Ophthalmology – Internuclear Ophthalmoplegia

Basics

Description

Internuclear ophthalmoplegia (INO) is a disorder of horizontal eye movements caused by a lesion of the medial longitudinal fasciculus (MLF).

The MLF normally carries signals from the abducens nucleus of one side to the contralateral oculomotor nucleus, allowing the two eyes to move together during horizontal gaze.

In a typical INO, when the patient looks to one side:

• The abducting eye moves normally
• The contralateral eye has impaired adduction
• The abducting eye often develops horizontal abducting nystagmus

INO is named according to the eye with impaired adduction.

Thus, a right INO means that the right eye fails to adduct normally during left gaze.

Partial and Complete INO

INO can vary in severity.

A partial INO may show only slowing of the adducting saccade rather than complete failure of adduction.

This subtle form is more common than complete paralysis and may require careful examination of rapid horizontal saccades.

A more severe lesion may prevent the affected eye from adducting beyond the midline.

Convergence

Convergence is often preserved in a typical INO because convergence uses a pathway that can bypass the damaged internuclear fibers.

Preserved convergence helps distinguish an MLF lesion from a primary medial rectus or oculomotor nerve disorder.

However, convergence may be impaired when the lesion extends into nearby midbrain structures.

Anatomy

The horizontal gaze pathway begins in the paramedian pontine reticular formation (PPRF) and abducens nucleus.

When looking to the right, for example:

1. The right PPRF activates the right abducens nucleus.
2. Motor neurons directly activate the right lateral rectus.
3. Internuclear neurons cross the midline.
4. They ascend in the left MLF.
5. They activate the left oculomotor medial rectus subnucleus.
6. The left medial rectus contracts.

A lesion of the left MLF therefore produces impaired left-eye adduction during right gaze.

Pathophysiology

INO usually results from either:

• Demyelination, or
• Ischemic injury of the MLF

The lesion is generally located in the pons or midbrain.

The characteristic abducting nystagmus is thought to result from an imbalance in conjugate gaze commands and an adaptive increase in neural drive to overcome the weak adduction of the opposite eye.

Epidemiology

The exact incidence and prevalence are unknown.

INO is relatively common in patients with multiple sclerosis, particularly when demyelinating lesions involve the brainstem.

Both unilateral and bilateral forms occur.

Risk Factors

Risk factors are essentially those of the underlying disorder.

Important associations include:

• Multiple sclerosis
• Cerebrovascular disease
• Hypertension
• Diabetes mellitus
• Smoking and other vascular risk factors
• Brainstem tumors
• Head trauma
• Central nervous system infection
• Drug toxicity or overdose

Etiology

Multiple Sclerosis

Multiple sclerosis is one of the most important causes, especially in younger patients.

MS-associated INO is commonly:

• Bilateral
• Asymmetric
• Associated with other neurologic findings

A bilateral INO in a young adult should strongly raise suspicion for demyelinating disease.

Brainstem Stroke

Small ischemic infarcts of the pons or midbrain are another major cause.

Stroke-associated INO is particularly common in older adults and is often unilateral.

Acute onset with additional neurologic symptoms should trigger urgent evaluation for cerebral ischemia.

Other Causes

Less common causes include:

• Brainstem hemorrhage
• Brainstem tumor
• Trauma
• Encephalitis
• Hydrocephalus
• Neurosarcoidosis
• Chiari malformation
• Nutritional or metabolic disease
• Sedative or anticonvulsant toxicity

Certain medications or drug overdoses may occasionally cause reversible internuclear eye movement abnormalities.

Commonly Associated Conditions

INO may coexist with:

• Multiple sclerosis
• Optic neuritis
• Lacunar stroke
• Brainstem hemorrhage
• Brainstem tumor
• Skew deviation
• Other brainstem ocular motor syndromes

Because the MLF lies near several vestibular and ocular motor pathways, associated abnormalities are common.

Diagnosis

History

Many patients with mild INO are asymptomatic.

