There are five main causes of neurogenic blepharoptosis: myasthenia gravis (MG), oculomotor nerve palsy (ONP), Horner syndrome (HS), Marcus-Gunn Jaw wink (MGJW), and ptosis as inadvertent neurogenic etiology induced by botulinum toxin injections which is a relatively new addition to the list of causes of neurogenic ptosis.³ MGJW is discussed separately in Chapter 38.

Although MG is considered the archetypal example of an autoimmune disease involving the neuromuscular junction,⁴,⁵,⁶ it is an etiologically as well as an immunologically heterogeneous disease.⁶ While in the majority of patients IgG1 antibodies directed against acetylcholine receptors (AChRs) are responsible for the characteristic muscle fatigability, a smaller minority, the so-called seronegative MG, possess IgG4 antibodies to muscle-specific tyrosine kinase (MuSK), and not to AChRs.⁵ Both antibodies probably represent two distinct immunopathologic mechanisms, as they are mutually exclusive and do not usually manifest simultaneously in the same patient.⁶ Also, thymus pathology is different. In seropositive MG the thymus is frequently involved, whereas in MuSK MG it is not.⁵,⁷

The primary autoimmune form mentioned above is not the only underlying cause of MG. Thymic pathology, acute infections, and several medications may trigger or exacerbate myasthenia probably through presynaptic or even postsynaptic inhibition of acetylcholine release.⁸ Pathological thymic changes, including thymic hyperplasia (follicular or diffuse thymitis) earlier in the course of the disease, and thymomas, as well as an atrophic thymus gland (late in the disease), are seen in 80% of seropositive myasthenia patients.⁹ Systemic infections (viruses, bacteria, and even fungi) may trigger a myasthenic crisis.¹⁰,¹¹ The list of drugs inducing MG is extensive,⁷ but drugs that are relevant to the current discussion are antibiotics including fluoroquinolones (ciprofloxacin and levofloxacin), macrolide antibiotics (telithromycin and azithromycin), and aminoglycosides (amikacin, and gentamycin).⁸,¹²,¹³,¹⁴,¹⁵ Therefore, if a patient develops an acute exacerbation of MG due to a systemic infection, the very antibiotics used to treat the infection may exacerbate the symptoms even more.⁸

ONP may be congenital or acquired. The most common cause of acquired ONP is a microvascular infarct which is commonly caused by systemic illnesses such as diabetes mellitus, hypertension, atherosclerosis, and collagen vascular disease. Direct or indirect compression by an intracranial posterior communicating artery, posterior cerebral artery, or superior cerebellar artery aneurysm is another common cause of isolated ONP.¹⁶,¹⁷

HS or oculosympathetic paresis results from interruption of the sympathetic nerve supply to the eye and orbit. The course of the three-neuron oculosympathetic pathway (central, presynaptic, and postsynaptic) is well established, arising from the hypothalamus and ultimately ending at the ipsilateral dilator muscle of the iris sphincter in a convoluted roughly U-shaped course.¹⁸ The etiology of HS has traditionally been divided into congenital and acquired.¹⁹ It may rarely present at birth due to head or neck trauma during delivery and may even be inherited in an autosomal dominant
fashion.²⁰ Acquired pediatric and adult HS is usually a sequela of trauma or surgery to the head, neck, or chest,¹⁹,²¹ but an isolated HS without a history of trauma in children should always raise the suspicion of neuroblastoma.¹⁹ The full list of etiologies causing HS is extensive and can be categorized according to the location of the lesion along the oculosympathetic chain. Central or first-order neuron lesions occur in the posterior hypothalamus, brain stem, or the cervical spine (C8-T2) and may be caused by skull base tumors, cerebrovascular accidents, demyelinating disease, or more commonly neck trauma. Preganglionic or second-order neuron lesions are usually caused by an apical lung mass (Pancoast tumor), aortic aneurysm, or aortic dissection. Postganglionic lesions include internal carotid artery disease (dissecting aneurysm or arteritis), Raeder syndrome (paratrigeminal syndrome), or carotid-cavernous fistula.²²

Ptosis due to the inadvertent spread of the botulinum toxin is the most common complication in any esthetic practice.³ While an inexperienced injector may primarily be responsible for this complication, other predisposing factors can facilitate the spread of the toxin to the eyelid, including excessive product dilution with injection of a large volume, a history of prior facial surgery, particularly recent eyelid surgery, as well as early massage or rubbing of the injected region.³

