Article topic: Internuclear Ophthalmoplegia
Author: Sarah Mahfouz, Ziad Azar
Editors: Lubna AL-Rawabdeh
Reviewer: Ethar Hazaimeh

keywords: Internuclear Ophthalmoplegia, medial longitudinal fasciculus, lateral gaze, multiple sclerosis, brainstem infarction.

Overview

Internuclear Ophthalmoplegia (INO) is a visual disorder most prevalent in the elderly population, often associated with a history of multiple sclerosis (MS) or brainstem infarction.

INO results from damage to the medial longitudinal fasciculus (MFL), a bundle of nerves located in the brainstem, specifically in the paramedian area between the midbrain and pons. This disorder is characterized by a lateral horizontal visual impairment, marked by deficient adduction in one eye, the one adjacent to the lesion, and abducting nystagmus in the other [1]. First described in 1903, INO has since been better defined as a neurological condition and visual phenomenon [1].

In this article, we aim to introduce internuclear ophthalmoplegia, briefly describing its clinical features and etiological process. We will also unfold its relationship with multiple other disorders and syndromes, highlighting its diagnostic and clinical value.

Etiology and Pathogenesis

The medial longitudinal fasciculus (MLF) is a highly specialized and heavily myelinated fiber tract that establishes a crucial connection between the abducens nerve and the paramedian pontine reticular formation (PPRF), ultimately linking to the oculomotor nerve nuclei on the contralateral side [3]. This intricate neural pathway serves as the ultimate common denominator for various forms of ocular motility, Figure (1).

Figure (1): Internuclear ophthalmoplegia. Sharma R, Fahrenhorst-Jones T, Yap J, et al. Figure 1 displays the Internuclear Ophthalmoplegia diagram [2].A lesion affecting the MLF gives rise to a distinct form of ophthalmoplegia and can result in the impairment of horizontal conjugate eye movements, primarily due to the disruption of communication between the oculomotor nerve nuclei (III) and abducens nerve nuclei (VI) [1].

It is imperative to recognize that the MLF is susceptible to damage from a variety of sources: (demyelinating, neoplastic, inflammatory, ischemic …)

• Demyelinating

In younger patients, Internuclear Ophthalmoplegia (INO) typically forms a component of multiple sclerosis (MS) presentations. It may even manifest as the initial symptom, as demyelination can impact various segments of the Medial Longitudinal Fasciculus (MLF), with bilateral INO being the most common outcome.

Additionally, INO may be a feature in other demyelinating syndromes such as Myelin Oligodendrocyte Glycoprotein-IgG-Associated Disorder and Neuromyelitis Optica. In such instances, ophthalmoplegia can occur unilaterally or bilaterally.

• Ischemic 

In the elderly population, lesions affecting the Medial Longitudinal Fasciculus (MLF) predominantly arise as a result of cerebrovascular accidents.

These incidents typically involve the small perforating paramedian arteries originating from the basilar arteries, responsible for providing blood supply to the region housing the sixth nerve nucleus. Simultaneously, the small perforating branches of the P2 segment of the posterior cerebral artery are responsible for irrigating the midbrain where the third nerve nucleus is situated.

Therefore, occurrences such as small embolic events, hypertensive strokes, vascular dissection, and vasculitis impacting these arteries can give rise to lesions within the MLF and subsequently lead to the manifestation of Internuclear Ophthalmoplegia (INO) [3].

• Infections

Infections represent a less frequently encountered etiological factor contributing to Internuclear Ophthalmoplegia (INO), and they can be categorized as follows:

1. Bacterial infections, including conditions such as Syphilis and Lyme disease.
2. Viral infections, encompassing diseases such as HIV and herpes zoster.
3. Fungal infections, exemplified by cryptococcosis.
4. Parasitical infections, with cysticercosis being an illustrative example.

