Article Text

Download PDFPDF

Internuclear ophthalmoplegia
  1. Jonathan D Virgo1,2,
  2. Gordon T Plant1,2,3
  1. 1Moorfields Eye Hospital, London, UK
  2. 2St Thomas’ Hospital, London, UK
  3. 3The National Hospital for Neurology & Neurosurgery, London, UK
  1. Correspondence to Dr Jonathan D Virgo, Neuro-Ophthalmology, Moorfields Eye Hospital NHS Trust, 162 City Road, London EC1V 2PD, UK; j.d.virgo{at}


A brainstem lesion of any type that involves the medial longitudinal fasciculus (MLF) can cause internuclear ophthalmoplegia (INO). This primarily affects conjugate horizontal gaze and classically manifests as impaired adduction ipsilateral to the lesion and abduction nystagmus contralateral to the lesion. Here, we describe the anatomy of the MLF and review the clinical features of INO. We also describe conjugate horizontal gaze palsy and some of the ‘INO-plus’ syndromes.

  • Internuclear ophthalmoplegia
  • medial longitudinal fasciculus

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

The medial longitudinal fasciculus (MLF) consists of paired white matter tracts in the brainstem that lie close to the midline just ventral to the cerebral aqueduct in the midbrain and ventral to the fourth ventricle in the pons and medulla (figure 1). Ascending, descending and decussating fibres within the MLF link together several brainstem nuclei (figure 2):

  • the rostral interstitial nucleus of the MLF in the rostrodorsal midbrain;

  • the interstitial nucleus of Cajal and the oculomotor nucleus in the rostral midbrain at the level of the superior colliculus;

  • the trochlear nucleus in the caudal midbrain at the level of the inferior colliculus;

  • the abducens nucleus and the paramedian pontine reticular formation (PPRF) in the caudal pons;

  • the vestibular nuclei in the rostral medulla.

Figure 1

Medial longitudinal fasciculus (MLF). Postmortem 9T MR images showing the MLF and adjacent structures at the level of the oculomotor nucleus (left panel) and abducens (right panel) nucleus. Images were kindly provided by Dr Indran Davagnanam (UCL Neuroradiology) and Professor Janice Holton (UCL Brain Bank).

Figure 2

Horizontal eye movements: anatomy and physiology. CN3, cranial nerve 3 (oculomotor); CN6, cranial nerve 6 (abducens); FEF, frontal eye fields; LLR, left lateral rectus; LMR, left medial rectus; MLF, medial longitudinal fasciculus; PPRF, paramedian pontine reticular formation; RLR, right lateral rectus; RMR, right medial rectus.

Excitatory and inhibitory interneurones travelling within the MLF coordinate the activity of agonist and antagonist muscles during horizontal, vertical and torsional eye movements.1 The MLF also conveys tectospinal fibres that mediate reflex movements of the head and neck in response to visual or auditory stimuli and vestibulospinal fibres to limb extensor muscles that maintain posture against gravity.

Table 1 and figure 3 summarise the pathophysiology and clinical features of internuclear ophthalmoplegia (INO), conjugate horizontal gaze palsy and the ‘INO-plus’ syndromes. First, we will briefly explain how normal horizontal gaze is mediated (figure 2). Horizontal saccades are initiated by the frontal eye field area of the contralateral frontal lobe (ie, the right frontal eye field initiates leftward saccades). This is why acute frontal lobe pathology (eg, stroke) is often accompanied by deviation of the eyes towards the lesion. The PPRF is activated by the contralateral frontal eye field and in turn it activates the adjacent abducens nucleus via excitatory burst neurones. Horizontal gaze is then mediated by abducens motor neurones to the ipsilateral lateral rectus muscle and via excitatory abducens interneurones, which decussate before ascending in the MLF to the medial rectus subnucleus of the contralateral oculomotor nucleus. A lesion in the caudal pons involving the PPRF and/or abducens nucleus therefore causes a conjugate horizontal gaze palsy, in which neither eye can look towards the side of the lesion (figure 3A). Ipsilateral facial weakness often accompanies conjugate horizontal gaze palsy due to the close proximity of the facial nucleus and its nerve fibres (figure 1).

Table 1
Figure 3

Horizontal eye movements: pathophysiology. (A) Right conjugate horizontal gaze palsy due to a lesion in right caudal pons involving the abducens nucleus and/or paramedian pontine reticular formation (PPRF). (B) Unilateral internuclear ophthalmoplegia on left gaze due to a right medial longitudinal fasciculus (MLF) lesion (i) with dissociation of convergence (ii). (C) One-and-a-half syndrome due to a lesion(s) involving the MLF and adjacent abducens nucleus and/or PPRF. CN3, cranial nerve 3; CN6, cranial nerve 6; LLR, left lateral rectus; LMR, left medial rectus; RLR, right lateral rectus; RMR, right medial rectus.

