Pendular Seesaw Nystagmus in a Patient With a Giant Pituitary Macroadenoma: Pathophysiology and the Role of the Accessory Optic System

Seesaw nystagmus is characterized by cyclic eye movements with a conjugate torsional component and a dissociated vertical component. In the first half of the cycle, one eye elevates and intorts, whereas the other eye depresses and extorts. The pattern is reversed in the remaining half of the cycle. We describe a patient with a giant pituitary adenoma who developed pendular seesaw nystagmus. Disturbance in the visuovestibular system is postulated to contribute to this form of seesaw nystagmus. Lesions compressing the optic chiasm and the accessory optic system could interrupt the transmission of retinal error signals to the inferior olivary nucleus and the interstitial nucleus of Cajal, thus interfering with the adaptive mechanism of the vestibulo-ocular reflex and leading to pendular seesaw nystagmus.

Clinical Observation Pendular Seesaw Nystagmus in a Patient With a Giant Pituitary Macroadenoma: Pathophysiology and the Role of the Accessory Optic System Peter Yat-Ming Woo, MBBS, MMedSc, FRCS, Saori Takemura, MBChB, Allen Ming-Yan Cheong, BSc, JD, PhD, FAAO, Alberto Chi-Ho Chu, MBBS, FRCS, Yung Chan, MBBS, FRCS, Hoi-Tung Wong, MBChB, FRCS, Kwong-Yau Chan, MBChB, FRCS Abstract: Seesaw nystagmus is characterized by cyclic eye movements with a conjugate torsional component and a dissociated vertical component. In the first half of the cycle, one eye elevates and intorts, whereas the other eye depresses and extorts. The pattern is reversed in the remaining half of the cycle. We describe a patient with a giant pituitary adenoma who developed pendular seesaw nystagmus. Disturbance in the visuovestibular system is postulated to contribute to this form of seesaw nystagmus. Lesions compressing the optic chiasm and the accessory optic system could interrupt the transmission of retinal error signals to the inferior olivary nucleus and the interstitial nucleus of Cajal, thus interfering with the adaptive mechanism of the vestibulo-ocular reflex and leading to pendular seesaw nystagmus. Journal of Neuro-Ophthalmology 2018;38:65-69 doi: 10.1097/WNO.0000000000000575 © 2017 by North American Neuro-Ophthalmology Society S eesaw nystagmus (SSN) is a rare ocular motor phenomenon characterized by the cyclic movement of the eyes with 2 discrete elements, namely a conjunctive torsional and dissociated vertical component. In the first half of the Department of Neurosurgery (PY-MW, ST, AC-HC, YC, H-TW, K-YC), Kwong Wah Hospital, Hong Kong, China; and School of Optometry (AM-YC), The Polytechnic University of Hong Kong, Hong Kong, China. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Peter Yat-Ming Woo, MBBS, MMedSc, FRCS, Room 1101, 11/F, Main Building, Kwong Wah Hospital, 25 Waterloo Road, Yaumatei, Hong Kong, China; E-mail: [e-mail] Yat-Ming Woo et al: J Neuro-Ophthalmol 2018; 38: 65-69 cycle, intorsion and elevation are observed in one eye, whereas extorsion and depression occur in the other. The movement pattern is reversed in the remaining half of the cycle. Nystagmography studies have classified this peculiar sign as exhibiting either a pendular or jerk waveform (1-5). We report a patient with this rare eye movement disorder and discuss a possible pathophysiologic mechanism. CASE REPORT A 55-year-old woman was admitted to the hospital for progressive drowsiness and headache for 1 month. Three months before admission, she experienced oscillopsia and blurring of vision. On admission, the patient was alert with a visual acuity of 20/200 bilaterally, bitemporal hemianopia and band optic atrophy in each eye. The most striking feature was the presence of pendular SSN characterized by elevation with intorsion in one eye and depression with extorsion (counter-clockwise torsion) of the fellow eye in all gaze positions (see Supplemental Digital Content, Video, http://links.lww.com/WNO/A265). The vertical and rotatory oscillations continuously alternated with each eye in the absence of a fast phase. Function of the ocular motor cranial nerves was intact, and there were no signs of vestibular disturbance. Serum levels of thyroid-stimulating hormone, free thyroxine, morning cortisol, and prolactin