The Canadian eTEXTBOOK OF EYE MOVEMENTS - C.

CLINICAL DISORDERS
INTERNUCLEAR OPHTHALMOPLEGIA contributed by Jason J S Barton, University of British Columbia, May 2008 The name of this disorder reflects its origin in dysfunction of the medial longitudinal fasciculus (MLF), a tract that contains axons projecting from the VI nucleus to the medial rectus subnuclei of the contralateral III nuclear complex. The cardinal findings in INO are impaired adduction and abducting nystagmus during conjugate version movements.
Symptoms and signs

Patients may complain of dizziness or diplopia on lateral gaze. In subtle cases these gaze-evoked symptoms may be fleeting, lasting only until the slow adducting eye catches up with the abducting eye. Mild cases are almost always asymptomatic. INO can be associated with other signs that produce symptoms. Vertical gaze-evoked nystagmus is frequent, most commonly an upbeat nystagmus in upgaze (7, 11, 12). Vertical diplopia in primary position may be caused by a skew deviation, with the weakly adducting eye hypotropic. A few cases have exotropia in primary position causing horizontal diplopia. The most sensitive sign is slowed adducting saccades (1, 2). This is appreciated as a lag in the adducting eye compared to the abducting eye in reaching the saccadic endpoint during repetitive gaze shifts. The difference between abduction and adduction is also manifest in the fast beats of OKR (3, 4) and caloric or per-rotatory vestibular nystagmus (5, 6). When more severe, INO will limit the range of adduction, but this is seen in only half of patients (2, 7). This limitation causes a gaze-evoked exotropia, and at its extreme there may be no adduction beyond the midline for any eye movement (7). In 90% of patients with INO, conjugate gaze shifts produce not only impaired adducting movements but also a dissociated nystagmus in the abducting eye (2). This nystagmus may be prolonged but often only a few beats occur (7). Ocular motor recordings also show that the abducting movements of the normal eye are hypermetric (2, 8-10). See Video, Bilateral INO. See Video, Complete INO. Ocular motor recordings can also confirm reduced adducting saccadic peak velocity (1, 2, 13, 14) and adducting saccade lag (13). Dysconjugacy of the horizontal velocities of the abducting and adducting eye on these recordings may be particularly sensitive signs of INO and may detect a mild defect that would be missed 70% of the time on clinical exam (15). A survey of patients with multiple sclerosis showed that while 15% had clinical signs of INO, eye movement recordings detected subclinical INO in another 20%, based upon this dysconjugacy of saccadic velocity (16). The MLF also carries ascending projections from the vestibular nuclei in the medulla to the III and IV nuclei (17). Reduced vertical VOR, smooth pursuit and VOR-cancellation have been described (12, 18). The VOR abnormality may be more selective for movement in the plane of the contralateral posterior semicircular canal (19).

Recording of a saccade by a patient with multiple sclerosis. Top solid trace is horizontal position of the right eye, bottom trace is the left eye. Dotted traces are position of the target. With a leftward saccade, the right (adducting) eye is slow and hypometric, whereas the left (abducting) eye is fast and slightly hypermetric, with postsaccadic rightward drift, leading to dissociated abducting nystagmus (arrow).
Associated signs

Other signs with INO reflect involvement of adjacent neural elements. Mildly reduced abducting saccadic velocities in the same eye with impaired adduction occur in half of patients with INO and suggest subclinical effects on nearby pontine horizontal gaze structures such as the VI nucleus, PPRF, or VI fascicle (14). This hypothesis is supported by MR studies (20). Thus some INOs may be milder versions of the 'one-and-a-half' syndrome (21). In some patients fixation in the primary position is disrupted by monocular saccadic intrusions, in which one eye makes a sudden small abducting saccade followed by a slow drift back to the center (22). It was proposed that these reflect impaired control of omnipause cells in the nearby raphe nucleus in the pons. INO from a midbrain lesion can be accompanied by downbeat or upbeat nystagmus in primary position (23, 24), or a contralateral trochlear palsy (25), but these combinations are rare.
Varieties of INO

