Why is there ptosis in myasthenia gravis

In clinical practice, patient subgrouping based on disease-specific Abs is a prerequisite for personalized management 3. It has a bimodal incidence pattern with a peak in young women and a larger peak in elderly men and is associated with thymus hyperplasia and thymoma, both playing a role in autoimmunization against AChR 3. Clinical phenotype is dominated by cranial and bulbar weakness 4.

Lastly, some patients, often with juvenile onset and limited disease, do not have detectable serum Abs. Dysfunction of ocular motility is common in MG and very few patients fail to experience ptosis or diplopia at some point of their disease.

Hereinafter, we review OMG pathophysiology and clinical aspects and discuss issues that are still controversial in its management. Gaze control requires the precise and sustained activity of the oculomotor system and, in normal individuals, EOM contraction is stable under high rate motoneuron firing EOMs have a unique biological organization with different compartments and six distinct fiber types according to innervation singly and multiply innervated , metabolic arrangement, and protein expression pattern 10 , EOM increased susceptibility to MG can be related to structural and molecular properties different from those in other striated muscles.

While the relevance of the fetal AChR as Ab target is unclear, its functional characteristics may foster susceptibility to MG. Fetal AChR has a longer open time and higher affinity for agonists 15 and, in a recent study, was found to recover more slowly from desensitization than the adult isoform OMG should be suspected in patients with painless ophthalmoparesis and intact pupillary reflexes.

Symptom fatigability, fluctuations in severity, and a remitting—relapsing course increase the likelihood of OMG diagnosis. Initial manifestations may consist of unilateral ptosis or diplopia due to weakness of a single EOM 17 — Nonetheless, at the first examination, most patients have ptosis and diplopia with multiple muscle pareses 17 — Weakness of the orbicularis oculi which is a facial muscle , although uncommon at presentation 20 , is frequent in the later course of the disease Ptosis is usually asymmetrical, with rapid fluctuations and shifting from one eye to the other.

EOMs can be involved in different combinations with a broad variability of unconjugated pareses. Complete external ophthalmoplegia occurs rarely and mostly in chronic disease In patients with MuSK, Abs ocular symptoms tend to be less evident, often consisting in symmetrical gaze limitations with transitory diplopia and bilateral, largely symmetrical, ptosis 21 — The pattern of ocular dysfunctions associated with anti-LRP4 other Abs has not been described.

MG epidemiology has changed over the last decades with a steady increase in incidence 24 — 26 and prevalence rates 27 , 28 , particularly among elderly males. From recent data, it seems that these changes also include OMG. In a recent population-based survey, the annual incidence of OMG was 1. OMG prevalence depends on the generalization rate, which is related to several factors, such as disease duration, treatment, and, above all, ethnicity and age at onset. In Asian countries, particularly in China, a high proportion of patients present in childhood and remain affected with OMG 34 , 35 , and, irrespective of ethnicity, progression to GMG is more rare in children with prepubertal onset than in adults 35 — Presence of thymoma 38 , signs of NMT failure in limb muscles on electrophysiological testing 39 , 40 , detection of AChR 31 , 41 and MuSK Abs 42 , and increased serum levels of microRNA miRe-5p 43 were found to be associated with increased risk of secondary generalization.

A protective role of immunosuppression was found in some studies 41 , 44 , 45 , but was not confirmed by others Moreover, in subjects treated early with steroids, disease progression may be delayed and become evident after treatment tapering or withdrawal. Recent data support this possibility showing that conversion time can be considerably longer than previously reported OMG is easily suspected in patients with fluctuating asymmetric ptosis and diplopia caused by involvement of multiple EOMs, as very few conditions can mimic such a pattern.

On the other hand, the diagnosis can be tricky when ocular symptoms can be due to single nerve paresis or fatigability is not obvious. OMG confirmation relies on serological, electrophysiological, and bed-side tests. The detection of either Ab confirms the diagnosis, with no actual necessity for electrophysiological or clinical tests.

These results strengthen the value of AChR Ab standard assay and warrant confirmation. More recently, the development of sensitive cell-based assays CBAs , in which Abs bind to antigens concentrated on cell membranes, has expanded the serological diagnosis of MG. Although these results are encouraging, it must be considered that CBAs require specific skills and facilities and are not largely available. With different assays, LRP4 Abs were detected at variable rates from Methodological standardization and studies involving large cohorts are needed to establish the diagnostic yield of new Abs At present, these assays should be reserved for dSN patients with positive results on electrophysiological testing or responsive to cholinesterase inhibitors ChE-Is.

Cortactin, an intracellular muscle protein expressed at the NMJ, contributes to the stabilizations of AChR clusters Abs to cortactin are likely not pathogenic and are not diagnostic of MG. Their possible role as marker of OMG 57 needs confirmation. Electrophysiology diagnostic yield depends on testing weak muscles, although SF-EMG can detect an increased jitter in subclinical MG In different studies, positivity rates ranged from However, these diseases rarely manifest with purely ocular symptoms.