A range of different pathological processes can affect the MLF and cause INO. In the largest case series of 410 patients, infarction accounted for 38% of cases and 87% of these were unilateral, while demyelination accounted for 34% of cases and 73% of these were bilateral.2 The remaining 28% of cases were due to ‘unusual causes’, including trauma, tentorial herniation, infection (HIV, cysticercosis and syphilis), tumour (medulloblastoma, glioma, lymphoma and metastasis), iatrogenic injury, brainstem haemorrhage and vasculitis (systemic lupus erythematosus and Sjögren's syndrome).

Patients with INO typically report intermittent horizontal diplopia and/or oscillopsia, although these symptoms may be surprisingly mild. Signs manifest primarily during conjugate horizontal gaze. An on-line supplementary educational video on INO (see screenshot in figure 4) is available via the Practical Neurology website. The cardinal feature of INO is impaired adduction of the eye ipsilateral to the MLF lesion. This occurs because abducens excitatory interneurones fail to reach the oculomotor medial rectus subnucleus (figure 3Bi). The impairment may only be mild and just visible during large horizontal saccades as a slowing of the adducting eye relative to the abducting eye (adduction lag). Focusing on the bridge of the nose during a large horizontal saccade can help to identify subtle adduction lag in such cases. At the other extreme, INO can cause total loss of adduction beyond the midline.

Figure 4

Screenshot from on-line supplementary video. The video is a simulation of unilateral internuclear ophthalmoplegia (INO) and bilateral INO. The unilateral INO depicted is on left gaze and due to a right medial longitudinal fasciculus (MLF) lesion. The bilateral INO is depicted as being symmetrical, but this is often not the case in clinical practice. When comparing the velocity of the adducting saccade with that of the conjugate abducting saccade, it is best to fixate on a point equidistant between the two eyes on the forehead. It is easier to compare velocities when the targets being compared (in this case, the two eyes) are falling in the periphery at a similar eccentricity (distance from the fixation point) than if one is fixed and the other viewed in the periphery. Note that normal peak velocities for saccades greater than 10° in amplitude are much, much faster than 120°/s. This simulation is in relatively ‘slow motion’ for the sake of clarity. As the velocity of the adducting saccade becomes slower, the INO is easier to detect. In mild cases, there is slowing of adduction only. Smooth pursuit in such cases would appear normal as the pursuit movement operates at velocities that the system can still generate (up to 40°/s). Eventually, however, in its severest form, there is no adduction of the affected eye beyond primary position—in other words, a total failure of the action of the medial rectus during conjugate horizontal gaze. For both the unilateral and bilateral examples, sparing of convergence is illustrated. This dissociation of medial rectus function in horizontal saccades and in vergence movements confirms that the abnormality is due to an MLF lesion and not due to another cause of an isolated medial rectus paresis (such as myasthenia gravis—so-called ‘pseudo-INO’). This test is only possible where the velocity of the adducting saccade is slower than the velocity generated by the vergence system (about 30°/s) or the amplitude of the adducting saccade is less than the amplitude of the vergence movement. Vergence may or may not be spared in an INO, but it is not spared in all other causes of medial rectus underaction, including ocular myopathies and mechanical causes, as well as neurogenic and neuromuscular transmission defects.

The sign most frequently associated with impaired adduction in INO is abduction nystagmus of the eye contralateral to the MLF lesion. This is thought to occur due to an adaptive compensatory response to the adduction weakness and is best understood in relation to Hering's law of equal innervation.3 Increased signalling towards the medial rectus muscle ipsilateral to the MLF lesion is accompanied by increased signalling towards its yoke muscle, the lateral rectus muscle of the unimpaired abducting eye contralateral to the MLF lesion (figure 3Bi). This results in visible oscillations of the abducting eye (overshoot abduction saccades and postsaccadic adduction drift) with subclinical oscillations of the weak adducting eye. Three findings support the above theory:

  • abduction nystagmus does not develop in acute experimentally induced INO;4

  • patching the paretic eye reduces abduction nystagmus in some, but not all, patients with unilateral INO;5

  • abduction nystagmus can develop in patients with surgically induced weakness of the medial rectus muscle.6

An alternative, but not mutually exclusive, explanation for abduction nystagmus in INO might be a gaze-evoked nystagmus that is dissociated simply because the impaired medial rectus cannot generate it. Lesions of the MLF involving the adjacent paramedian tracts to and from the flocculus could produce an INO with gaze-evoked nystagmus7 that would not be influenced by patching.

Some people with INO can converge to an accommodative near target, while during horizontal gaze there is impaired adduction of the eye ipsilateral to the lesion. This is termed dissociation of convergence (figure 3Bii). When present, it is a useful sign that strongly suggests INO because it does not occur in pseudo-INO due to myasthenia gravis, oculomotor nerve palsy or indeed in an isolated medial rectus paresis from any other cause. It used to be thought that convergence was preserved in INO if the MLF lesion was below the level of the oculomotor nucleus (posterior INO of Cogan) and convergence was absent if the lesion was at this level (anterior INO of Cogan).8 However, subsequent lesioning experiments and imaging studies have shown this rule to be unreliable.3 Variable loss of convergence in INO may simply reflect background variation in our natural ability to converge to a near target. In patients with mild INO who have only subtle adduction lag but a full range of eye movements, it does not help to check for dissociation of convergence. The adduction lag that does occur in these cases is most obvious during large horizontal saccades.