Various classifications of INO have been proposed. Bilateral and unilateral forms are recognized, a distinction with some etiologic use. As many as half of clinically unilateral cases are bilateral on eye movement recordings (7). Unilateral INO results from a lesion of the ipsilateral MLF, since the internuclear axons from the VI nucleus cross immediately in the pons. The proximity of the left and right MLF to each other presumably accounts for the high incidence of bilateral INO. Ischemia may lead to bilateral INO in some cases because paramedian tegmental pontine arteries may branch in their terminal portions to supply both sides of the medial pontine tegmentum (26). The most severe bilateral INO cases will have a significant exotropia in primary, and carry the name 'WEBINO' (wall-eyed bilateral INO). Some also distinguish between an anterior (rostral) and posterior (caudal) INO, in which associated impairment of convergence localizes to the midbrain, whereas sparing of convergence but associated gaze or abduction defects in the opposite direction indicate a pontine lesion (11). Absent convergence is not a reliable sign, though, since it is so variable in the normal

population, especially the elderly. Some report no difference in the lesions on MRI scans of those with and without preserved convergence (20).
Etiology

The two major causes of INO in adults are brainstem ischemia and multiple sclerosis (2, 7, 11): each of these accounts for about a third of cases (27). It is stated that unilateral INO usually results from ischemia and bilateral INO from demyelination (11), but there is considerable overlap and Fisher has provided evidence for why a unilateral vascular lesion might cause bilateral INO (26). Other inflammatory conditions such as brainstem encephalitis (11), Behcet's disease (28), cryptococcosis (29), Guillain-Barr syndrome, and rarely systemic lupus erythematosis (30) have caused INO. Arnold-Chiari malformation type II (11, 31) and neoplasm (23) may affect the MLF but rarely in isolation. INO also occurs in some cases of progressive supranuclear palsy but not in Parkinson's disease (32). It has been associated with diffuse gaze paresis in a case of possible Hallevorden-Spatz disease (33). Toxic and metabolic causes of INO have been reported. Thiamine deficiency (Wernicke's encephalopathy) can cause INO and may also have played a role in two cases of naloxoneresponsive INO occurring in chronic alcoholics with narcotic overdoses (34, 35). Bilateral INO is one of the ocular motor signs in a number of inborn errors of metabolism (see below), including Bassen-Kornzweig (abetalipoproteinemia) (36, 37), adult onset hexosaminidase A deficiency (38) and neonatal branched-chain ketoaminoaciduria and non-ketotic hyperglycinemia (39). Drugs associated with INO include phenothiazines (40), phenytoin (41) and doxepin (42), all in excessive doses. Intrathecal methotrexate and cranial irradiation have caused INO (43) as has d-penicillamine, probably through vasculitis(44). Toluene abuse can cause a presumably demyelinative bilateral INO (45). Head trauma is a rare cause (46), but increasingly recognized, especially in males: about half are bilateral INO and half unilateral, and most are due to falls, blunt trauma or falls (27, 47). In children, neoplasms such as pontine gliomas or medulloblastomas in the fourth ventricle are important causes, though there are often other brainstem signs (48).
Table: Causes of INO

1. Inflammatory o multiple sclerosis o Behcet's o Guillain Barr o systemic lupus erythematosis 2. Infectious o brainstem encephalitis o cryptococcosis 3. ischemia, brainstem 4. degenerative

progressive supranuclear palsy 5. structural o Chiari malformation 6. metabolic - acquired o thiamine deficiency o narcotic overdose 7. metabolic - inherited o abetalipoproteinemia o adult-onset hexosaminidase deficiency o neonatal branched-chain ketoaminoaciduria o non-ketotic hyperglycinemia 8. toxic o phenothiazines o phenytoin o doxepin o intrathecal methotrexate o penicillamine o toluene 9. neoplasm o pontine glioma o medulloblastoma 10. trauma Internuclear ophthalmopleg ia (INO): iatrogenic trauma to the medial longitudinal fasciculus. 29 year-old woman with a seizure disorder developed WEBINO (wall-eyed bilateral internuclear ophthalmopleg ia) and vertical gazeholding nystagmus

after placement of depth electrodes that inadvertently traumatized her pons.

