Internuclear ophthalmoparesis

INTRODUCTION — Internuclear ophthalmoparesis (INO), also commonly referred to as internuclear ophthalmoplegia, is a specific gaze abnormality characterized by impaired horizontal eye movements with weak and slow adduction of the affected eye, and abduction nystagmus of the contralateral eye. It is one of the most localizing brainstem syndromes, resulting from a lesion in the medial longitudinal fasciculus (MLF) in the dorsomedial brainstem tegmentum of either the pons or the midbrain [1].

OCULOMOTOR CIRCUITRY — Foveation or visual targeting with binocular fusion and stereoscopy (depth perception) requires highly synchronous eye movements that place objects of visual interest on the corresponding points of both retinas. This process is dependent upon the precise coordination between cranial nerves II, III, IV, and VI, and their interneuronal pathways that project through the medial longitudinal fasciculus (MLF) (figure 1).

The paramedian pontine reticular formation (PPRF) is often referred to as the conjugate gaze center for horizontal eye movements. During horizontal eye movement, the PPRF burst cells innervate the abducens nucleus, which contains two distinctive sets of neurons:

●Axons of the abducens motor neurons directly innervate the ipsilateral lateral rectus muscle.

●Axons of the abducens interneurons cross the midline to become the MLF and subsequently innervate the medial rectus subnucleus of the oculomotor complex (cranial nerve nucleus III). Motor neurons from this subnucleus innervate the medial rectus muscle (ipsilateral to the medial rectus subnucleus and contralateral to the abducens nucleus).

The MLF exists as a pair of white matter fiber tracts that lie near the midline just under (or ventral to) the fourth ventricle and cerebral aqueduct, and extend through the dorsomedial pontine and midbrain tegmentum. Because of their close physical proximity near the midline, bilateral injury is common. While the MLF is primarily involved in coordinating synchronous horizontal eye movements, it also contains pathways involved in the regulation of vertical pursuit, vertical vestibular signals, and vertical alignment of the two eyes (a process mediated by the otolith organs of the inner ear and their central projections) [2-8].

An INO results from injury to the MLF within the dorsomedial pontine or midbrain tegmentum. The side of the INO is named by the side of the adduction deficit, which is ipsilateral to the MLF lesion [9,10].

CLINICAL FEATURES

Symptoms — Patients with INO may complain of horizontal diplopia when there is a significant adduction weakness or limitation on lateral gaze [3]. Diplopia is not usually present in primary gaze. However, some patients complain of vertical diplopia in the primary position due to skew deviation of eyes.

The dysconjugate movement of the two eyes during horizontal gaze results in an interruption in binocular fusion that can lead to visual confusion, oscillopsia, diplopia, reading fatigue, and loss of stereopsis (depth perception) [11]. Some patients also complain of vertigo [3]. Visual symptoms may be particularly problematic with head turning, especially while walking or driving, and can increase the risk of falls and motor vehicle accidents [11].

Signs — Important findings on examination include impaired adduction on lateral gaze, with nystagmus in the contralateral, abducting eye. Other signs may also be observed. Many patients, particularly those with demyelinating disease, will have bilateral involvement.

Adduction weakness — Depending on the severity of the lesion, adduction of the involved eye may be impaired or absent. If the defect is severe (as in severe demyelination and/or with axonal transection), then the observer may identify partial or even complete absence of adduction.

In milder forms, the deficit may be limited to a decrease in adduction velocity without ocular limitation (figure 2). Evidence of milder forms of INO may be best elicited by asking the patient to perform fast horizontal eye movements (saccades) away from a fixed central point, or by observing the speed of the adducting eye during its return to a central point of fixation from an eccentric point of gaze holding. Perhaps the most sensitive method to demonstrate a subtle adduction lag is to observe the fast phase (saccade) of optokinetic (OKN) nystagmus, while using an alternately striped fabric strip.

Interruption of the ascending axons in the medial longitudinal fasciculus (MLF) that arise from the internuclear neurons in the contralateral abducens nucleus likely explains the observed adduction deficit.

Normal convergence — Most lesions of the MLF are located in the pons or caudal mesencephalon, sparing the vergence pathways, including the fibers deriving from the medial rectus subnucleus of cranial nerve III [12,13]. As a result, convergence is intact in the majority of patients despite adduction weakness on lateral gaze. Intact convergence can help distinguish an INO from a partial third nerve palsy; however, impaired convergence does not rule out an INO. (See 'Differential diagnosis' below.)

