Internuclear ophthalmoplegia is an ocular movement disorder caused by a lesion of the medial longitudinal fasciculus. It is characterized by impaired adduction of the ipsilateral eye with nystagmus of the abducting eye. Although the medial longitudinal fasciculus was identified in the 1870s, internuclear ophthalmoplegia was first described in 1903.
Internuclear ophthalmoplegia is a condition caused by a lesion of the medial longitudinal fasciculus (MLF), a fiber tract responsible for transmitting information that is vital for coordination of different eye movements. It is a paired white matter tract passing close to the midline, through the brainstem lying ventral to the cerebral aqueduct in the midbrain and the fourth ventricle in the pons and medulla. It is the final common pathway for different types of conjugate eye movements like saccades, smooth pursuit, vestibulocochlear reflex, and forms a communication between all the ocular motor nuclei. A lesion of the medial longitudinal fasciculus can produce impaired horizontal conjugate eye movements.
About a third of the cases of internuclear ophthalmoplegia are caused by infarctions and are commonly unilateral and seen in older individuals. Demyelinating disorders like multiple sclerosis (MS) account for another third of cases and are mostly bilateral and seen in young adults and adolescents. Some studies have shown that internuclear ophthalmoplegia is seen in about 23% of MS patients. Other causes of internuclear ophthalmoplegia include trauma, tentorial herniation, infections (like HIV, syphilis, cysticercosis, herpes zoster, tuberculoma), tumors (medulloblastoma, glioma, lymphoma, metastases), vasculitis (systemic lupus erythematosus (SLE), Sjogren syndrome), iatrogenic injury, and brainstem hemorrhage. The incidence of internuclear ophthalmoplegia in males and females is almost equal. Nearly half of all cases of internuclear ophthalmoplegia resolve within one year. Internuclear ophthalmoplegia is extremely rare in the pediatric population. Tumors like medulloblastoma and Pontine gliomas are important causes besides trauma, vasculitis, infarction, and hemorrhage.
Internuclear ophthalmoplegia occurs due to a lesion in the medial longitudinal fasciculus (MLF) by blocking the connection between contralateral sixth nerve nucleus and the ipsilateral third nerve nucleus, thus affecting horizontal gaze. One of the most important functions of the medial longitudinal fasciculus is its role in saccadic eye movements. Saccades are initiated by the frontal eye field (FEF), which sends signals to the contralateral paramedian pontine reticular formation (PPRF) for horizontal saccades and the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) for vertical saccades. The paramedian pontine reticular formation activates the ipsilateral abducens nucleus which sends signals to the Lateral rectus muscle of the same side and via abducent excitatory interneurons (after decussation) to the contralateral medial rectus subnucleus of the oculomotor nucleus through the medial longitudinal fasciculus, thus resulting in horizontal gaze opposite to the initiating frontal eye field. The cardinal sign of internuclear ophthalmoplegia is slowing or impaired adduction on the same side as the medial longitudinal fasciculus lesion. The cause is because the abducent excitatory interneurons fail to reach the medial rectus subnucleus.
The contralateral abducting eye may demonstrate a dissociated horizontal nystagmus. This is thought to be a compensatory response to overcome the weakness of the adducting eye explained by Herring’s law of equal innervation. Increased innervations to the medial rectus muscle are accompanied by an increase in innervation to its yoke muscle, the contralateral lateral rectus, resulting in nystagmus.
Although there is impaired adduction in the ipsilateral eye, some patients may have normal convergence. This is called dissociation of convergence and is an important sign which helps distinguish internuclear ophthalmoplegia from pseudo internuclear ophthalmoplegia (e.g., myasthenia gravis, third nerve palsy). It was initially thought that patients with medial longitudinal fasciculus lesion below the level of the oculomotor nucleus (posterior internuclear ophthalmoplegia of Cogan) had retained convergence and lesions above the oculomotor nucleus level (anterior internuclear ophthalmoplegia of Cogan) had absent convergence. However, recent studies have disproved this theory and retained convergence is thought to reflect the innate ability to converge to near targets.
Patients with internuclear ophthalmoplegia report symptoms of varying severity. Some patients may report blurry vision or diplopia or dizziness on lateral gaze. Surprisingly, some patients may complain of vertical diplopia. Vertical diplopia in the primary position is due to skew deviation of eyes with the weak adducting eye being hypertrophic. Skew deviation is a vertical misalignment of eyes caused by asymmetrical disruption of supranuclear input from the otolithic organs of the inner ear.
The hallmark of internuclear ophthalmoplegia is impaired adduction in the eye ipsilateral to the affected medial longitudinal fasciculus, which can range from mild limitation to severe restriction of adduction. There is a nystagmus in the abducting eye associated with this, which usually lasts for a few beats. Some patients with internuclear ophthalmoplegia may converge to a near target. The dissociation of the medial rectus function during horizontal saccades and convergence helps to confirm a medial longitudinal fasciculus lesion, ruling out other causes of medial rectus weakness. In all cases of internuclear ophthalmoplegia, the physician should be on the lookout for other brainstem signs to confirm the diagnosis of internuclear ophthalmoplegia and localize the site of the medial longitudinal fasciculus lesion. Lesions of the medial longitudinal fasciculus associated with adjacent brainstem structures can produce a variety of ocular motor signs and are called internuclear ophthalmoplegia plus syndromes.
The physical examination in most patients with internuclear ophthalmoplegia helps practitioners to arrive at a diagnosis. However, investigations like neuroimaging assist in finding the underlying cause. MRI can be a valuable tool in this regard, and up to 75% of patients may have a visible lesion. For demyelinating lesions, proton density imaging is considered to be ideal. Supplementary blood and cerebrospinal fluid (CSF) studies may be undertaken to detect uncommon causes.
Treatment depends on the underlying cause. Acute strokes require hospitalization and neurological evaluation. Other pathologies require management by a physician (e.g., MS, infections, SLE). Most patients with demyelination, infectious, and traumatic etiologies show complete recovery. Patients with cerebrovascular disorders had a less favorable recovery. Recovery is said to be more likely if internuclear ophthalmoplegia is isolated than if other neurological signs accompany it. According to some studies, recovery is also said to be less likely if there was a visible lesion causing internuclear ophthalmoplegia.
The majority of the patients with persistent internuclear ophthalmoplegia have minimal symptoms. Those with diplopia may benefit from botulinum toxin injections or Fresnel prisms. Surgical correction of strabismus may be used for patients with wall-eyed bilateral internuclear ophthalmoplegia.
A simple physical examination is often all that is required to diagnose a case of internuclear ophthalmoplegia. Although most cases of isolated internuclear ophthalmoplegia have a favorable prognosis, patients should be evaluated to determine the underlying cause. The medial longitudinal fasciculus with its periventricular location represents an accessible site for stem cell delivery to test newer innovative neuroprotective and restorative therapies such as stem cell remyelination.