Internuclear Ophthalmoplegia

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Internuclear Ophthalmoplegia


Disease Entity

Introduction

Internuclear ophthalmoplegia or ophthalmoparesis (INO) is an ocular movement disorder that presents as an inability to perform conjugate lateral gaze and ophthalmoplegia due to damage to the interneuron between two nuclei of cranial nerves (CN) VI and CN III (internuclear).[1] This interneuron is called the medial longitudinal fasciculus (MLF) and it may be affected by ischemia, demyelination, ischemia, among others.

Anatomy

The MLF is a heavily myelinated nerve tract connecting the oculomotor nucleus (CN III) of the ipsilateral side with the paramedian pontine reticular formation (PPRF) and CN VI in the contralateral pons. Thus, demyelinating lesions in the midbrain or pons often produce a unilateral or bilateral INO, usually in young patients. The MLF is located at the dorsomedial brainstem tegmentum (midbrain and pons) ventral to the aqueduct or the fourth ventricle. MLF lies very near to the midline. As both MLFs are close to each other and near to midline, bilateral INO is not rare.

Foveation and binocular single vision of the mobile and immobile objects require coordination between the cranial nerves (II, III, IV, and VI), their interneurons, and various supranuclear influences. CN VI is the final common pathway for lateral horizontal gaze. The PPRF or paraabducens nucleus is the key structure in conjugate horizontal gaze and horizontal saccades. Damage to the PPRF results in impaired horizontal saccade in the same direction. Typically, the PPRF receives information from the higher cortical centers such as the frontal eye fields, occipital and parietal lobes, and the superior colliculus. The frontal eye field controls contralateral saccades and the parietal lobe controls ipsilateral pursuits.[2]

PPRF sends a signal to the CN VI. Some axons from the CN VI innervate the ipsilateral lateral rectus resulting in the abduction of the ipsilateral eye. The signal for contraction of the contralateral medial rectus (for adduction of the contralateral eye) is sent from the CN VI to the contralateral medial rectus subnucleus of CN III via the internuclear pathway called MLF. The activation of the contralateral medial rectus and ipsilateral lateral rectus muscle produces horizontal conjugate eye movement. The side of the INO is named by the side of the adduction deficit, which is ipsilateral to the MLF lesion. The MLF is also involved in multiple other functions including oculovestibular reflex, vertical pursuit, optokinetic (OKN) nystagmus, and coordinates the conjugate ocular movements in response to movement of the head and neck.[3]

INO pathway Copyright: American Academy of Ophthalmology https://www.aao.org/image/internuclear-ophthalmoplegia

Clinical features

Symptoms

Symptoms of INO may vary in severity. Symptoms range from, horizontal diplopia, difficulty in tracking high-speed objects, or dizziness on lateral gaze. Horizontal diplopia is caused by the limitation of adduction in the ipsilateral eye. The diplopia becomes more prominent on looking at objects on the opposite side of the lesion and diplopia is usually not seen in the primary gaze. The patient may also complain of headaches or other deficits due to the involvement of the brainstem. Vertical oblique diplopia related to associated skew deviation may also be another symptom. Interruption of binocular vision resulting from defective conjugate horizontal movements of eyes may cause reading fatigue, visual confusion, loss of stereopsis, oscillopsia, and diplopia. The difficulty in looking at the sides may lead to difficulties during driving or walking and may increase the risk of road traffic accidents or falls. The patients may complain of headaches and vertigo.

Signs

A good ocular examination is often all that is required to diagnose INO. The INO is characterized clinically by an ipsilesional adduction deficit (partial or complete) with a contralateral, dissociated, horizontal abducting saccade/nystagmus on attempted gaze to the contralesional side. There is a slow adducting saccadic velocity in the affected side. A skew deviation with the ipsilateral hypertropic eye may be noted. Vertical gaze nystagmus may be noted on upgaze. The INO can be unilateral or bilateral and may present with or without (neurologically isolated) other brainstem findings.

