Presentation and course
Esodeviations
Nonparalytic inward (toward the nose) eye deviations are classified into congenital and acquired esotropia. Congenital (also known as infantile or early onset) is the most common ocular misalignment in children under 6 months of age. Esotropia developing after 6 months of age is considered acquired and may be subclassified into accommodative, partially accommodative, and nonaccommodative. Nonaccommodative acquired esotropia includes acute onset esotropia, sensory esotropia (resulting from poor vision in one eye), and consecutive esotropia after a previous surgery to correct exotropia. Other causes of esotropia include convergence excess, convergence spasm, divergence insufficiency, sagging eye syndrome, heavy eye syndrome, and acquired distance esotropia in myopic patients.
Congenital or infantile esotropia. The terms "congenital” and “infantile” esotropia are used interchangeably to describe an esotropia of large angle, developing prior to 6 months of age. Infantile esotropia may be the more accurate term.
Infantile esotropia does occur in families (10). Children born with a neurologic deficit such as cerebral palsy, hydrocephalus, and neonatal or postnatal seizures, as well as prematurity, have a higher frequency of infantile esotropia. Infantile esotropia may be associated with other ocular motor abnormalities that include inferior oblique overaction, dissociated vertical deviation, and latent nystagmus.
Inferior oblique overaction. Inferior oblique muscle overaction manifests as excessive elevation of the eye in adduction and is reported in up to 70% of patients with esotropia, usually appearing after the age of 2 to 3 years. Unlike an inferior oblique muscle overaction noted in cases of true superior oblique (fourth nerve) palsy, there is no vertical deviation in primary position (ie, when looking straight ahead) in patients with primary inferior oblique overaction (40).
Dissociated vertical deviation. Dissociated vertical deviation is an ocular motor abnormality that may occur in isolation or more commonly as part of the infantile esotropia syndrome. Dissociated vertical deviation most often occurs in the context of preexistent infantile strabismus, typically infantile esotropia (may affect up to 90% of cases of infantile esotropia), but it may also occur in the context of other conditions with intense disturbance of binocular vision, such as other childhood misalignments, eg, presumed infantile microstrabismus and exotropia and in association with acquired loss of vision in childhood. The common feature of all these scenarios associated with dissociated vertical deviation is “intense disturbance of binocular vision” early in childhood. This spontaneous deviation occurs when the patient is tired, distracted, or when fusion is interrupted by covering one eye. It consists of a triad of elevation, abduction, and excyclotorsion of the eye (rotation of the globe about an anteroposterior axis with the 12 o’clock point moving outward or toward the ear). It may be unilateral or bilateral. These deviations are notoriously difficult to measure by cover testing as the deviation continues to increase as more and more vertical prisms are added; therefore, the deviation builds on cover testing. The confirming clinical sign of a dissociated vertical deviation is that as the uncovered, deviated eye shifts downwards to take up the fixation, the eye fixing earlier does not show a corresponding downward shift, thus, violating the Herring law, as there is no accompanying hypotropia (downward deviation) of the opposite eye. Large, frequently apparent dissociated vertical deviations require surgical correction (18).
Latent nystagmus. Latent nystagmus frequently is not present under binocular viewing conditions and manifests only with occlusion of one eye, as a jerk nystagmus that develops in both eyes with the fast phase towards the viewing eye (41).
Cross fixation is often noted in infantile esotropia with large angle of deviation and manifests as using the left eye to look to the right side and the right eye to look at the left side, without moving the eyes out. This often results in an apparent under action of the lateral rectus, giving the appearance of bilateral sixth nerve palsy. Evaluation of abductions after occluding one eye or alternatively by dolls-head maneuver (“spinning the child while in an upright position”) can differentiate both conditions. If these techniques fail, patching one eye for several hours may help show the full range of abduction (28).
Infantile esotropia requires surgical correction of the misalignment before the age of 2 years. Younger age at first surgery (before 10 months) may be associated with a higher rate of binocularity and stereopsis; however, rarely do these children obtain excellent stereo acuity. Several preoperative factors, such as larger preoperative angle of deviation, lateral rectus under action, and presence of amblyopia, have been reported to be associated with higher rates of horizontal reoperation. Early surgery, which is preferred for better binocular function, has been associated with a higher risk of reoperation as well. Botulinum toxin chemodenervation of the medial rectus muscle has been described as a substitute for or an adjunct to surgery (26). A good result is considered when a condition called monofixation syndrome is established, which consists of a small angle esotropia less than 8 prisms, with mild amblyopia, peripheral fusion, and some stereopsis (22; 54).
