Signs and Symptoms

Internuclear ophthalmoplegia (INO) can present in either the young or old and can be due to various etiologies. Patients with INO generally report a painless visual disturbance involving horizontal diplopia in lateral gaze, but typically no diplopia in primary gaze.1-4 Those who complain of diplopia in primary gaze typically have a concurrent skew deviation.5

Clinically, the patient will manifest a relative adduction deficit on the involved side, as well as a nystagmus of the fellow eye in extreme abduction (abducting nystagmus). The adduction deficit may range from a complete inability to move the eye beyond the midline to a subtle limitation of adducting capacity. Cover testing in lateral gazes can help identify a non-comitant deviation; a greater exo deviation away from the eye with the adduction deficit would be seen in INO. The differential diagnosis for this pattern could include a cranial nerve III palsy and myasthenia gravis, though the abducting nystagmus will identify INO. Some patients with INO will be able to converge their eyes while others will not; this ability or inability can localize the area of the causative lesion.

Several variations of INO may be encountered clinically, four of which are profiled below.

The first is bilateral internuclear ophthalmoplegia (BINO), in which both eyes are affected by the same underlying dysfunction. Patients with BINO demonstrate an adduction deficit in both eyes and contralateral abducting nystagmus of the each of the fellow eyes on lateral gaze.

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is a syndrome in which a BINO is superimposed on a concurrent exotropia; hence, the patient presents with a divergent ocular posture in primary gaze (from involvement of CN III nucleus) as well as the adduction deficits and abducting nystagmus.5,6

Skew deviation often accompanies INO, but it is less likely seen with BINO.5 In skew deviation, the eyes demonstrate a vertical misalignment as well as torsion. The higher eye will be intorted, and the lower eye will be extorted. Patients with skew deviation will complain not only of horizontal diplopia in lateral gaze but also of vertical diplopia in primary gaze.

Finally, one-and-a-half syndrome describes a rare form of ophthalmoparesis in which the patient demonstrates conjugate horizontal gaze palsy in one direction (i.e., the eyes do not move at all), combined with INO in the opposite direction.7 Upon attempted lateral gaze, one eye will remain essentially “frozen in space,” while the other will only be able to turn outward with an associated nystagmus. However, the gaze palsy may not be complete. There may also be additional associated nystagmus occurring beyond the abducting nystagmus characteristic of INO; this may include upbeat or downbeat nystagmus. 8-10


As the name implies, INO is an ophthalmoplegia that occurs secondary to a disruption of communication between two nerve nuclei; namely, the abducens nerve (in the pons) and the oculomotor (in the mesencephalon). The interaction and communication of cranial nerves III and VI to produce synchronous horizontal eye movements is accomplished via the medial longitudinal fasciculus (MLF), a neural pathway that interconnects these cranial nerve nuclei. The MLF can be considered to be a neural highway that connects the horizontal gaze control center in the pons with the medial recti subnuclei in the mesencephalon some distance away.

In INO, one or more lesions disrupt this pathway, interrupting communication between the cranial nerves VI and III, responsible for horizontal eye movements through control of the lateral rectus and medial rectus, respectively.11,12

To illustrate: In the case of a right INO, for a patient attempting to gaze to the left, the left supranuclear control center of horizontal eye movements (paramedian pontine reticular formation, or PPRF) must signal the left cranial VI nucleus to contract the left abducens muscle to turn the left eye outwards. At the same time, the PPRF must signal the right cranial nerve III nucleus, via the right MLF, to contract the right medial rectus so that it simultaneously turns the right eye inward. A lesion of the right MLF effectively prevents the neural impulse from reaching the right medial rectus. In that case, the left eye would abduct but the right eye would not adduct with it. This additionally forces the left eye into an abducting nystagmus. Note that an INO is named for the eye with the adducting deficit—a right INO indicates a right adduction issue.

Most MLF lesions are located in the pons, or caudal mesencephalon. The center for convergence is in the midbrain. So, if convergence is affected, the lesion is more likely in the midbrain. This is considered an anterior INO or BINO.14 On the other hand, an INO with intact convergence ability means the midbrain is not affected, so the lesion is more likely in the pons. This is considered a posterior INO or BINO.13

In one-and-a-half syndrome, the PPRF or CN VI nucleus and MLF are both involved. On attempted gaze to the affected side, there is no abduction on the involved side or adduction of the fellow eye, hence a gaze paresis. On attempted gaze opposite the lesion, the fellow eye will abduct and demonstrate abducting nystagmus while the other eye does not move. Thus, there is a total gaze paresis on the involved side and an INO when looking opposite.

The most common cause of INO is vascular infarction of the brainstem, followed by demyelinating disease such as multiple sclerosis (MS). In older patients with INO, the most common etiology is vascular infarction.7,15 In younger patients, MS is the most common etiology of INO.2,16-18 In fact, INO is the most prevalent ocular motility dysfunction encountered in those with MS.18 MS can cause a bilateral presentation, whereas ischemic vascular infarction tends to cause a unilateral presentation.19 Other possible causes include brainstem and fourth ventricular tumor, viral infection, trauma, syphilis, Lyme disease, systemic lupus erythematosus, drug intoxication (phenothiazines and tricyclic antidepressants) and subdural hematoma.20-24

Recently, a cerebral vascular accident localized to the top of the basilar artery was reported to cause tegmental midbrain infarction resulting in BINO and WEBINO.25,26 Also, myasthenia gravis can produce a pseudo-INO with a motility pattern identical to true INO.27-29


There is no direct treatment for patients with any form of internuclear ophthalmoplegia. Optimal management of INO involves identifying the underlying cause, followed by appropriate medical treatment of the discovered etiology. Diagnostic testing is critical in disclosing the cause. Typically, patients without a known, pre-existing illness should undergo an MRI of the brainstem (with and without contrast media) including pons and mesencephalon. Other work-up items may include blood pressure evaluation, diabetes testing, a complete blood count with differential and platelets, syphilis testing, Lyme assay and toxicology screen.

In INO secondary to ischemic vascular infarction, the motility pattern almost invariably returns to normal with time. In a study of 30 INO patients with brainstem infarction, 100% of subjects recovered within one year, and nearly 77% resolved within one month of onset.30

In persistent cases, medial rectus resection can be performed to relieve symptoms.31 However, this typically is not needed, as any form of INO from either vascular infarct or demyelination will resolve over time.

Clinical Pearls

Beyond MRI studies to rule out a compressive lesion, infarct and MS, patients require medical evaluation for underlying ischemic vascular diseases such as diabetes and hypertension. Fortunately, cases of INO associated with ischemia typically resolve rapidly.

Always remember that myasthenia gravis can mimic the motility pattern of INO. The key to proper diagnosis is remembering that myasthenia tends to be variable from day to day and usually worsens at the end of the day. By contrast, INO generally is a sudden-onset disorder that remains static at least for days to weeks before showing gradual resolution. The abducting nystagmus can also help in differentiation.

Abduction deficit from isolated medial rectus palsy is extremely rare. In cases where there is solely an abduction deficit, examine the fellow eye closely for an abducting nystagmus indicative of INO. Most cases of isolated “medial rectus palsy” are in reality INO.


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