The pick-up rate for diagnosing INO via a physical examination alone increases with the degree of adduction weakness. In a study that used quantitative infrared oculography to grade the severity of adduction weakness, 279 physicians were shown video footage of patients and correctly identified INO in 94% of severe cases, 75% of intermediate cases and 29% of mild cases.9

In all cases of INO, but especially those that are mild, it is helpful to look for other brainstem signs to help to localise the lesion. Due to the complex role of the MLF and its close proximity to other important structures, patients with INO often have additional brainstem signs. At one extreme, INO may be overlooked in the setting of a patient with long tract signs and reduced level of consciousness due to brainstem stroke. Smaller lesions involving the MLF and some of the adjacent structures mentioned above can cause a range of ocular motor deficits, collectively termed the ‘INO-plus’ syndromes.

As already mentioned, a lesion involving the PPRF and/or abducens nucleus can cause a conjugate horizontal gaze palsy (figure 3A). If such a lesion also involves the adjacent MLF, then there will be an additional INO. This combination of deficits is termed ‘one-and-a-half syndrome’ and it manifests as loss of all horizontal eye movements aside from abduction of the eye contralateral to the lesion (figure 3C).

Unilateral INO is sometimes accompanied by vertical strabismus due to simultaneous skew deviation or trochlear nerve palsy. Such cases present a diagnostic challenge and a formal orthoptist assessment is helpful. Skew deviation in some cases of INO is probably due to interruption of otolithic projections that ascend within the MLF to the trochlear nucleus, oculomotor nucleus and interstitial nucleus of Cajal. This interruption causes hypertropia and incyclorotation of the eye ipsilateral to the MLF lesion due to an imbalance of the two eyes in the roll axis. Conversely, MLF lesions in the caudal midbrain involving the adjacent trochlear nucleus cause INO with hypertropia and excyclorotation of the eye contralateral to the lesion due to superior oblique underaction; it is the contralateral muscle that is affected because the trochlear nerves decussate before exiting the midbrain dorsally. Vertical strabismus can be assessed using the Parks–Bielschowsky three-step test:

  1. determine which eye is hypertropic in primary position

  2. determine whether the hypertropia increases in right or left gaze

  3. determine whether the hypertropia increases in right or left head tilt.

Hypertropia due to superior oblique palsy Worsens on Opposite Gaze and is Better on Opposite head Tilt (WOGBOT). A relatively new and very reliable (90% sensitive and 100% specific) clinical test that distinguishes skew deviation from other forms of vertical strabismus, such as superior oblique palsy, is the upright-supine test.10 ,11 A vertical misalignment that decreases by 50% or more in the supine position compared with the upright position is positive and indicates skew deviation.

Vertical eye movement abnormalities may also occur in INO. These include impaired vertical vestibular ocular reflexes and vertical pursuit, as well as gaze-evoked vertical nystagmus on upgaze or downgaze. Gaze-evoked vertical nystagmus should not be confused with upbeat nystagmus or downbeat nystagmus, which by definition is present in primary position. These vertical eye movement abnormalities are more frequent and persist for longer in bilateral INO.

Finally, wall-eyed bilateral INO (WEBINO) is a rare disorder in which bilateral INO is accompanied by bilateral exotropia. As INO alone does not account for the exotropia, it was previously thought that the lesions must be located in the midbrain with involvement of the oculomotor medial rectus subnuclei. However, this theory has not been supported by postmortem examination of affected patients or by studies using high-quality MRI.12 Exotropia may result from interruption of ascending otolithic projections causing an imbalance of the two eyes in the yaw axis.

Key points

  • Infarction accounts for 38% of internuclear ophthalmoplegia (INO) cases and most of these (87%) are unilateral; demyelination accounts for 34% of INO cases and most of these (73%) are bilateral.

  • The cardinal feature of INO is impaired adduction of the eye ipsilateral to the medial longitudinal fasciculus (MLF) lesion.

  • In mild cases of INO with a full range of conjugate horizontal eye movements, adduction lag is best demonstrated during large horizontal saccades.

  • In moderate-to-severe INO where there is medial rectus underaction during conjugate horizontal gaze, dissociation of convergence, when present, strongly suggests INO.

  • Other brainstem signs often occur alongside INO; they should be sought for as their presence can help to confirm the diagnosis of INO and to localise the MLF lesion.



  • Contributors The manuscript is written by JDV and reviewed by GTP with corrections. Diagrams are produced by JDV. Animations are produced by Emma Plant. MR images are provided by Dr Indran Davagnanam (UCL Neuroradiology) and Professor Janice Holton (UCL Brain Bank).

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Christian Lueck, Canberra, Australia.

Other content recommended for you