Eye Movement Disorders Occurring in Midbrain Stroke

Anatomical Basis of Eye Motor Control at the Mesencephalon

The neural substrate subserving vertical- and horizontal-gaze subsystems is organized differently. A detailed description of all complex pathways underlying generation and control of the functional classes of human eye movements is beyond the scope of this review.

The mesodiencephalic junction is the critical site of prenuclear (supranuclear) vertical and torsional eye motion control.^[9-12] At this level, the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF – the vertical-gaze center), the interstitial nucleus of Cajal (INC), the posterior commissure (PC) and the nucleus of Darkschewitsch – all clustered around the Sylvian aqueduct – are the anatomical structures mediating vertical-gaze inputs to the oculomotor nuclei.^[13-17] The riMLF is located rostrally to the oculomotor nucleus, dorsomedially to the anterior pole of the red nucleus and ventrally to the periaqueductal gray matter.^[15] It houses essential neurons for the generation of fast eye movements in vertical directions and torsional saccades.^[15,18] At this level, the neurons for upward saccades are placed more laterally than those for downgaze.^{[10,11,15-17]} The riMLF burst neurons fire at high frequencies, beginning just before the saccadic movement; otherwise, they are silent.^[14] Moreover, the omnipause neurons located in the nucleus raphe interpositus cease firing during vertical and torsional saccades.^[12] Inputs to each riMLF come from the superior colliculus, the nucleus of the PC, the contralateral riMLF, the fastigial nucleus of the cerebellum and the cerebral hemispheres.^{[12,13,18,19]} From each riMLF, impulses traveling ventrally to the Sylvian aqueduct pass to the subnuclei of the eye muscles controlling upward and downward movements in both eyes, whereas impulses are uncrossed for torsional saccades.^[20-22] Moreover, motoneurons for eye elevator muscles receive bilateral signals from the riMLF crossing through the oculomotor nuclear complex, while afferent signals for depressor muscles are only ipsilateral.^[12,21]

The INC (lying just below the riMLF) is important for integration of premotor signals (eccentric gaze holding or neural integrator) of the saccadic and torsional movements in vertical plane and head posture.^[23-25] The neural integrator is defined as a neural circuit required for gaze maintenance, where the velocity-encoded motor command must be integrated to produce an appropriate eye position command or the gaze-holding mechanism.^[12] The INC projects by way of the PC to motoneurons of the contralateral nuclei of the third and fourth cranial nerves and the contralateral INC.^[12,26,27] Inputs to the INC come from the riMLF and caudal brainstem structures (i.e., the pons, medulla and the anterior semicircular canal) mainly by way of the MLF, the INC participates in vertical smooth-pursuit and vertical vestibular eye movements.^[28] Finally, the PC contains fibers crossing from the INC to the contralateral structures involved in vertical gaze, while nuclei of the PC coordinate lid and eye movements occurring in saccade and pursuit movements in the vertical plane (Figure 1).^[29,30]

Figure 1.

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Main cortical and brainstem structures involved in generation and control of saccadic and smooth-pursuit movements in horizontal and vertical axes. Dotted lines indicate saccadic pathways. Solid lines indicate smooth-pursuit pathways.
DLPC = Dorsolateral pontine cortex; DLPN = Dorsolateral pontine nucleus; EBN = Excitatory premotor burst neuron; FEF = Frontal eye field; FL = Flocculus; FN = Fastigial nucleus; IBN = Inhibitory premotor burst neuron; INC = Interstitial nucleus of Cajal; LIP = Lateral intraparietal area; MLF = Medial longitudinal fasciculus; MST = Medial superior temporal; MT = Middle temporal; MVN = Medial vestibular nucleus; NPH = Nucleus prepositus hypoglossi; NRTP = Nucleus reticularis tegmenti pontis; OCV = Oculomotor cerebellar vermis; OPN = Omnipause neuron; PC = Posterior commissure; PEF = Parietal eye field; PPRF =Paramedian pontine reticular formation; riMLF = Rostral interstitial nucleus of the medial longitudinal fasciculus; SC = Superior colliculus; SEF = Supplementary eye field; UV = Uvula; III = Oculomotor nucleus; IV = Trochlear nucleus; VI = Abducens nucleus.