Binocular INO [4]

Ipsilesional adduction deficit (partial or complete)

The partial adduction defect may be made clinically more apparent by performing horizontal saccades. There is adduction lag or reduced adducting saccadic velocity on the ipsilateral eye. The OKN drum also can reveal such a subtle reduction in adducting saccadic velocity. The defective input to the medial rectus subnucleus of CN III from the CN VI via MLF causes this ipsilesional adduction deficit or lag.

Contralateral, dissociated, horizontal abducting saccade/nystagmus on attempted gaze to the contralesional side

Hering’s law of equal innervation has been hypothesized as a possible explanation for the dissociated contralateral horizontal gaze-evoked nystagmus in the abducting eye. Increased innervation to the underacting adducting muscle would result in an enhanced stimulus to the contralateral abducting muscle.[5] Damage to the adjacent structures including the vestibular nucleus may also contribute to gaze-evoked nystagmus. The explanation of dissociation of both eyes (abducting nystagmus in the opposite eye and the ipsilateral eye does not usually show clinically visible nystagmus on adduction) has been hypothesized to be due to the adductor weakness in the ipsilateral eye. Electro-ocular techniques may detect subclinical nystagmus in the eye with adduction deficit (ipsilateral eye)

Abnormal vertical eye movements

These may be present in INO and are not necessary for the diagnosis of INO. These are usually seen with bilateral INO and may represent INO plus syndromes. Such abnormal vertical ocular movements include:[3]

  • Hypertropic skew deviation in the ipsilateral eye due to pontine lesions (with incyclotorsion in the ipsilateral eye)[6]
  • Abnormal OKN nystagmus and pursuits,
  • Vertical gaze-evoked nystagmus on upgaze,
  • Abnormal vestibulo-ocular reflex,
  • Contraversive ocular tilt reaction,[7] and
  • Reduced vertical gaze holding.
  • Oblique saccades in adduction[8]


Normal convergence

Usually, convergence is not affected even in the eye with adduction deficit in horizontal gaze. This is called ''dissociation of convergence''. This is due to the sparing of the convergence pathway including the fibers from the medial rectus subnucleus of the CN III in INO. However, the absence of convergence does not rule out the diagnosis of INO. Previously, the anterior INO of Cogan was thought to arise due to lesion at the level of the CN III nucleus and it was characterized by the absence of convergence.[9] Posterior INO of Cogan was thought to involve the MLF below the CN III nucleus and the convergence was preserved. However, recent studies have found this rule to be debatable.[10]

[Video Courtesy: Moran CORE, University of Utah, https://morancore.utah.edu/]


Associated Syndromes:

WEBINO

Location of lesion: Bilateral INO

Wall-Eyed Bilateral Internuclear Ophthalmoplegia exists when there is bilateral damage to the MLF.[11] This damage causes a primary position exotropia (eyes are looking at the opposite “wall.”, thus the possibly outdated term “wall-eyed”). The most common etiology is infarction of the midbrain in older patients and demyelinating disease in young patients.[12] The exotropia (XT) is likely decompensation of fusional mechanisms and the XT is not present in every case of bilateral INO. Bilateral INO may also show vertical gaze-evoked nystagmus on superior gaze. Such nystagmus occurs due to the lesion in the ascending tracks (involved in gaze holding and vertical vestibular pursuit) from the vestibular nuclei. Bilateral INO is characterized by bilateral adduction lag and bilateral abduction nystagmus.

See video: [1] https://www.aao.org/master-class-video/bilateral-internuclear-ophthalmoplegia-ino

WEMINO

Location of lesion: Monocular INO

This is a less common variant of INO, similar to the WEBINO above.[7][13] As in WEBINO, patients with a unilateral MLF lesion (monocular INO) have a primary position XT.[7]

One and a half syndrome:

Location of lesion: The MLF and the PPRF and/or CN VI nucleus on the same side

This syndrome[14] is characterized by no horizontal movement in the ipsilateral eye. The contralateral eye's abduction is preserved, while adduction is nule and there is a abduction nystagmus.[15] However, the convergence, elevation, and depression on both eyes are usually intact. In primary gaze, the contralateral eye is exotropic (paralytic pontine exotropia).[3] When the CN VI nucleus is spared, on volitional horizontal gaze, a gaze palsy is present. However, the vestibulo-ocular reflex[16] and ocular response to caloric stimulus in the ear is normal.


