary examinations and undue financial burden to the patient and health system.?

MG and LEMS are rare neuromuscular conditions and as such Awareness campaigns such as the Annual MG Awareness Month every June are important for highlighting the often-forgotten key diagnostic elements to aiding in an early diagnosis. Misdiagnosis and delayed diagnosis are far too common, with many patients suffering from disability for years without appropriate treatment. With greater awareness, we may find that MG is not as rare as we currently believe it to be. Please help spread MG Awareness this June and share my article with your colleagues.?

Suzann Beaupark

Orthoptist,?Grad Dip Genetic Counselling

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 or LEMS in many patients, all MG and LEMS patients have their unique signs and symptoms. It outlines many subtle eye signs and general symptoms that have been documented as signs and symptoms of Myasthenia Gravis (MG) and LEMs 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

Ariatti A, Galassi G, Rovati R, Chiari A. 2013. Cutting the edge of idiopathic recurrent orbital myositis. Central European Journal of Medicine. 732-735?

Blum S, Lee D, McEniery DF, Reddel S and McCombe P. 2015. Clinical features and impact of myasthenia gravis disease in Australian patients. Journal of Clinical Neuroscience 22, 1164-1169.?

Breen LA, Gutman L, Brick JF, Riggs JR.1991. Paradoxical lid elevation with sustained upgaze: a sign of Lambert Eaton Syndrome. Muscle Nerve. 14,863-6?

Cogan D. 1965. Myasthenia gravis: a review of the disease and a description of lid twitch as a characteristic sign. Arch Ophthalmol (74) 217–221.?

De Baets Marc H, Oosterhuis Hans J. G. H. Edition, Myasthenia Gravis. illustrated. Publisher, CRC-Press, 1993?

Gattellari M, Goumas C and Worthington JM. 2012. A national epidemiology study of Myasthenia Gravis in Australia. Eur J Neurol, 19, 1413-20.?

Hake Austin and Kaminski Henry J. 2011. Ocular Myasthenia Analysis of Diagnostic and Treatment Options.?Autoimmune Disorders - Current Concepts and Advances from Bedside to Mechanistic Insights, Dr. Fang-Ping Huang (Ed.), ISBN: 978-953-307-653-9, InTech, Available from:https://www.intechopen.com/books/autoimmune-disorders-current-concepts-and-advances-from-bedside-tomechanistic-insights/ocular-myasthenia-analysis-of-diagnostic-and-treatment-options

?Lisak R. 1994 Handbook of Myasthenia Gravis and Myasthenic Syndromes. New York, Marcel Dekker.?

Matsumoto H and Ugawa Y. 2016. Lambert-Eaton Myasthenic Syndrome: A Review. Journal of General and Family Medicine. 17(2), 138-143.

Miller NR, Newman NJ, Biousse V, eds. Walsh and Hoyt's Clinical Neuro-Ophthalmology, 6th edition. Philadelphia, PA: Lippincott, 2005.

Oh, SJ. 2015. Myasthenia Gravis Lambert-Eaton Overlap Syndrome. Muscle and Nerve, 53(1), 20-26.?

Oosterhuis H. 1982. The ocular signs and symptoms of myasthenia gravis. Doc Ophthalmol. 52:363–378.?

Puklin, J.E, Sacksi, J.G and Boshes, B. 1976 Transient eyelid retraction in myasthenia gravis Journal of Neurology, Neurosurgery and Psychiatry 39, 44-47?

Sanders, DB. 1995. Lambert-Eaton myasthenic syndrome: Clinical diagnosis, immune-mediated mechanisms, and update on therapies. Ann Neurol 37(Suppl1): S63?

Zhou Y, Kaminski HJ, Gong B, Cheng G, Feuerman JM, Kusner L. 2014. RNA expression analysis of passive transfer myasthenia supports extraocular muscle as a unique immunological environment. Invest Ophthalmol Vis Sci. 2014;55:4348–4359