Midbrain Vascular Supply

Although the midbrain is a small anatomic structure, the blood supply is quite complex. An overlap between arterial territories of the basilar artery (BA), posterior cerebral artery (PCA) and superior cerebellar artery (SCA) can occur, and the degree of arterial contribution will depend on the midbrain level. The BA gives off direct perforators supplying the paramedian region (anteromedial territory), that is, short circumferential branches of the SCA that loop around the mesencephalon and feed the caudal two-thirds of the latero-dorsal region.^[31,32] At the upper half of the midbrain, the proximal segment of the PCA branches into the thalamo–subthalamic and mesencephalic arteries. The former irrigate the riMLF, among other subthalamic structures.^[33] Peduncular arteries, directed to the lateral upper midbrain stem, from the postcommunicating-PCA or P2 segment.^[34]

Midbrain Stroke

Midbrain ischemia accounts for anywhere from 3 to 9.5% of all infarcts in the posterior circulation and often coexists with larger infarcts involving other brainstem arterial territories, mostly the neighboring pons and the thalamus.^{[31,32,35,36]} Less often, midbrain ischemia may be exclusively restricted to the midbrain.^[31,32,36] Up to 70% of patients with mesencephalic infarcts, commonly covering the middle and upper thirds, may exhibit a broad variety of neuro-ophthalmologic signs, sometimes in a complex pattern, which are usually observed with additional clinical features reflecting midbrain or brainstem involvement, but can also (less commonly) be isolated clinical findings.^{[31,32,35,36]} Spontaneous hemorrhages rarely occur in the midbrain.^[37-41]

Supranuclear Eye Movement Abnormalities in Midbrain Stroke

Supranuclear (prenuclear) vertical-gaze palsy, occurring in midbrain stroke, may be conjugate or disconjugate. Conjugate prenuclear palsy most commonly affects upgaze and downgaze together, but selective upgaze palsy or, more rarely, selective downgaze palsy may occur. Supranuclear vertical-gaze palsy is often due to ischemia in the most caudal territory of the thalamo–subthalamic artery and, less often, of the anterior choroidal artery, when this artery feeds the midbrain.^[10] Vertical-gaze palsy may be due to midbrain hemorrhages, although this is far from common.^{[11,37,39,41]}

Combined upgaze and downgaze palsy often arises from upper-midbrain bilateral tegmental lesions, involving the riMLF, the INC, the PC or the periaqueductal gray matter due to either occlusion of midbrain–thalamic perforating arteries or because both paramedian arteries stem from one side or from a single pedicle, as occurs in a third of all brains.^{[15,16,42-45]} A similar combined gaze deficit may occasionally result from unilateral lesions damaging the same areas as those produced by bilateral lesions.^{[15,17,33,46,47]} Thus, unilateral lesions may affect the ipsilateral riMLF, as well as the contralateral riMLF fibers after their decussation, owing to damage of excitatory burst neurons of the riMLF.^{[17,33,46,47]} Rapidity of all types of upward or downward eye movements may be affected or these movements may be lost altogether.^[17,47] When a lesion is restricted to the riMLF, both vertical vestibulo–ocular reflex response and smooth-pursuit movements (SPMs) may be spared or impaired in only one direction.^{[15,16,45,48]}

Isolated upgaze palsy results from bilateral or unilateral lesions that involve the riMLF and the PC region and, thus, affect the INC or riMLF efferents traveling to the oculomotor neurons on both sides.^{[11,46,48,49]} Unilateral infarcts may give rise to a functionally bilateral lesion of fibers at the PC level.^[46] Small bilateral periaqueductal gray matter hemorrhages that spare the riMLF and the PC may produce this type of selective gaze palsy, although infrequently.^[50] Although combined upgaze and downgaze palsy and isolated upgaze palsy have more frequently been reported with paramedian thalamic–subthalamic infarcts, purely midbrain infarcts may also produce these conjugate vertical-gaze palsies.^[31]

Selective downgaze palsy requires bilateral infarcts in the territory of the thalamo–subthalamic paramedian artery affecting the mediocaudal region of the riMLF,^{[10,16,46,51-53]} although it may very rarely also be caused by small bilateral hemorrhages in the periaqueductal gray matter.^[54] Other eye movement disorders ^[55-57]observed in midbrain or thalamo–mesencephalic infarcts are summarized in Box 1 .

Disconjugate supranuclear eye movement disorders attributed to midbrain vascular lesions include monocular elevation palsy, crossed paralysis, the vertical one-and-a-half syndrome, skew deviation (SD), see-saw nystagmus (SSN) and V-pattern pseudobobbing.^[10,11,46]

Monocular elevation palsy (MEP; also known as double-elevator palsy) is a combined palsy of the elevator muscles reported in rostral midbrain infarcts. Ipsilateral MEP is due to interruption of efferents just after they leave the riMLF toward the oculomotor nuclear complex and before crossing. MEP can occasionally be accompanied by unilateral internuclear ophthalmoplegia (INO).^[46,58] In contralateral MEP, ischemia affects riMLF fibers after decussating and before they reach the oculomotor nuclear complex.^[46,59] Crossed vertical-gaze paresis is a very peculiar finding attributed to a unilateral mesodiencephalic junction infarct that impaired ipsilateral downgaze (monocular depressor paresis) and contralateral upgaze fibers (monocular elevator paresis) arising from the riMLF.^[60] Moreover, a mild bilateral ptosis was found.^[60]