Accommodative esotropia. Accommodative esotropia frequently presents at about the age of 2.5 years with a range of 6 months to 6 years. Classically, the parents describe an intermittent esotropia of variable amount most notable when the child is tired, upset, or fixing on a near target. A family history of a similar type of turn may be found in first degree relatives in about 25% of patients (58; 04). The diagnosis and correct treatment of an accommodative esotropia is an urgent pediatric ophthalmology problem as these children, if left untreated for several weeks to months, will develop an amblyopia and a possible permanent loss of stereopsis and sensory fusion. Cycloplegic refraction reveals a moderate (+2.50) or greater amount of hyperopia that when corrected, results in good alignment at near and far distances with the use of glasses. If corrected early these children are not only spared amblyopia but maintain excellent stereopsis (14; 30).
Parents are frequently disappointed to learn that glasses rather than surgery are the mode of treatment for this entity. The disappointment arises from two concerns: (1) esthetic, that is, their child has to wear glasses, and (2) the fact that when the glasses are removed the deviation persists. It’s important to empathize full-time glasses wear and regular follow up to prevent amblyopia. It may be reassuring to mention to caregivers that although the course of their child cannot be predicted, some children can be weaned of their glasses over several years and maintain straight eyes. For those who require glasses through their adulthood, refractive surgery can be a viable option when their refraction stabilizes to achieve straight eyes without glasses.
A subcategory of accommodative esotropia is those children where the glasses correct the deviation at distance but there remains a large deviation when the patient fixes at a near target. These patients have an abnormal convergence response to an accommodative stimulus, a high accommodative convergence to accommodation ratio. This group requires the use of bifocal glasses to maintain alignment on a near target. A portion of these children will eventually be able to discontinue the use of bifocals as they reach 6 to 8 years of age but may continue to require hyperopic spectacles to maintain proper ocular alignment throughout life.
Some children with accommodative esotropia, with or without a high accommodative convergence to accommodation ratio, will deteriorate and come to a point where glasses alone will no longer suffice to maintain good ocular alignment. These patients, termed "partially accommodative esotropes" will require both surgery and glasses to keep their eyes straight. Often, they will have responded well to glasses alone maintaining excellent alignment with their glasses, but after a few years they develop an intermittent deviation, which is no longer corrected with glasses. They require surgical correction of the residual deviation, and parents must be warned that glasses will still be required postoperatively.
Acute-onset esotropia. The most vexing type of childhood strabismus is the acquired nonaccommodative esotropia, which appears at about the age of 3 or 4 years. This may occur suddenly (usually with diplopia) and may at first be intermittent or constant. Careful history taking with an emphasis on review of symptoms questioning about complaints of headaches, loss of balance, and minor trauma is of great importance as posterior fossa tumors have rarely been reported in association with acute comitant esotropias in children (16). However, the large majority of these children are otherwise well, though those of recent onset with diplopia will complain of their double image or blurred vision. Careful assessment of ocular motility to rule out subtle lateral rectus palsy is of utmost importance. Cycloplegic refraction to rule out an accommodative component is compulsory. Close observation and subsequent strabismus surgery are required. If undertaken early, these patients have a good prognosis for restoration of binocular vision (29).
Convergence spasm. Also known as spasm of the near reflex, convergence spasm is a common cause of acquired esotropia, which is usually a functional disorder triggered by prolonged near work and stress and presents with blurry vision, periocular pain, and headache. Convergence spasm may be misdiagnosed as sixth nerve palsy; however, the first is always accompanied by near triad features of miosis and acquired nearsightedness (pseudo-myopia) that, in addition to full monocular abductions, normal vestibulo-ocular reflex and optokinetic response help to differentiate it from the latter. Although convergence spasm most commonly has a functional etiology, it is rarely caused by lesions in midbrain or thalamus and has been reported with multiple sclerosis, NMO-spectrum disorder, peripheral vestibulopathy, thalamic hemorrhage, posterior fossa tumor, and Arnold-Chiari malformation (23).
Treatment options for isolated idiopathic or functional convergence spasm include long-acting cycloplegic drops, occlusion of the medial portion of spectacles, psychiatric consultation, and rarely, the use of prism glasses (06).
Divergence insufficiency. Divergence insufficiency presents as a comitant esotropia and diplopia, which is greater at distance than at near and is most commonly an isolated condition caused by involutional orbital changes mainly in the lateral rectus-superior rectus band degeneration in elderly people. Divergence insufficiency may be mimicked by subtle bilateral sixth nerve palsies; however, convergence insufficiency usually has gradual onset and slow progression, in contrary to sixth nerve palsy that usually has a sudden onset. Slowed abducting saccades and possibly papilledema from elevated intracranial pressure in cases of bilateral sixth nerve palsy help in the distinction.