Abduction nystagmus — The contralateral abducting eye will usually exhibit a horizontal nystagmus, which is less prominent in the adducting eye, although this does not always occur.

The underlying mechanisms causing abducting nystagmus are unknown. There is evidence that more than one mechanism may play a role in different patients and even in the same patient [13]:

●One theory with empiric support is that abduction nystagmus results from an adaptive response to overcome the weakness of the contralateral medial rectus [13,14]. This is explained by Hering's law of equal innervation, which states that attempts to increase innervation to the weak (medial rectus) muscle in one eye are accompanied by a commensurate increase in innervation to the yoke (lateral rectus) muscle in the other eye.

●Alternatively, gaze-evoked nystagmus may occur in patients with INO because of involvement of adjacent structures, such as the vestibular nuclei [13]. The nystagmus is dissociated because adductor weakness limits its manifestation in the affected eye. Subclinical nystagmus in the adducting eye has been demonstrated with electro-ocular techniques [15].

Abduction slowing — In some patients, INO can produce slowing of abduction as well as adduction in the affected eye [13,16]. This small degree of abduction slowing is expected in the context of adduction weakness, because of the loss of the contribution of the off-pulse of innervation (defective relaxation) when the medial rectus acts as an antagonist [17]. This can be distinguished from a sixth nerve palsy by noting that the eyes are aligned in primary position, there is full range of abduction on pursuit, and there are preserved abduction saccades with caloric testing [1].

Abnormal vertical eye movements — Patients with INO often exhibit abnormalities with vertical eye movements, including [12]:

●Vertical gaze-evoked nystagmus.

●Skew deviation with the elevation of the weak adducting eye.

Pontine lesions produce hyperdeviation (elevation) of the ipsilateral eye, often in conjunction with a homolateral INO. For example, a right dorsomedial pontine tegmentum lesion can produce a right eye hyperdeviation due to skew deviation, as well as a right INO, with slow adduction of the right eye during attempted leftward saccades.

●Contraversive ocular tilt reaction – In the ocular tilt reaction, the head tilts away from the side of the higher eye, the upper pole of the higher eye is intorted toward the nose, and the upper pole of the lower eye is extorted away from the nose. By contrast, in a fourth nerve palsy with superior oblique muscle weakness, there is extorsion of the higher eye.

●Diminished vertical gaze holding.

●Abnormal OKN and pursuit responses.

●Suppressed vestibular ocular reflex (VOR).

These supplementary signs are inconsistently present, more often with bilateral than unilateral INO, and are not required for the diagnosis of INO [18]. Rather, they might be more accurately designated as so-called INO+ syndromes.

Associated syndromes

One-and-a-half syndrome — This syndrome consists of a gaze palsy in one direction with an INO on horizontal gaze in the opposite direction. With attempted horizontal gaze, only abduction of the contralateral eye remains. Convergence is spared. In primary (neutral gaze), the contralateral eye is slightly abducted (so-called paralytic pontine exotropia). This syndrome is produced by damage to the paramedian pontine reticular formation (PPRF) and/or abducens nucleus and MLF on the same side. If the abducens nucleus is spared, the gaze palsy is apparent on volitional horizontal gaze, but is normal with oculocephalic maneuvers, as volitional eye movement requires activation of the PPRF, but the VOR does not.

As an example, a left paramedian pontine tegmentum lesion affecting the PPRF, abducens nucleus, and MLF produces a left gaze paresis as well as a left INO on attempted right gaze. During primary (forward) gaze, the right eye is slightly abducted.

Wall-eyed bilateral INO (WEBINO) — If the lesion affects the MLF within the upper midbrain, vergence pathways and the oculomotor apparatus can be disrupted, resulting in a variety of eye movement abnormalities that include impaired convergence [13,14,16,19]. These lesions are typically bilateral and produce divergence of the eyes (wall-eyed), along with bilateral INO, the WEBINO syndrome.

Eight-and-a-half syndrome — This syndrome consists of the one-and-a-half syndrome plus lower motor neuron pattern facial weakness on the side ipsilateral to the INO [20-26]. This occurs when there is involvement of the fascicle of the ipsilateral facial nerve (CN VII) at the level of the facial colliculus [27,28].

CAUSES — There are many potential causes of INO (table 1). Most cases (approximately 70 percent) of INO are due to multiple sclerosis (MS) or cerebrovascular disease [29].

Multiple sclerosis — MS underlies approximately one-third of cases of INO and is the most common cause in a young person (<45 years). The deficit is bilateral in most (73 percent) [29].