Nystagmus, which may also occur in midbrain stroke, mainly with lesions located at the mesodiencephalic junction, has a high localizing significance. Convergence-retraction nystagmus, associated with selective upgaze paresis and ipsilateral hypotropia, may, in rare cases, be the outstanding clinical finding as the result of a minute infarct strategically involving the periaqueductal region, the PC and the INC.^[61,62]

See-saw nystagmus is characterized by alternate elevation and depression of one eye accompanied by a similar movement in the other eye (but in the opposite direction). While one eye goes up and intorts, the other goes down and extorts. Although rare, jerk SSN (hemi-SSN) has also been reported with upper brainstem infarcts or hemorrhages, in which case the torsional component of the nystagmus fast phases rotates the upper poles of the eyes toward the side of the lesion.^[63,64]

A central disturbance of otholitic input has been identified as a pathogenic mechanism.^[11,65] A dissociated vertical nystagmus (up- and down-beating) plus INO has been reported in a single patient with a tiny periaqueductal caudal midbrain infarct in the MLF region.^[66] The vertical nystagmus was more prominent on the INO side.^[66] Pendular SSN has been described in patients with unilateral mesodiencephalic infarcts or hemorrhages involving the INC.^[17,65,67] Upbeat nystagmus may be observed after small midbrain ischemia located along the course of the ventral tegmental tract (Figure 2).

Figure 2.

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39-year-old male patient with an upbeat nystagmus and a midline tegmental midbrain infarction. (A) Eye movements are normal in all directions of gaze. (B) Axial, sagittal MRI T2 sequences, sagittal T1 sequences and axial diffusion weighted images show a tegmental caudal midbrain infarction.

In certain rare cases, a vertical impairment sparing a single direction in one eye may occur in bilateral or unilateral thalamo–mesencephalic infarctions.^[68] The so-called vertical one-and-a-half syndrome is characterized by bilateral supranuclear impairment of all fast and slow downward eye movements on one side, combined with monocular paresis of elevation due to bilateral infarction.^[68] The opposite may also occur: vertical upgaze palsy along with monocular depressor paresis on the side of the lesion,^[46,69] or contralateral to the lesion,^[46,69] has been described with thalamo–mesencephalic infarction, best explained by selective upward-gaze fibers at the PC level.^[46] For downward-gaze palsy, a clear explanation has not been provided; nevertheless, an impairment before or after decussation in contralateral or ipsilateral lesions has been postulated.^[46] Coexisting vertical and horizontal one-and-a-half syndromes have rarely been associated with ischemia involving the medial thalamus and the upper midbrain.^[70] INO,^[71-75] skew deviation^[76] and ocular tilt reaction (OTR)^[77,78] can be observed in midbrain infarcts, along with supranuclear gaze abnormalities Box 1 .^[79]

Nuclear or Fascicular Dysfunction of the Oculomotor & Trochlear Nerves in Midbrain Stroke

Oculomotor palsies are a common finding in middle midbrain infarcts; up to 90% of patients with ischemia affecting either the ventral or ventrolateral territories may have nuclear or fascicular third-nerve dysfunction.^[31] These palsies result from occlusion of the small paramedian arteries of the BA when ischemia is the etiology, and may be the best indication of a midbrain stroke or be associated with other clinical signs of brainstem involvement.^{[10,31,36,80,81]} Oculomotor nuclear complex lesions may have a constellation of clinical signs reflecting the particular topographical arrangement of the subnucleus and the selective vascular supply. They essentially present as complete homolateral oculomotor palsy together with contralateral superior rectus palsy (due to decussation of the fibers for superior rectus within the nuclear complex) and partial bilateral ptosis.^[82,83] A nuclear lesion can have other forms of presentation.^[11,84,85]

Fascicular third-nerve lesions may have a form of presentation very similar to that found in peripheral etiologies; in both situations, signs of central neurological dysfunction are usually absent. Involvement may be partial or complete, depending on fascicular arrangement in the ventral midbrain.^[31,86,87] Mostly, intra-axial lesions are attributed to infarcts or, much less commonly, to hemorrhages Box 1.^[85-96] Contralesional hemiparesis, ataxia and involuntary movements along with ipsilesional intra-axial third nerve lesions constitute the different classic eponymous midbrain syndromes Box 1.^[83,97-99]

Nuclear or fascicular trochlear involvement is exceptional for two reasons: first, the dorsal position of the nucleus in the brain stem and, second, the fascicle’s short intra-axial course. A superior oblique palsy contralateral to the lesion and a central Claude Bernard Horner syndrome on the side of the lesion may be characteristic and have a high localizing value.^[11,100] Contralateral fourth-nerve palsy with a homolateral INO due to a small infarct in the caudal midbrain tegmentum has also been reported.^[101]