On the other hand, finding an increased jitter in conditions that can closely mimic OMG, as chronic progressive ophthalmoplegia, incomplete Miller-Fisher syndrome MFS , and ptosis following botulinum toxin injection, may complicate the diagnosis This non-invasive technique is a promising diagnostic tool and warrants confirmation in further studies. A positive response as unequivocal improvement strongly supports the diagnosis.

The infusion of the short-acting agent edrophonium chloride max dosage 10 mg has been used for several decades as confirmatory test. Edrophonium injection often elicits lacrimation, sweating and fasciculations; as more serious adverse effects AEs as bronchoconstriction and severe bradycardia can occur, atropine should always be kept at reach.

Responsiveness to ChE-Is can also be tested with neostigmine 1—2 mg, i. These slow-acting ChE-Is may have a lower diagnostic sensitivity than edrophonium given the more gradual clinical effect.

False responses have been described in amyotrophic lateral sclerosis, peripheral neuropathy, and, rarely, in patients with mitochondrial myopathy 72 and intracranial tumors The ice pack, rest, and sleep tests are particularly helpful in patients with ptosis. A positive response consists in clear-cut symptom relief. The ice pack test sensitivity was When the effects of the ice pack test and the rest test were compared in patients with ptosis, the former produced a stronger response These assessments can be safely performed in patients with contraindications to edrophonium.

In a recent study, the combination of positive results of the ice pack test and SF-EMF was associated with higher specificity Table 1 summarizes the sensitivity and specificity of the main diagnostic tests in OMG. Variability among studies may reflect differences in the study population. Table 1. Sensitivity and specificity of diagnostic tests in ocular myasthenia gravis. OMG may mimic intracranial lesions, ocular neuropathy, migraine, internuclear ophthalmoplegia, MFS without obvious ataxia and pupillary abnormalities, progressive external ophthalmoplegia, levator aponeurosis, and orbital inflammatory disease.

Thyroid disease is frequently associated with OMG Magnetic resonance imaging of the brain and orbits is indicated when OMG is uncertain and even in patients with established diagnosis with atypical symptoms Ptosis and, even more, diplopia interfere with daily activities and impact on health-related quality of life QoL In addition, patients are concerned about the possibility of symptom generalization and frequently ask whether this may be prevented. Clinical management is complicated by lack of Class I evidence ChE-Is are generally well-tolerated and AEs, mostly consisting of diarrhea, hyperhidrosis, and muscle cramps, can usually be controlled by dose adjusting.

These agents do not reduce the risk for secondary generalization. In addition, patients with chronic symptomatic OMG can develop permanent ophthalmoparesis and muscle atrophy, with reduced chance of recovery Patients with unsatisfactory response to ChE-Is are candidate for immunosuppressive treatment. The study was closed early because of slow enrollment 11 patients were randomized of the 88 planned. Ann Thorac Surg.

Myasthenia gravis: A study from India. Neurol India. Grigg J. Extraocular muscles: Relationship of structure and function to disease. Aust N Z J Ophthalmol. Ocular myasthenia gravis. A critical review of clinical and pathophysiological aspects.

Doc Ophthalmol. Medical treatment options for ocular myasthenia gravis. Curr Opin Ophthalmol. The course of myasthenia gravis and therapies affecting outcome. Ann N Y Acad Sci. Oosterhuis HJ. Observations of the natural history of myasthenia gravis and the effect of thymectomy. Keane JR. Vertical diplopia. Semin Neurol. Why are eye muscles frequently involved in myasthenia gravis? Myasthenic abduction mystagmus in a patient with hyperthyroidism.

Rapid eye movements in myasthenia gravis. Electro-oculographic analysis. Arch Ophthalmol. Ice pack test for myasthenia gravis. Pupillary dysfunction in myasthenia gravis. Ann Neurol. Yamazaki A, Ishikawa S. Abnormal pupillary responses in myasthenia gravis. A pupillographic study. Br J Ophthalmol. Manson N, Stern G. Defects of near vision in myasthenia gravis. The effect of temperature change upon transmitter release, facilitation and post-tetanic potentiation.

J Physiol. The use of the ice pack test in myasthenia gravis. The ice test versus the rest test in myasthenia gravis. The ice pack test in the differential diagnosis of myasthenic diplopia. Extraocular muscle responses to orbital cooling ice test for ocular myasthenia gravis diagnosis. Barton JJ, Fouladvand M. Ocular aspects of myasthenia gravis. Diagnosis of myasthenia gravis in the s. The laboratory diagnosis of mild myasthenia gravis. Treatment of myasthenia gravis based on its immunopathogenesis.