INO is also the most common eye movement abnormality in MS. The reported prevalence of INO among patients with MS varies between 17 and 41 percent of patients, depending in part on whether the INO is a clinical manifestation or an incidental finding on examination, as well as on the techniques used to elicit this finding [30-33] (see 'Diagnosis' below). The periventricular location of the medial longitudinal fasciculus (MLF) is thought to make this area particularly susceptible to autoimmune inflammatory demyelination [1].

Clinical signs in MS may be exacerbated by small increases in body temperature (as with exposure to high ambient temperature, fever, during exercise; also known as Uhthoff phenomenon) (see "Manifestations of multiple sclerosis in adults", section on 'Heat sensitivity'). This has been modeled in our laboratory in MS patients with INO, using infrared eye movement recording techniques [34-36].

Cerebrovascular disease — The most common cause of INO in an older patient is ischemic infarction. These patients are typically older than patients with MS, with an average age of 62 to 66 years [3,37]. In addition to advanced age, vascular risk factors (hypertension, diabetes mellitus, smoking) are prevalent in these patients. In contrast to MS, INO in this setting is usually (in 87 to 93 percent of cases) unilateral [3,29].

The underlying stroke subtype is usually small artery occlusion or lacunar disease involving the penetrating arteries originating from the basilar artery. Large branch artery occlusions in the basilar, superior cerebellar, and posterior cerebral arteries have also been associated with infarctions producing INO [3]. In large case series, individual cases of INO are reported with many other stroke subtypes, including hemorrhage (hypertensive, vascular malformation), vertebral artery dissection, temporal arteritis, and other vasculitides [29].

More than half of patients with an INO due to brainstem infarction have other neurologic symptoms and signs in addition to INO, including sensory deficits, dysarthria, gait ataxia, and lower motor neuron facial palsy, but isolated INO can occur as well [3].

Others — A large number of causes make up the one-quarter to one-third of INO cases that are not due to MS or cerebrovascular disease (table 1) [6,29]. The most common of these are infection, trauma, and tumor. In some remarkable cases, mild head injury can produce an isolated unilateral or bilateral INO [38-40].

DIFFERENTIAL DIAGNOSIS — A partial third nerve palsy with prominent medial rectus weakness may be confused with an INO. Distinguishing features include other third nerve deficits (weakness of elevation, ptosis, pupil dilation), impaired convergence, and absence of the contralateral abduction nystagmus, all of which point to a third nerve palsy rather than an INO. (See "Third cranial nerve (oculomotor nerve) palsy in adults".)

There are reports of eye movement abnormalities in progressive supranuclear palsy (PSP) that suggest bilateral INO [41]. Parkinsonism and other features of PSP are present in these individuals, and the eye movement abnormality can be overcome with oculocephalic maneuvers in PSP (because the lesion is supranuclear) but not in an INO. (See "Bradykinetic movement disorders in children".)

A pseudo-internuclear ophthalmoparesis is a well-described phenomenon in patients with myasthenia gravis and Guillain-Barré syndrome [18,29,42-44]. In practice, this is most often observed in the setting of an established diagnosis of these disorders, but can be observed at first presentation. The presence of ptosis and lid fatigue will alert the clinician to myasthenia, while areflexia, often with ataxia or limb weakness, will suggest the Miller-Fisher variant of Guillain-Barré syndrome. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Clinical manifestations of myasthenia gravis".)

Findings suggestive of a bilateral INO have also been reported in the setting of drug overdose; however, these individuals universally have an impaired level of consciousness [29,45].

EVALUATION AND DIAGNOSIS

Diagnosis — The diagnosis of an INO is made by the combined presence of impaired horizontal eye movements with weak, slow adduction of the affected eye, and abduction nystagmus of the contralateral eye.

Subtle forms of INO can be overlooked on examination and may only be evident on formal oculographic recording, which measures the velocity and acceleration of abduction and adduction [15,18,30,46,47]. Compared with these quantitative oculographic techniques, the accuracy of clinical examination by clinicians to detect an INO was imperfect (with both false positives and negatives), even by neuro-ophthalmologists [33,48].

The bedside neurologic examination for INO can be improved by the use of an optokinetic (OKN) tape. This is a highly sensitive technique for observing subtle adduction slowing in INO, and allows for more effective observation of saccadic dysconjugacy during the fast phase of nystagmus [49]. (See 'Adduction weakness' above.)