• Other conditions

Internuclear Ophthalmoplegia (INO) can be attributed to a spectrum of diverse underlying conditions, including but not limited to:

• Inflammatory disorders, such as Sarcoidosis, Systemic Lupus Erythematosus, Behcet’s Disease, and Sjogren’s Syndrome.
• Tumorous growths comprise conditions like medulloblastoma, glioma, lymphoma, and metastatic tumors.
• Nutritional disorders, exemplified by Pernicious Anemia and Wernicke Encephalopathy.
• Toxic effects induced by drugs, with substances like lithium, narcotics, phenothiazines, and tricyclic antidepressants implicated.
• Traumatic head injuries.
• Congenital malformations, including the Arnold-Chiari malformation.
• Metabolic conditions, such as Fabry Disease and hepatic encephalopathy.
• Degenerative conditions.
• Iatrogenic causes.
• Subdural hematoma.
• Hydrocephalus.

Saccadic eye movements represent a pivotal ocular function in which the Medial Longitudinal Fasciculus (MLF) plays a substantial role. This intricate process involves the transmission of signals originating from the Frontal Eye Field (FEF) to the contralateral Paramedian Pontine Reticular Formation (PPRF) and the rostral interstitial nucleus of the MLF, specifically for horizontal and vertical saccades, as elucidated in reference [4].

Subsequently, the PPRF serves to stimulate the ipsilateral abducens nucleus, which, in turn, conveys signals to the ipsilateral lateral rectus muscle. Simultaneously, signals are transmitted through the MLF to reach the contralateral medial rectus subnucleus of the third cranial nerve nucleus. This coordinated effort results in the establishment of a horizontal gaze towards the eye opposite the initiating FEF.

As a fundamental diagnostic indicator in cases of Internuclear Ophthalmoplegia (INO), the clinical presentation often includes deceleration or impairment of adduction in the affected eye on the same side as the lesion. In the contralateral eye, a dissociated nystagmus may manifest, believed to represent a compensatory mechanism aimed at mitigating the weakness observed in the adducting eye. This phenomenon aligns with Herring’s law of equal innervation, which posits that an increase in innervation to a muscle is accompanied by a corresponding increase in innervation to its yoke muscle. In the context of INO, these muscles are the medial rectus muscle and the contralateral lateral rectus muscle, as expounded in reference [1].

Clinical Presentations and Complications

The principal clinical hallmark characterizing a patient afflicted with internuclear ophthalmoplegia (INO) is the manifestation of either partial or complete ipsilesional impairment of adduction in conjunction with horizontal dissociated saccades and nystagmus directed contralaterally while attempting to fixate on an object situated in the direction opposite to the site of the lesion [1]. To illustrate, in the event of a lesion within the left medial longitudinal fasciculus (MLF) and an attempt to direct gaze to the right, one would observe dissociated nystagmus, characterized by an involuntary rhythmic eye movement [6], and/or saccades, which denote rapid eye movements following a sudden shift in the point of fixation [7], in the right eye. Simultaneously, there would be an impaired adduction in the left eye, instead of the expected normal leftward adduction and rightward abduction.

Concomitant symptoms attributed to MLF lesions may encompass a spectrum of manifestations, ranging from mild symptoms like headaches to more intricate complications indicative of brainstem dysfunction, including conditions such as aspiration pneumonia and respiratory failure [1]. Of particular note are:

• Dizziness, ranks among the most frequently reported symptoms associated with MLF impairment, especially when elicited during lateral gaze examination [8].
• Blurred vision [1].
• Difficulty in tracking rapidly moving objects [3].
• Horizontal diplopia, or double vision characterized by the lateral separation of two images, as a consequence of impaired ipsilesional adduction [3,9].
• Vertical diplopia, marked by one image appearing higher than the other, typically stemming from skew deviation. Skew deviation arises from asymmetric disruption of supranuclear input from the inner ear, leading to a misalignment of the eyes and prompting the ipsilateral eye to deviate upward (hypertropia) [1,3,9].
• Furthermore, disruptions in the coordinated horizontal eye movements may result in the loss of binocular vision [3].
• This, in turn, engenders visual confusion, wherein two distinct images are perceived as superimposed upon the same spatial plane [3,10]. Additionally, depth perception, as represented by stereopsis, may also be compromised [3].
• Oscillopsia, characterized by unstable vision due to the misperception of a moving environment [3,11], may ensue, alongside symptoms such as reading fatigue, among others [3].

It is important to keep in mind that these symptoms vary in intensity and likelihood depending on several factors, but mostly depending on the specific etiology of the presented INO.

• It is also important to note that visual difficulties looking sideways hampers the ability to drive or even walk properly, which increases the risks of car crashes and falls [3].