Internuclear ophthalmoplegia

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Internuclear ophthalmoplegia
Authors
Teresa C Frohman, BS
Elliot M Frohman, MD, PhD
Section Editor
Paul W Brazis, MD
Deputy Editor
Janet L Wilterdink, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2012. | This topic last updated: Dec 2, 2011.

INTRODUCTION — Internuclear ophthalmoplegia (INO) is a specific gaze abnormality

characterized by impaired horizontal eye movement with weak 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].

Internuclear ophthalmoplegia
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Official reprint from UpToDate® www.uptodate.com
©2012 UpToDate®
Print | Back
Internuclear ophthalmoplegia
Authors
Teresa C Frohman, BS
Elliot M Frohman, MD, PhD
Section Editor
Paul W Brazis, MD
Deputy Editor
Janet L Wilterdink, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2012. | This topic last updated: Dec 2, 2011.

INTRODUCTION — Internuclear ophthalmoplegia (INO) is a specific gaze abnormality

characterized by impaired horizontal eye movement with weak 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 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 from the
abducens motorneurons 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) and finally the medial rectus
muscle.

The MLF exists as a pair of white matter fiber tracts that lie near the midline just under the
fourth ventricle and cerebral aqueduct and extend through the dorsomedial pontine and midbrain
tegmentum. Because of their close physical proximity, bilateral injury is common.

An internuclear ophthalmoplegia (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 medial longitudinal fasciculus (MLF) lesion.

SYMPTOMS AND SIGNS — Patients with internuclear ophthalmoplegia (INO) may complain

of horizontal diplopia when there is a significant adduction weakness or limitation on lateral gaze
[2]. Diplopia is not usually present in primary gaze. 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) [3].
Some patients also complain of vertigo [2].

Important findings on examination include impaired adduction on lateral gaze, with nystagmus
in the contralateral, abducting eye. Other signs may also be observed:

Adduction weakness — Depending on the severity of the lesion, adduction of the involved eye
may be impaired or absent. In milder forms, the deficit may be limited to a decrease in adduction
velocity without ocular limitation (picture 1). 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. Interruption of the ascending axons that arise from the internuclear neurons
in the abducens nucleus likely explains the observed adduction deficit.

Normal convergence — Most lesions of the medial longitudinal fasciculus (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 [4,5]. As a result, convergence is intact in
the majority of patients despite adduction weakness on lateral gaze. This finding can help
distinguish an INO from a partial third nerve palsy (see 'Differential diagnosis' below).

Abduction nystagmus — The contralateral abducting eye will usually exhibit a disassociated

horizontal nystagmus, 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 [5]:

 One theory with empiric support is that abduction nystagmus results from an adaptive
response to overcome the weakness of the contralateral medial rectus [5,6]. This is
explained by Hering's law of equal innervation, which states that attempts to increase
innervation to the weak muscle in one eye are accompanied by a commensurate increase
in innervation to the yoke 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 [5]. 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 [7].

Abduction slowing — INO can produce slowing of abduction as well as adduction in the

affected eye [5,8]. 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 [9].

Abnormal vertical eye movements — The MLF also contains pathways involved in the
regulation of vertical pursuit, vertical vestibular signals, and vertical alignment [2,10-14].
Patients with INO will therefore often exhibit abnormalities with vertical eye movements,
including:

 Diminished vertical gaze holding

 Abnormal optokinetic and pursuit responses
 Suppressed vestibular ocular reflex (VOR)
 Vertical gaze-evoked nystagmus
 Skew deviation and/or contraversive ocular tilt reaction

These signs are inconsistently present and are not required for the diagnosis of INO [15].

Associated 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 also spared. This syndrome is produced by
damage to the paramedian reticular formation (PPRF) and/or abducens nucleus and MLF on the
same side.

Wall-eyed bilateral INO — 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 [5,6,8,16]. These lesions are typically bilateral
and produce divergence of the eyes (wall-eyed).

CAUSES — There are many potential causes of internuclear ophthalmoplegia (INO) (table 1).
Most cases (approximately 70 percent) of INO are due to multiple sclerosis or cerebrovascular
disease [17].
Multiple sclerosis — 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) [17].

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
the techniques used to elicit this finding (see 'Specialized neuroophthalmologic
techniques' below) [18-20]. The periventricular location of the medial longitudinal fasciculus is
thought to make this area particularly susceptible to autoimmune inflammatory demyelination
[1].

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 [2,21]. In addition to advanced age, vascular risk factors (hypertension, diabetes,
smoking) are prevalent in these patients. In contrast to MS, most (87 to 93 percent) INO in this
setting is unilateral [2,17].

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 [2]. 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 [17].

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 [2].

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) [12,17]. 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 [22-24].

DIFFERENTIAL DIAGNOSIS — A partial third nerve palsy with prominent medial rectus
weakness may be confused with an internuclear ophthalmoplegia (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 [25]. 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 ophthalmoplegia is a well-described phenomenon in patients with
myasthenia gravis and Guillain-Barré syndrome [15,17,26-28]. 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 "Clinical features and diagnosis of Guillain-Barré syndrome in adults" and
"Clinical manifestations of myasthenia gravis".)

Findings suggestive of bilateral INO have also been reported in the setting of drug overdose;
however, these individuals universally have an impaired level of consciousness [17,29].

DIAGNOSIS

Magnetic resonance imaging — Patients who present with an internuclear ophthalmoplegia

(INO) require brain magnetic resonance imaging (MRI) [30]. 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:

 In one study of 58 patients with multiple sclerosis (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, FLAIR) were less sensitive [1].
 Another case series described MRI findings in 30 patients with brainstem infarction [2].
In two cases, diffusion-weighted MRI identified an acute infarction that was not detected
on T2-weighted MRI.

Specialized neuroophthalmologic techniques — 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 [7,15,18,31]. 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 neuroophthalmologists
[32].

Neurologic examination for INO can be improved by the use of an opticokinetic (OKN) tape.
This is a highly sensitive technique for observing subtle adduction slowing in INO, and allows
more effective observation of saccadic dysconjugacy during the fast phase of nystagmus [33].

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

PROGNOSIS AND TREATMENT — The deficits associated with internuclear ophthalmoplegia

(INO) often resolve over a few to several months [12]. In one series, patients with a
cerebrovascular origin were less likely to recover; 63 percent had persistent symptoms after three
years. However, others have observed a better prognosis with INO due to brainstem infarction,
with 79 to 87 percent recovery in two to three months [2,21]. 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 [2,12,21]

Patients may be treated with patching of one eye for symptomatic relief of diplopia. Since the
double vision is typically only in eccentric gaze, the use of prisms is usually not helpful.

SUMMARY AND RECOMMENDATIONS

 Internuclear ophthalmoplegia (INO) is a specific gaze abnormality, characterized by

impaired horizontal eye movement with 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 (see
'Symptoms and signs' above).
 An INO is one of the most localizing brainstem syndromes, resulting from a lesion in the
medial longitudinal fasciculus 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 'Diagnosis' above.)
 Most patients will recover within a few to several months. However, some will have
deficits that persist for greater than one year. (See 'Prognosis and treatment' above.)