When symptoms occur, patients may report:

• Horizontal diplopia
• Blurring during rapid gaze shifts
• Difficulty tracking moving objects
• Oscillopsia
• Vertical or oblique diplopia if skew deviation is also present

Symptoms may be most noticeable when looking toward the side opposite the affected eye.

Physical Examination

The defining finding is impaired adduction of one eye during conjugate horizontal gaze.

For example, in a right INO:

• Looking right may be normal.
• Looking left causes poor or slow adduction of the right eye.
• The left eye abducts and often develops nystagmus.

The deficit may range from subtle slowing to complete inability to cross the midline.

Saccadic Testing

Rapid horizontal saccades are particularly useful for detecting partial INO.

The examiner asks the patient to alternate fixation rapidly between two horizontal targets.

The affected eye shows:

• Delayed adduction
• Reduced adduction velocity
• Disconjugate horizontal saccades

This may be more sensitive than asking the patient simply to follow a slowly moving target.

Abducting Nystagmus

The abducting eye commonly shows coarse horizontal nystagmus.

This finding strongly supports INO but is not essential for the diagnosis.

The nystagmus usually becomes most prominent during gaze away from the side of the affected MLF.

Skew Deviation

A vertical ocular misalignment may accompany INO because the MLF also carries vestibular pathways.

This is called skew deviation.

It may produce vertical or oblique diplopia in addition to the horizontal symptoms of INO.

Bilateral INO

When both MLFs are involved, both eyes demonstrate impaired adduction.

Bilateral INO is particularly associated with multiple sclerosis, although vascular and other brainstem diseases can also cause it.

WEBINO Syndrome

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is a severe bilateral form.

Features include:

• Bilateral INO
• Exotropia in primary gaze
• Marked bilateral adduction deficits
• Often impaired convergence

The term “wall-eyed” refers to the divergent position of the eyes.

One-and-a-Half Syndrome

A larger pontine lesion can involve both:

• The ipsilateral PPRF or abducens nucleus, and
• The ipsilateral MLF

This produces one-and-a-half syndrome.

For example, with a right-sided lesion:

• Neither eye can look to the right because of the right horizontal gaze palsy.
• During left gaze, the right eye cannot adduct because of the right MLF lesion.
• The only preserved horizontal movement is abduction of the left eye.

Thus, three of the four horizontal half-movements are impaired.

Pseudo-INO

Not every apparent adduction deficit represents a true MLF lesion.

The most important mimic is myasthenia gravis, sometimes called pseudo-INO.

Features suggesting myasthenia include:

• Variable or fatigable weakness
• Ptosis
• Changing ocular motility pattern
• Orbicularis weakness
• Absence of a corresponding brainstem lesion

Myasthenia can closely mimic the adduction deficit and abducting nystagmus of true INO.

Other Differential Diagnoses

Other considerations include:

• Partial third-nerve palsy
• Medial rectus weakness
• Restrictive orbital disease
• Thyroid eye disease
• Duane syndrome
• Mechanical restriction after orbital trauma
• Ocular motor apraxia in selected neurologic disorders

A complete neurologic and ocular motor examination helps differentiate these conditions.

Diagnostic Tests and Interpretation

MRI

MRI of the brain with attention to the brainstem is the preferred imaging test.

Small MLF lesions may be visible on:

• T2-weighted imaging
• FLAIR sequences
• Diffusion-weighted imaging for acute infarction
• Post-gadolinium imaging for active demyelination or inflammation

The lesion is often small.

In some clinically definite cases, conventional MRI may appear normal.

CT

CT is much less sensitive than MRI for small brainstem lesions and may fail to demonstrate the cause of INO.

It is therefore not the preferred study when an MLF lesion is suspected.

Stroke Evaluation

In patients with acute-onset INO and suspected vascular disease, investigation may include:

• Diffusion-weighted MRI
• Vascular imaging
• ECG
• Cardiac evaluation
• Blood pressure assessment
• Diabetes and lipid screening
• Other standard stroke investigations

Management should proceed according to the overall neurologic presentation.