[Video Courtesy: Instant Neuro, lesion on the right side]

Eight and a Half Syndrome:

Location of lesion: The MLF, the PPRF and/or CN VI nucleus, and facial fascicular nerve (CN VII) on the same side

This syndrome[17] is characterized by having one-and-a-half syndrome and a facial fascicular nerve (CN VII) palsy. The fascicle of CN VII wraps around the nucleus of CN VI in the dorsal pons. The ipsilateral eye does not have any horizontal gaze movement and there is ipsilateral lower motor neuron CN VII palsy. The contralateral eye does not have adduction as a part of horizontal gaze palsy, but this eye abducts with abduction nystagmus. The proximity of the PPRF, facial nerve nucleus, and MLF located in the dorsal pons makes this syndrome much more likely. The lesion is most often vascular or demyelinating in the dorsal tegmentum of the caudal pons[18].

[Video Courtesy: JAMA Network, Lesion is on the left side. Skaat A, Huna-Baron R. Eight-and-a-half syndrome: a rare pontine neuro-ophthalmologic syndrome. Arch Neurol. 2012 Jul;69(7):934-5. doi: 10.1001/archneurol.2011.2185. PMID: 22393168.]

Half and Half Syndrome:

Location of lesion: MLF and fascicle of CN VI

This syndrome[19] consists of an INO in one eye combined with an ipsilateral CN VI fascicular involvement with sparing of the sixth nerve nucleus. Thus, there is “half” of a horizontal gaze palsy (INO) plus an additional “half” (abduction deficit from CN VI fascicular palsy).

Internuclear Ophthalmoplegia of Abduction (Lutz Posterior INO)

Location of lesion: Variable (including paramedian pontine rostral formation (PPRF),[20] pontine MLF,[21] pre-nuclear rostral pons,[22] abducens fasiculus, and midbrain.[21] )

Other names for this entity include reverse INO and pseudo abducens palsy. This syndrome is a rare ophthalmoplegia, either bilateral or unilateral that exhibits contralateral adducting eye (rather than abducting eye) nystagmus with abduction restriction on physical exam. It is the reverse of the typical INO, and although the lesion localization is not consistent, it likely is due to CN VI pre-nuclear input asymmetry.[23]

Comparison of reverse INO (lesion at the left side) and INO (lesion at the right side)

Etiology

A lesion in the MLF interrupts the neural communication to the CN III subnuclei that allows for conjugate horizontal gaze arising from the final common pathway for horizontal gaze (CN VI nuclei). The MLF can be damaged by any lesion (e.g., demyelinating, ischemic, neoplastic, inflammatory) in the pons or midbrain. The MLF is supplied by branches of the basilar artery and ischemia in the vertebrobasilar system can produce an ischemic INO.[24]

An INO is a common presentation of multiple sclerosis (MS) in younger patients. Demyelination of the MLF in MS can involve any segment and is frequently bilateral. [25] Internuclear ophthalmoplegia can serve as an important sign for diagnosing MS as it can occur as its first symptom. [26] The relationship between INO and MS has also been extended showing that INO can be used as a biomarker of axonal and myelin integrity in MS. [27]

Additionally, other demyelinating etiologies such as Myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD) [28] and Neuromyelitis optica (NMO) previously known as “Devic’s diasease” with uni or bilateral involvement[29], even though their most typical neuro-ophthalmologic finding is optic neuritis.

Less common causes for an INO include traumatic, neoplastic, inflammatory (e.g., sarcoid, Behçet disease, lupus), or infectious [e,g., cryptococcosis, Borrelia burgdorferi (Lyme disease)], nutritional and metabolic etiologies.[30] [31].