Esotropia greater at distance may also be a feature of other neurologic disorders like cerebellar diseases, including spinocerebellar degeneration and Chiari malformation. Careful attention to symptoms and signs of cerebellopathy is paramount in suspicious cases. Divergence insufficiency secondary to neurologic disease is much higher in children. Treatment of isolated divergence insufficiency include prisms or eye muscle surgery (06).
Sensory esotropia. Sensory esotropia results from poor central vision in one eye in very young children. Older children and adults with unilateral poor vision tend to develop sensory exotropia, instead. Sensory esotropia may result from severe optic nerve or retinal disease or from ocular media opacity (eg, congenital cataract) and should be urgently worked up for possible treatable disorders. Sensory esotropia may be the first presenting feature of retinoblastoma, a life-threatening malignancy of the retina in infants. Full eye assessment, including a dilated fundus examination, is required for children presenting with esotropia.
Cyclic esotropia. This is a very rare type of esotropia that appears and disappears in a periodic cyclic pattern, usually in a 48- to 72-hour cycle. On squinting days, the esotropia is large and associated with suppression and no diplopia. On nonsquinting days, no deviation or only a small phoria is identified, and fusion is present. Abnormal electroencephalogram, behavioral changes, and excessive sleepiness have been reported in some patients on squinting days (49).
Heavy eye syndrome. Heavy eye syndrome, also known as myopic strabismus fixus or convergent strabismus fixus, was first coined by Bagshaw in 1966 in a report of two cases that were attributed to a presumed heavy ocular globe secondary to high myopia (03). Heavy eye syndrome is an acquired, progressive strabismus typically seen in eyes with increased axial lengths and high myopia, typically more than 25 diopters, and presents with a progressive, usually large angle esotropia and hypotropia with limited abduction and supraduction. There are some case reports of convergent strabismus fixus in the absence of high myopia and strabismus fixus in the setting of exotropia; however, these cases are rare and more controversial.
Several theories have tried to explain the pathophysiology of heavy eye syndrome. The most plausible theory postulates that the superotemporal quadrant of the posterior globe prolapses out of the muscle cone secondary to myopic globe elongation. This causes the elongated globe to herniate between the superior rectus and lateral rectus muscles, thereby displacing the superior rectus medially and the lateral rectus inferiorly, which increases the force of adduction and leads to limited supraduction and abduction, respectively. Patients with heavy eye syndrome typically present with diplopia secondary to progressive esotropia and hypotropia, with limitation of abduction and supraduction. Patients can also have pseudoptosis in the setting of hypotropia and pseudoproptosis in the setting of high myopia, with an elongated globe and a head tilt to the side of the hypotropic eye to achieve single vision or a chin-up posture to compensate for the hypotropia. Heavy eye syndrome should be differentiated from sagging eye syndrome and from abducens palsy. Differentiating heavy eye syndrome from abducens palsy relies on investigating timing and acuteness of onset, any underlying patient risk factors (ie, hypertension, hyperlipidemia, cardiovascular disease), refraction, and if the deviation is concomitant or inconcomitant as an inconcomitant deviation makes a cranial nerve VI palsy more likely. A high-resolution orbital MRI shows severe superotemporal globe prolapse that displaces the lateral rectus pulley inferiorly and the superior rectus muscle medially (33; 20).
Sagging eye syndrome. Sagging eye syndrome was coined by Rutar and Demer in 2009 to describe strabismus with possible secondary to age-related degeneration of the collagenous extraocular muscle pulley system, resulting in downward “sagging” of lateral rectus pulley. Associated with downward sagging of the lateral rectus pulley, the superior rectus–lateral rectus fibrous band enlarges, ruptures, and eventually disappears on further progression. If the lateral rectus pulley and the superior rectus–lateral rectus fibrous band change symmetrically, distance esotropia occurs. If change is asymmetric, hypertropia develops. Characteristic facial features in patients with sagging eye syndrome resulting from ocular adnexal changes include baggy eyelids, deep superior lid sulcus deformity, and aponeurotic ptosis. Such features may not be noticeable if the patient has undergone rejuvenation procedures and need to be asked about specifically. Orbital MRI is helpful in the diagnosis of sagging eye syndrome, but unlike conventional orbital MRI, which includes fat suppression, fat suppression should be avoided here to allow for better evaluation of the muscle bellies. Treatment options include prism glasses or surgery.
Acquired distance esotropia in myopic patients. Acquired distance esotropia in myopic patients is an unusual, acquired, and slowly progressive esotropia that is greater at distance than at near. It occurs in young adults with myopia, and its pathogenesis is still unknown, but it may be related to long periods of near work (57).
Nystagmus blockage syndrome. Nystagmus blockage syndrome is a form of infantile esotropia associated with nystagmus on abduction of either eye, apparently limited abduction, abnormal head posture (face turn towards the side of the dominant eye), and frequent amblyopia. The differential diagnosis includes abducens palsy and crossed fixation. The treatment options include patching and surgery, but the results of surgery are less predictable than with ordinary types of esotropia (52).