Investigations

Improvements in neuroimaging have increased the likelihood of detecting the sometimes small lesions associated with INO. Among all etiologies, up to 75% may have a visible lesion (49). About half of patients with presumed brainstem ischemia underlying their INO do not have a demonstrable lesion on MRI (50), although another report found that only 4 of 34 patients did not have a lesion (51). For demyelinating lesions, proton-density imaging (PDI) may be superior to both T2 and fluid-attenuated inversion recovery (FLAIR) sequences, with MLF lesions detected on 100% of PDI images, compared with 88% of T2 and 48% of FLAIR images in a series of 58 patients with INO (52). Post-processing registration of visible ischemic lesions with a stereotactic anatomic atlas has shown a nice confirmation of the relation of INO to damage to the MLF, usually in the rostral pons (53). Internuclear ophthalmoplegia (INO): imaging of a pontine stroke affecting the medial longitudinal fasciculus. This man developed a sudden onset right internuclear ophthalmoplegia . Left shows the diffusionweighted image, showing an acute stroke of the dorsal

tegmental pons, also evident on the FLAIR sequence on the right.

Prognosis and management

In another retrospective study not specific for etiology - in which a third of patients had ischemia, a third multiple sclerosis, and a sixth infectious causes - INO resolved in 50% of 65 patients, with half resolving in the first 3 months and the remainder over 3-9 months (49). Patients with multiple sclerosis, infection or trauma recovered about 60-70% of the time. Recovery was less likely if the lesion causing the INO was visible. While this study found recovery in only 40% of patients with INO from presumed brainstem ischemia, another documented recovery in 80% of 33 patients with ischemia, usually over 2-3 months (50). Recovery was more likely if the INO was isolated than if accompanied by other brainstem signs. Another study of 30 patients noted improvement in all over a mean follow-up period of 15 months (51), but again noted longer duration of INO in those with additional neurological signs (64 days) than in those with isolated INO (18 days). Most patients with persistent INO are minimally symptomatic. For those with diplopia in primary, prisms may be useful if the exodeviation in primary is small. A retrospective review of botulinum toxin injections into the lateral rectus in 16 patients with exotropia in primary position ranging from 6 to 50 diopters was able to reduce the deviation and improve diplopia in 13 of the 16, with some improvement in convergence and stereopsis in a few subjects (54). Five of the patients were willing to continue with injections. Strabismus surgery is another option for patients with WEBINO (55). POSTERIOR INTERNUCLEAR OPHTHALMOPLEGIA OF LUTZ While Cogan (11) used the term 'posterior INO' to refer to INO associated with signs of pontine damage, the term was also used by Lutz (56) to refer to a motility pattern the reverse of typical INO: that is, slowness of abduction with dissociated adducting nystagmus. This abduction defect is said to be distinguished from VI nerve palsy by orthotropia in primary position and the adducting nystagmus. It has been hypothesized that the disorder results from damage to prenuclear pathways, either pyramidal input at the level of the pons (57) or projections from the PPRF to the VI nucleus (58). However, such hypotheses predate our knowledge that the VI nucleus is actually a horizontal gaze center itself, containing neurons projecting to the lateral rectus and to the contralateral medial rectus subnucleus (interneurons) via the opposite MLF. Both types of neurons are intermingled and receive the same neural input, and a lesion of the VI nucleus produces ipsilateral gaze palsy rather than abduction weakness; hence it is unlikely that a prenuclear lesion could create an abduction deficit. More recently it has been proposed that an ipsilateral inhibitory projection from the PPRF to the III nuclear complex exists, which normally inhibits the antagonist ipsilateral medial rectus during ipsilateral conjugate gaze (59). Failure of

this inhibition leads to a restrictive limitation of abduction. Such an inhibitory projection may run parallel to the MLF, since no such inhibitory signals have been found within the MLF itself. Evidence for posterior INO of Lutz is sketchy. The clinical arguments are unconvincing, since mild VI nerve palsies may not create a primary position esotropia, and dissociated adduction nystagmus can be associated with VI nerve palsies (60) as the result of central adaptation to paresis or limitation of any type (61). MRI (62) and pathology (63) has also shown damage to the course of the VI fascicle in two cases. Thus, posterior INO of Lutz may simply be VI nerve or fascicle palsies in some patients. In other cases, though, there may be an association of abduction deficits with abnormal ipilateral or bilateral masseter reflexes . The latter implies damage to the trigeminal mesencephalic tract and nucleus, and may circumstantially localize the abduction deficit to the midbrain, much like the vertical gaze palsy that is sometimes seen with an abduction deficit. This has suggested that posterior INO of Lutz may be similar to pseudoabducens palsy or thalamic esotropia, and may be due to disinhibition of the medial rectus or abnormal convergence during lateral gaze, from lesions in the neighbourhood of the interstitial nucleus of Cajal, where convergence neurons are located.
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