Wernekink’s commissure syndrome is a rare mesencephalic syndrome caused by lesions to the Wernekink commissure which is the decussation of the superior cerebral peduncles. INO is the most frequent opthalmoplegia associated with Wernekink’s commissure syndrome due to its adjacency to the MLF. This is a rare syndrome due to the rich blood supply to the midbrain preventing a pure midbrain infarct. Both Wernekink’s commissure and the MLF are supplied by the inferior paramedian mesencephalic arteries (IPMAs). [32]

INO is rare in children but may result from neoplasms (e.g., medulloblastomas or pontine gliomas), hydrocephalus, or similar etiologies to adults [33]. In one review of INO, some of the most common causes included: 1) Infarction - 38%- Unilateral INO in 87% of cases; 2) Multiple sclerosis in 34%-Unilateral in 27%; and 3) Unusual causes included trauma, tentorial herniation, infection, tumor, iatrogenic injury, hemorrhage, vasculitis. [34]. The vascular lesions causing dorsal brainstem infarcts may involve the basilar artery, superior cerebellar artery, and posterior cerebellar artery.[24]

In the elderly population, Medial longitudinal fasciculus lesions are most commonly due to CVA with a typical age of onset of 62-66 years old. The MLF is found in the dorsal brainstem and projects to the nuclei controlling the extraocular muscles for CN VI and CN III. The CN VI nucleus is in the inferior aspect of the dorsal pons. This region is supplied by the small perforating paramedian arteries arising from the basilar artery. The CN III nucleus is in the midbrain and is supplied by the small perforating branches of the P2 segment of the posterior cerebral artery. Small embolic events, hypertensive stroke, vascular dissection, and vasculitides in these arteries are all potential causes of CVA that implicates the MLF. [35], [36]

The integrity of convergence can be used to differentiate between anterior (midbrain) or posterior (pons) INO. If the lesion to the MLF occurs at the level of the CN III nucleus (anterior INO) convergence is impaired. A lesion occurring below the CN III nucleus (posterior INO) will present with intact convergence. [37]

Most Common causes (around 70%)
  • Multiple Sclerosis (younger patients usually under 45 years, usually bilateral)
  • Cerebrovascular accidents (older patients, usually unilateral, history of vascular risk factors including hypertension, diabetes, smoking)
Infections
  • Bacterial (including syphilis, Borrelia burgdorferi or Lyme disease)
  • Viral
  • Fungal (including cryptococcosis)
  • Other infections causing meningoencephalitis
Inflammation
  • Sarcoidosis
  • Systemic lupus erythematosus
  • Behçet disease
Trauma
  • Head trauma
Congenital malformations
  • Arnold-Chiari malformation
Neoplasia/ tumors
  • Tumors of fourth ventricle or brainstem (including medulloblastoma, pontine glioma)
  • Cancer
Nutritional disorders
  • Pernicious anemia
Toxicity of drugs
  • Lithium
  • Propranolol
  • Tricyclic antidepressants
  • Narcotics
  • phenothiazines
Degenerative conditions
Metabolic conditions
  • Maple syrup urine disease
  • Hepatic encephalopathy
  • Abetalipoproteinemia
Other conditions
  • Subdural hematoma
  • Hydrocephalus
  • Supratentorial arteriovenous malformation

Diagnosis

Evaluation

The diagnosis is made clinically with testing of the eye’s ability to perform conjugate movements.

Saccadic velocity and OKN drums or tapes are important tests to detect subtle dysconjugate saccades in the affected eye.

Quantitative infrared oculography may increase the precision for the diagnosis of subtle INO cases. In a study, INO was not identified in cases with mild slowing of adduction velocity by 71% of physician observers. [38] Twenty five percent of the physician observers could not detect intermediate dysconjugacy.[38]

Imaging tests such as a CT (computed tomography) scan or MRI (magnetic resonance imaging) brain (stroke protocol and with contrast for demyelination) are ordered after a diagnosis is made to discover where the damage is located so that the physician can then assess which route to take based on what is causing the damage. In general, MRI is superior to CT scan for evaluation of INO. MRI should involve fine overlapping cuts to ensure detection of lesions that may be very small and may otherwise be missed. Proton density imaging was noted to be the preferred modality to identify MLF lesion in multiple sclerosis with INO when compared to T2-weighted imaging, and fluid-attenuated inversion recovery (FLAIR) imaging.[39] Diffusion-weighted imaging with MRI may detect brainstem infarcts causing INO that may not be detected with T2-weighted imaging alone.[24]