Exodeviations
These may be classified according to fusion status as an exophoria, an intermittent exotropia, or a constant exotropia. Exotropia may be further divided according to distant near relationship. A deviation is considered basic if the out-turning measures the same at distance and when fixing at a near target. Divergence excess deviation refers to a larger deviation at distance than at near. A convergence insufficiency deviation measures greater on a near target than at distance.
Infantile exotropia. This is an out-turned eye developing during the first 6 months of life. The deviation is usually of large amplitude but may be intermittent. Infantile exotropia is a rarer entity than infantile esotropia. In contrast to infantile exotropia, infantile exotropia is usually associated with congenital neurologic abnormality (31; 53). There is no consensus on timing of surgery of infantile exotropia. Management of the accompanying amblyopia followed by early surgery and alignment within 24 months of onset of the misalignment may offer the best hope of obtaining a good long-term surgical outcome (56).
Intermittent exotropia. This is the most common type of out-turned eye. Age of onset is quite variable starting anywhere from age one to early teens. The deviation at first is present when the child is fatigued, ill or lacking concentration and may be only fleeting.
Parents may report that the child frequently closes one eye when in sunlight. Unlike other types of heterotropia, patients with intermittent exotropia tend to retain good vision in both eyes and stereopsis (43). In very young patients, surgical intervention should be met with some trepidation because a small esotropic overcorrection can result in a permanent loss of stereoacuity, and studies have shown that the natural history of intermittent exotropia is such that a loss of stereoacuity is quite rare (21). The optimal time to operate on these cases is debated, but surgery is generally indicated if there is a reduction in or loss of stereoacuity (at near or distance), deteriorating fusional control, a large angle of deviation, or a combination; however, potential thresholds remain poorly defined (27).
Nonsurgical treatment options are of limited long-term efficacy and include part-time alternate eye patching and prism glasses and orthoptic exercises by a certified orthoptist (08). Overminus glasses can help to control intermittent exotropia by inducing convergence along with accommodation. The first large-scale, randomized clinical trial assessing overminus spectacle therapy for the treatment of intermittent exotropia was conducted by the Pediatric Eye Disease Investigator Group. Although better control of distance exotropia was noted for the overminus group, this effect was short-lived after discontinuation of the overminus glasses. More importantly, treatment with overminus glasses was associated with an increased myopic shift that led to early discontinuation of the overminus lens therapy arm of the study (02; 07; 12).
Constant exotropia. In older patients, constant exotropia is often the consequence of a neglected intermittent exotropia, sensory exotropia (a poor seeing eye), or secondary exotropia in patients with prior strabismus surgery, usually for an esotropia. Poor vision in the deviated eye is frequently seen in constant exotropia.
Consecutive exotropia. This is a deviation that spontaneously replaces an esotropia. Often the esotropia is accommodative, and significant hyperopia as well as amblyopia is found. Treatment is surgical.
Sensory exotropia. Sensory exotropia results from poor central vision in one eye, usually in older children and adults (eg, in patients with acquired optic neuropathy).
Convergence insufficiency. Convergence insufficiency is a common condition that affects mainly adolescent and elderly age groups and presents with binocular horizontal diplopia or binocular blur at near (mainly with reading) and is usually associated with by eyestrain. Examination shows exotropia at near greater than 10 prism diopters or about 5 prism diopters greater exophoria at near compared to distance, decreased convergence fusional amplitude (to less than 15 prism diopters), and an increased near point of convergence (the closest distance of binocular fixation without binocular double vision or outward drift of one eye). Convergence insufficiency is usually an isolated process; however, it has been shown to be more prevalent in patients with parkinsonian disorders and patients with traumatic brain injury (25; 51). Treatment of convergence insufficiency include home exercises (most commonly “pencil pushups”), home computer-based therapy, and office-based therapy. Base in prisms for near work or surgical correction can be used for symptomatic unresponsive cases if all other measures fail (06).
Prognosis and complications
Amblyopia and loss of binocularity are the most common complications of strabismus, particularly with onset in childhood. Neck pain from head postures adopted to improve vision and psychosocial concerns related to appearance are other considerations in treatment planning.
Clinical vignette
An otherwise healthy 7-month-old infant is referred by his pediatrician for evaluation of suspected bilateral sixth nerve palsy. Examination shows large angle esotropia with limited abduction of both eyes. His neuro-ophthalmic exam is otherwise normal. Patching one eye at a time showed better abduction in both eyes. Rotating the child showed normal vestibulo-ocular reflex with full abduction in both eyes. Cross fixation in the setting of large angle infantile esotropia is the diagnosis, and sixth nerve palsy is ruled out.