The incidence of generalized MG is 5.3 per million person-years, and the estimated prevalence is 77.7 cases per million of the population.⁶ MG affects all age groups, genders, and ethnicities; however, it has a bimodal age distribution, being more prevalent both in young females (less than 30 years of age) and older males (more than 50).⁴,²³ The exact incidence and prevalence of ocular MG (OMG) are largely unknown, and a recent meta-analysis of population-based epidemiological MG studies did not list a single study singularly concerned with OMG.⁶ However, OMG is considered rarer than generalized disease²⁴ and shows a predilection for men.²⁵

About 40% to 50% of MG patients initially present with purely ocular symptoms with a history of chronic remitting, but generally progressive, painless weakness or fatigability of the extraocular muscles manifesting with double vision and ptosis. Over the course of the disease, the symptoms may alternate between both eyes, and an acute onset may rarely be encountered.⁴,²⁵,²⁶ Throughout the course of the disease, ocular muscles are involved in 90% of patients.⁷ On the other hand, 50% to 80% of ocular myasthenics ultimately develop the generalized disease, which usually occurs within the first 2 years from onset. However, the use of immunosuppressants may reverse this trend.⁵,⁷,²⁷ On examination, OMG is hallmarked by the presence of pupil-sparing ptosis and extraocular muscle weakness, which is typically characterized by being variable, increasing with sustained muscle use even for brief periods, and improving with rest or sleep.²⁵ Ptosis may be unilateral or bilateral and usually asymmetrical (Figure 12.1).²⁸ When ptosis is unilateral or markedly asymmetrical, two phenomena may be observed, and both are attributable to the Hering law of equal innervation.⁷,²⁹ The first is apparent or “pseudoretraction” of the contralateral normal upper eyelid,²⁵,²⁹ and the second phenomenon is “enhanced ptosis.” After manually elevating the more ptotic eyelid, ptosis may appear to be increased or “enhanced” in the contralateral less ptotic eyelid.⁷,³⁰ A more characteristic, albeit rarer and more difficult to elicit phenomenon, is the Cogan’s lid twitch sign, which is characterized by a brief episode of lid retraction after a vertical upward saccade from a downgaze position.²⁵ Clinicians should also be aware that MG may cause orbicularis muscle weakness.²⁵,³¹ When OMG patients are instructed to close their eyelids and keep them closed, a few seconds later the palpebral fissure widens and the cornea is exposed because of orbicularis fatigue.³¹ This sign has been dubbed the “eyelid peek” or “peek-a-boo sign” because the patient appears to peep or peek at the examiner.⁷,³¹ Orbicularis muscle weakness may also manifest with “afternoon ectropion” and “nocturnal lagophthalmos.”³¹,³²

Extraocular muscle involvement is also a common symptom in OMG and is found in as many as 90% of patients, usually associated with ptosis.⁷ It can mimic any pupil-sparing ocular motility disorder, ranging from a single extraocular muscle paresis to complete external ophthalmoplegia, but OMG patients may also present with full ocular motility.⁷

Systemically, patients may complain of difficulty in chewing solid food, dysphagia, or dysarthria, as well as difficulty whistling, using straws, or inflating balloons. MG patients may exhibit a nasal tone of voice which becomes increasingly apparent if history taking is prolonged. Patients with generalized MG may also demonstrate a depressed or expressionless facial appearance, and the characteristic myasthenic snarl may also be observed on attempted smile.²⁸ Air readily escapes through the lips, and liquid may escape through the nose during attempted swallowing with nasal regurgitation. Patients with limb weakness may complain of difficulty climbing the stairs or performing overhead tasks with their arms.²⁸

The diagnosis of MG and in particular OMG is primarily a clinical one, but diagnostic tests are used to support the diagnosis and can be categorized into clinical, laboratory, electrophysiologic, pharmacologic, and radiologic tests.³³ The details of these tests are beyond the scope of the current discussion and are summarized in Table 12.1, but in general, the typical workup of suspected MG usually includes AChR antibody testing, single-fiber electromyography, and CT or MRI of the mediastinum.²³ One important clinical point that should not be overlooked is that 10% of MG patients will have a thymoma on chest radiology and 70% will have thymic hyperplasia. Those relatively high figures are not observed in healthy patients, which argues for a central role of the thymus gland in the pathogenesis of the disease.³⁶ More importantly, a negative antibody workup does not rule out MG/OMG if the clinical signs are highly suggestive.⁷