Differential Diagnosis

The differential diagnoses include

  • Pseudo-INO: This is usually seen in established cases of myasthenia gravis,[40][41] and Guillain-Barré syndrome.[42] Pseudo-INO may also be the presenting feature of these disorders. However, the vertical nystagmus on the upgaze is not seen. Myasthenia gravis is characterized by variable ptosis, fatigue of the upper lid, reduced response on repetitive nerve stimulation test, and presence of anti-acetylcholine receptor antibody.The adduction limitation of myasthenia typically improves with intravenous edrophonium or with appropriate therapy of myasthenia. The Miller-Fisher variant of Guillain-Barré syndrome is characterized by a triad of areflexia, ataxia, and ophthalmoplegia.
  • Third nerve palsy: INO may simulate partial third nerve palsy. CN III palsy is also associated with pupillary dilation, loss of accommodation, ptosis, absence of abduction nystagmus in the fellow eye, impaired convergence, and limitation of elevation.
  • Progressive supranuclear palsy (PSP): Abnormal ocular movements similar to binocular INO may be seen in PSP. Features of Parkinsonism may be noted. The ocular movement abnormalities may be overcome by oculocephalic maneuvers in PSP (and not in INO) as the lesion is supranuclear.
  • Chiari malformation
  • Other INO-Mimmics: There are reports on patients with Idiopathic intracranial hypertension (IIH) in association with INO [43], as well as INO occurrence after placement of a fourth ventricle shunt for a dilated and ballooned fourth ventricle where the hypothesized mechanisms was acute decompression affecting the MLF located in the floor of the fourth ventricle[44], [45]. Rarely, patients with orbital metastasis may present mimicking INO, as in 2 reports of rectal adenocarcinoma and urothelial carcinoma of the bladder. [46] [47] This confirms the importance of obtaining brain imaging.


More recently, medical treatment of cancers with the immune check point inhibitor Nivolumab has been associated with side effects of INO with an unremarkable MRI. [48],[49],[50]

Management

Dalfampridine, a potassium channel blocker prescribed for gait impairment was used in a case series and the authors reported improvement in saccades[51].</ref>, binocular conjugacy, and ocular motility in patients with INO secondary to demyelination in Multiple sclerosis.[52] Improved neuronal conduction along MLF has been discussed as a possible explanation for this effect seen.[53] Some patients may also report 'visual improvement' after using this drug.[53] If the etiology of INO is inflammation or infection, high-dose corticosteroids can help. If the etiology is MS and not relapsing-remitting, then treatment becomes harder. Patients with WEBINO or WEMINO may benefit from patching, prism, or strabismus surgery to correct any residual primary position symptomatic deviation (XT) that does not recover.[54] Injection of botulinum toxin in one or 2 extraocular muscles may temporarily reduce the diplopia and improve binocular function in INO.[54] Prisms may not be helpful for most of the patients with INO.[3] Bothering diplopia may be avoided by patching one eye. The patients can be taught to move the head to compensate for the defective adduction.

Prognosis

The prognosis of most patients with an INO is good and most cases improve with time but the final outcome depends in part on the treatment of the underlying etiology. Ischemic and demyelinating INO typically recover. All patients achieved resolution of INO within 1 day to 1 year in a study of 30 patients with INO.[24] Rapid recovery is usually seen in the absence of other neurological signs including facial palsy, ataxia, hemiparesis, vertigo, pyramidal tract dysfunction, sensory symptoms, dysarthria, and absent lesion in T2-weighted imaging .[55] [56] In a series of 65 patients with INO, persistence of INO was noted in around half of the patients even after 1 year.[56] Another study noted that around 80% of patients with ischemic INO had resolution of diplopia in the primary position. The average time for resolution was 2.25 months.[55]

Suggested Reading

References

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