Clinical Reasoning: A 12-Year-Old Girl With Acute-Onset Diplopia, Dizziness, and Upbeat Nystagmus

Discussion

Weakness of adduction of one eye with attempted conjugate horizontal gaze is characteristic of INO, which is caused by a lesion of the MLF on the side of adduction paresis. The descending conjugate gaze command from the abducens nucleus interneurons is relayed to the oculomotor nucleus motor neurons, on the other side, via the MLF (Figure 2A). Thus, a lesion of the MLF leads to either complete adduction paresis or adduction lag of the ipsilateral eye.¹ The other cardinal feature of INO is dissociated abducting nystagmus of the contralateral eye. Because of the weakness of the adducting eye, there is an increase in innervation to the medial rectus subnucleus to get the adducting eye to target. There is a concurrent increase in the innervation of the normal abducting eye (because of the Hering law of equal innervation), hence leading to overshoot of the saccades, followed by backward postsaccadic drifts. This saccadic oscillation appears as nystagmus.¹

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Figure 2 Neuroanatomic Schematic

(A) Horizontal leftward conjugate gaze brainstem pathway. (B) Otolithic pathway for leftward head tilt. (C) Anterior semicircular canal VOR pathway. The pink oval shaded region at the right medial pontomesencephalic junction shows the location of the lesion. In (A), this lesion affects the MLF, causing right INO. In (B), the lesion affects MLF, carrying otolithic signals from the left utricle, thus producing right eye hypertropia (skew deviation) with cyclotorsion to the left (SR and SO would normally intort the left eye; IR and IO would normally extort the right eye) and rightward torsional nystagmus (OTR). In (C), the lesion affects both MLF and VTT, carrying signals from the ACC, thus producing a downward bias (by affecting the left SR and right IO muscles) and an upbeat nystagmus. ACC = anterior semicircular canal; CN = cranial nerve; IO = inferior oblique; IR = inferior rectus; LR = lateral rectus; MLF = medial longitudinal fasciculus; MR = medial rectus; MVN = medial vestibular nucleus; SO = superior oblique; SR = superior rectus; SVN = superior vestibular nucleus; VTT = ventral tegmental tract; III = oculomotor nuclear complex; IV = trochlear nucleus; VI = abducens nucleus. This figure was created with BioRender.com.

Skew deviation commonly occurs with INO and is the most likely cause of vertical misalignment in such patients.^1,5 Skew deviation is a component of the OTR, along with torsional nystagmus, and it is related to the interruption of the central otolithic pathway, mediating the vestibulo-ocular reflex (VOR) in the roll plane.⁵ This pathway carries signals from the utricle to the medial vestibular nucleus and superior vestibular nucleus (SVN). These nuclei, in turn, project to the oculomotor and trochlear nuclei via the MLF (Figure 2B).^1,5 A rostral MLF lesion causes the ipsilateral eye to be hypertropic.^1,5 Hence, in most cases of INO with skew deviation, the eye with adduction paresis is also elevated compared with the other eye.¹

Convergence may or may not be impaired in patients with INO. Generally, it is believed that intact convergence indicates a more caudal brainstem lesion and impaired convergence indicates a more rostral brainstem lesion.¹ This explanation indicates that impaired convergence is caused by either direct involvement of the medial rectus subnucleus of the oculomotor complex or because of the involvement of the convergence center in the dorsal midbrain.¹ Exotropia may be present with or without impaired convergence as well. Furthermore, exotropia in patients with INO does not necessarily imply involvement of the medial rectus subnucleus.^1,3 Hence, a lack of convergence with or without exotropia may have some localizing significance, but experts caution against using only this factor in localizing INO.¹

Different types of vertical/torsional nystagmus have been described in patients with INO.^1,6,7 The majority of patients with INO also have some elements of OTR (skew deviation, torsional nystagmus, and head tilt). This is because of the common involvement of the MLF.^1,6,7 Hence, many patients with INO have a torsional nystagmus with the top poles beating toward the side of the lesion.^1,6 Dissociated vertical-torsional nystagmus has been described in patients with INO. The most common pattern is an ipsilesional conjugate torsional nystagmus with an asymmetric upbeat nystagmus, with the larger upbeat component in the contralesional eye.⁶ Pure upbeat nystagmus is rarely reported in patients with INO.^2,3 There are 2 potential explanations for pure upbeat nystagmus. The excitatory signals from the anterior semicircular canal being relayed from the SVN are partly conducted via an extra-MLF pathway known as the ventral tegmental tract. This tract is more ventral in the pontine tegmentum and decussates in the midpons, after which it ascends more medially till it reaches the superior rectus and inferior oblique motor neurons in the oculomotor complex (Figure 2C).⁷ An MLF lesion extending to this pathway could create a downward bias, hence leading to an upbeat nystagmus.^1,-,3,7 The second mechanism suggests that the descending projections from the interstitial nucleus of Cajal (vertical and torsional gaze neural integrator) toward the cerebellum and medullary nucleus of Roller travel via the paramedian tracts and a lesion of these pathways could lead to upbeat nystagmus due to integrator failure.^1,-,3,7

Regardless of the exact mechanism, this unique combination of INO with exotropia, impaired convergence, and symmetric upbeat nystagmus reliably localizes to the dorsomedial pontomesencephalic junction.³ This presentation has been reported in adults with bilateral or unilateral INO.^1,-,3 The most likely diagnosis in our patient was an acute infarct related to a large PFO.