Multiple Sclerosis Evaluation

When demyelination is suspected, workup may include:

• MRI brain and spinal cord
• Gadolinium-enhanced imaging
• Lumbar puncture for oligoclonal bands in selected cases
• Neurologic examination for additional demyelinating signs

INO can occasionally be the presenting manifestation of MS.

Infrared Oculography

Specialized eye movement recording can objectively demonstrate slowed adduction velocity.

This may be useful in research or diagnostically difficult cases but is usually unnecessary because INO is primarily a clinical diagnosis.

Treatment

There is no specific ocular medication that repairs the MLF.

Treatment is aimed at the underlying disorder.

Multiple Sclerosis

Management of MS-associated INO is directed by neurology.

An acute demyelinating relapse may be treated with systemic corticosteroids when indicated.

Long-term disease-modifying therapy is based on the overall MS diagnosis rather than on the INO alone.

Stroke

Stroke-related INO requires standard cerebrovascular management.

This may include:

• Antiplatelet therapy when appropriate
• Treatment of hypertension
• Diabetes control
• Lipid lowering
• Smoking cessation
• Evaluation for cardioembolic or vascular causes

Symptomatic Diplopia

While the neurologic lesion recovers, diplopia may be managed with:

• Temporary occlusion
• Fresnel prism in selected cases
• Ground-in prism when deviation becomes stable

Because the alignment may change during recovery, temporary measures are usually preferred initially.

Botulinum Toxin and Surgery

Persistent symptomatic strabismus is uncommon but may occasionally require:

• Botulinum toxin
• Strabismus surgery

Surgical treatment should generally be delayed until the neurologic condition and ocular deviation have remained stable.

Referral

Patients should generally be referred to neurology or neuro-ophthalmology, especially when:

• The onset is acute
• There are additional neurologic symptoms
• MS is suspected
• Stroke is suspected
• Imaging is abnormal
• The diagnosis is uncertain

Follow-Up

Follow-up depends on the etiology and neurologic status.

Patients with stable or improving isolated INO may be reassessed over several months.

A 3–6 month ophthalmic reassessment is often reasonable for documenting recovery of eye movements and diplopia.

More urgent or frequent follow-up is required when the underlying neurologic disease is active.

Patient Education

Patients should understand that INO is a brainstem eye movement disorder, not a primary extraocular muscle problem.

The significance depends on the cause.

A younger patient may require evaluation for demyelinating disease, whereas an older patient with sudden onset may require urgent evaluation for stroke.

New neurologic symptoms such as weakness, numbness, dysarthria, severe vertigo, or difficulty swallowing should prompt immediate medical attention.

Prognosis

The prognosis depends on the underlying cause.

Recovery can be substantial in:

• Small ischemic lesions
• Drug-related cases
• Infectious or inflammatory disease successfully treated
• Some demyelinating attacks

INO may persist when caused by:

• Larger stroke
• Multiple sclerosis with permanent axonal injury
• Brainstem tumor
• Severe trauma
• Hemorrhage

Even when some eye movement abnormality remains, diplopia may improve because of neural adaptation and improved ocular alignment.

High-Yield Clinical Pearls

INO = impaired adduction of one eye + abducting nystagmus of the fellow eye during horizontal gaze.

INO is named for the eye that fails to adduct.

The lesion is in the medial longitudinal fasciculus.

Convergence is often preserved in classic INO.

Young patient + bilateral INO → think multiple sclerosis.

Older patient + acute unilateral INO → think brainstem ischemic stroke.

WEBINO = bilateral INO + primary-position exotropia.

One-and-a-half syndrome = ipsilateral horizontal gaze palsy + ipsilateral INO.

Myasthenia gravis is the classic cause of pseudo-INO.

MRI is the preferred imaging test because small MLF lesions can easily be missed on CT.