J Clin Neurol. Arch Neurol. Myasthenia gravis. Katzberg HD, Bril V. A comparison of electrodiagnostic tests in ocular myasthenia gravis. J Clin Neuromuscul Dis. Orphanet J Rare Dis. Ozdemir C, Young RR. The results to be expected from electrical testing in the diagnosis of myasthenia gravis.

Repetitive nerve stimulation in myasthenia gravis — relative sensitivity of different muscles. Clin Neurophysiol. Shape variability of potentials recorded by a single-fiber electrode and its effect on jitter estimation. Ann Biomed Eng. SFEMG in ocular myasthenia gravis diagnosis. Disorders of neuromuscular transmission. Neurology in Clinical Practice. Boston: Butterworth-Heine-Mann; Myasthenia gravis and thyroid disease: Clinical and immunologic correlation.

Double vision in a patient with thyroid disease: What's the big deal? Surv Ophthalmol. In: Chaudhari Z, Vanathi M, editors. Postgraduate Ophthalmology. The Cogan lid twitch is elicited by having the patient look in downgaze, followed with upgaze.

As the affected eye saccades up, the upper lid overshoots. Hering's law of equal innervation states that the reciprocal eye muscles of each eye are innervated equally. As such, manual elevation of the more ptotic eyelid decreases the muscle strength required to keep the lid elevated, and so the contralateral levator palpebrae superioris relaxes and causes worsening ptosis.

However, Hering's law can also be seen in other types of ptosis as well. Other common ocular signs are incomitant strabismus, external opthalmoplegia, mimicking motor cranial nerve palsies. The pupils are never involved in MG. Systemic signs include variable muscle weakness and fatigability of the muscles of mastication, facial expression, speech, neck extensors, proximal limb muscles, and respiratory muscles late in the disease.

The main symptom is variable muscle weakness and fatigability, which worsens throughout the day, culminating in the evening. The most commonly affected muscles are the levator palpebrae superioris, extraocular muscles, orbicularis oculi, muscles involved in facial expressions, mastication, speech, neck extensor muscles, and proximal limb muscles triceps, deltoid, iliopsoas.

The most common presenting symptoms are also found to be ocular. These are usually bilateral and asymmetric. Progression of symptoms is insidious over weeks to months. Ophthalmoparesis is common in MG. The EOMs are small muscles in which a small amount of muscle weakness becomes symptomatic compared with the bigger limb muscles.

This increases their sensitivity to fatigue. Involvement of the MR results in poor adduction and incomittant strabismus. One should have a high suspicion for MG when a patient's history and main signs and symptoms suggest variable muscle weakness and fatigability that worsens in the evening or with prolonged use, and improves with rest.

A quick test in the office can be to ask the patient to look up and hold that position, and then observe if there is fatiguability of the levator muscle such that the upper eyelids start to drift downwards while the patient is looking up. The definitive diagnosis is made through various clinical, pharmacological and serologic tests. Edrophonium chloride inhibits acetylcholinesterase, thereby prolonging the presence of acetylcholine at the neuromuscular junction.

This results in enhanced muscle strength. This test is only useful in patients with objective, measurable findings on physical exam, like ptosis or a tropia. In ptosis , a positive test is the elevation of eyelids in minutes post administration of Tensilon.

A negative response is no improvement within 3 minutes. Edrophonium chloride can cause overactivation of the parasympathetic system, and cause unwanted side effects like fainting, dizziness, involuntary defecation, severe bradycardia, apnea, and even cardiac arrest.

It is important to always have atropine at hand if such side effects should occur. The nerve to be studied is electrically stimulated six to ten times at 2 to 3 Hertz. Compound muscle action potential CMAP is recorded via surface electrodes placed on the muscle in question. A positive test is the progressive decline in CMAP amplitudes within the first stimuli.

This is a good diagnostic test for congenital myasthenia gravis. The sleep test is a simple clinical test. The patient is asked to note if there is marked improvement in symptoms upon awakening. Many experts believe that if the thymus is enlarged, removing it can improve the symptoms of myasthenia. Thymomas are present more often in patients with generalized myasthenia gravis compared to those with ocular myasthenia gravis.

Double vision that results from myasthenia gravis is most often treated by blocking the vision from one eye. Either an eye patch can be worn or scotch tape can be placed over one lens in the eyeglasses. If one eyelid is very droopy and blocks the vision in that eye, the double vision will not require a separate treatment. Usually special glasses with prisms are not helpful because of the considerable fluctuation in the amount of double vision in patients with myasthenia gravis.

Certain medications can worsen the symptoms of myasthenia and should be avoided. If a patient with myasthenia gravis requires a surgical procedure, the anesthesiologist should be aware and in order to use the proper medications. We believe that patients benefit from online medical information that is engaging, up to date, and reliable. Philanthropic support is vital to produce these educational resources.

To support these efforts, please click here. For over a century, a leader in patient care, medical education and research, with expertise in virtually every specialty of medicine and surgery. Stay Informed.