This specialized testing may have clinical utility in the setting of possible multiple sclerosis (MS), in which the identification of a second site of neurologic abnormality can influence diagnosis and treatment decisions.

Magnetic resonance imaging — Patients who present with an INO require brain magnetic resonance imaging (MRI) to include axial T2 or proton density-weighted images with 3 mm slice thickness [50]. A normal brain MRI should suggest an alternative cause of the extraocular movement disorder or pseudo-INO. Contrast enhancement and other specialized MRI sequences may enhance sensitivity, depending on the most likely etiology. We order these selectively.

●In one study of 58 patients with MS and INO, all had an abnormality within the region of the medial longitudinal fasciculus (MLF) on proton density imaging; other MRI sequences (T2-weighted, fluid-attenuated inversion recovery [FLAIR]) were less sensitive [1].

●Another case series described MRI findings in 30 patients with brainstem infarction [3]. In two cases, diffusion-weighted MRI identified an acute infarction that was not detected on T2-weighted MRI.

PROGNOSIS AND TREATMENT — Recovery from INO is variable. Deficits often resolve over a few to several months; however, symptoms and signs persist in many patients, regardless of the underlying etiology [3,6,33,37]. In one series, patients with a cerebrovascular origin were less likely to recover than those with other causes; 63 percent had persistent symptoms after three years [6]. However, others have observed a better prognosis with INO due to brainstem infarction, with 79 to 87 percent recovery in two to three months [3,37]. Restricted neurologic deficits and absence of a lesion on T2-weighted magnetic resonance imaging (MRI) appear to be associated with a better prognosis of recovery from INO in stroke patients [3,6,37].

Patients with severe diplopia may be treated with patching of one eye. In our experience, some patients with milder deficits can be trained to supplement horizontal eye movements by quick head movements. Prisms are not typically helpful in this setting.

Other treatment options are investigational. Dalfampridine (4-aminopyridine; fampridine), a potassium channel blocker, may improve axonal function in patients with demyelinating disease. One report documents objective improvement of ocular adduction in three patients with multiple sclerosis (MS) and chronic bilateral asymmetric INO [51]. Only one patient had subjective improvement in vision. In a small randomized trial including 23 patients with MS-related INO, fampridine produced objective improvement of saccadic eye movements; effects on patient symptoms were not reported [52]. While dalfampridine is approved for treatment of gait impairment in MS, the appropriate clinical use has not been clearly defined in that setting. (See "Symptom management of multiple sclerosis in adults", section on 'Dalfampridine'.)

In one center, injection of botulinum toxin into one or more extraocular muscles was associated with improved diplopia in 14 of 16 patients with an INO in the setting of brainstem hemorrhage, MS, or other cause [52,53]. However, this treatment approach is not yet widely used.

SUMMARY AND RECOMMENDATIONS

●Internuclear ophthalmoparesis (INO) is a specific gaze abnormality, characterized by impaired horizontal eye movement with slow, weak adduction of the affected eye and abduction nystagmus of the contralateral eye. In typical cases, convergence is spared. Abnormalities of vertical gaze are common but are not required features of an INO diagnosis. (See 'Clinical features' above and 'Diagnosis' above.)

●An INO is one of the most localizing brainstem syndromes, resulting from a lesion in the medial longitudinal fasciculus (MLF) in the dorsomedial brainstem tegmentum of either the pons or the midbrain. (See 'Oculomotor circuitry' above.)

●More than two-thirds of cases result from multiple sclerosis (MS) or cerebrovascular disease. Patients with MS are typically young (less than 45 years), and the INO is usually bilateral. Patients with cerebrovascular disease are rarely less than 45 years old, have prevalent vascular risk factors, and are more likely to have a unilateral INO. Infections, tumors, and trauma cause most other cases. (See 'Causes' above.)

●An INO can be confused with a partial third nerve palsy, other supranuclear gaze disturbances, or peripheral neuromuscular disease, especially ocular myasthenia gravis. However, a careful neurologic examination can usually distinguish between these entities. (See 'Differential diagnosis' above.)

●All patients who present with INO require brain magnetic resonance imaging (MRI). Contrast enhancement and other specialized MRI sequences can increase the sensitivity of MRI for specific diagnoses. (See 'Magnetic resonance imaging' above.)

●Most patients will recover within a few to several months. However, some will have deficits that persist. (See 'Prognosis and treatment' above.)

ACKNOWLEDGMENT — The authors would like to acknowledge Ethan Meltzer, MD, who contributed to a revision of this topic review.