levels were within normal limits. Brain MRI revealed a giant pituitary tumor (5.8 cm [height] · 5.7 cm 9 [width] · 6.3 cm [length]) (Fig. 1). The lesion extended into the parasellar region and encased the cavernous segment of the right internal carotid artery. Superiorly, the tumor compressed the optic chiasm and the third ventricle causing obstructive 65 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. Postcontrast axial (A), sagittal (B), and coronal (C) T1 MRI shows enhancing sellar mass with suprasellar extension compressing against the optic chiasm superiorly and the ventral midbrain (interpeduncular region) posteriorly. hydrocephalus. Its posterior border also abutted the right mesodiencephalic junction. Craniotomy and near-total excision of the pituitary tumor was performed using an anterior interhemispheric transcallosal approach. The histopathological diagnosis was a nonfunctional pituitary adenoma. The patient's visual acuity did not show significant improvement, and her bitemporal hemianopia and nystagmus persisted 6 months after the procedure. DISCUSSION The term SSN was first coined by Maddox in 1914 when he observed a patient with involuntary seesaw-like eye movements and bitemporal hemianopia (6). Two distinct forms of SSN exist, exhibiting either a jerk or pendular movement waveform. Jerk SSN, also known as hemiSSN, consists of slow torsional phases in one direction (a half-cycle) and quick phases in the opposite direction for the remaining half-cycle. By contrast, pendular SSN describes a slow smooth oscillating ocular rolling movement in the absence of a fast phase (7). Ascertaining the pattern of SSN may indicate the location of the lesion and offers insights into the complex interaction of the mechanisms involved in gaze stability. Pendular SSN is typically observed in patients with tumors of the parasellar region with compression of the optic chiasm (1,8). Other etiologies include chiasmal trauma, congenital achiasma, and methotrexate-induced visual pathway demyelination (4,9-12). The classic pattern of chiasmal visual field loss, bitemporal hemianopia, is frequently associated with this form of nystagmus (5,13). Although the pathogenesis of pendular SSN remains elusive, Nakada and Kwee (5) theorized that dysfunction of the visuovestibular mechanisms that control eye movement may play a pivotal role. Physiologically, the vestibulo-ocular reflex (VOR) is elicited when the head rotates around a cardinal axis (pitch, yaw, or roll) with the purpose of stabilizing 66 images on the retina. Vestibular detection of a change in the head position generates simultaneous stimulatory and inhibitory signals to the extraocular muscles to induce reciprocal ocular counter-rotation about the same axis. Although triggering the reflex does not require visual input, subcortical visuovestibular adaptive mechanisms are believed to exist to minimize an overshoot of ocular counter-rotation activity (5,14,15). One such subcortical mechanism involves the accessory optic system (AOS) that detects optokinetic stimuli through direction-selective retinal ganglion cells (15-17). This allows the AOS, which does not serve formed vision, to sense frameshift changes which can lead to corrective eye movements after signal processing through the cerebellum. During head movement, retinal error ("retinal slip") signals are conveyed through the AOS to the inferior olivary nucleus (ION) which projects climbing fibers to the floccular Purkinje cells of the cerebellum (Fig. 2) (5,14,15). Purkinje cells have been shown to transmit inhibitory signals to the vestibular nuclei and are critical in mediating the VOR adaptive properties of the AOS (5,15,18). Nakada et al (5) proposed that interruption of retinal error signals could lead to a disinhibited VOR, independent of head movement, and may be the underlying mechanism for pendular SSN. The torsional component of the nystagmus was hypothesized to be due to an absence of visual information from the temporal visual fields due to chiasm compression with subsequent disruption of eye movement calibrations in the roll plane (5). But given the rarity of pendular SSN in patients with bitemporal hemianopia secondary to pituitary tumors, other pathogenic mechanisms need to be considered. We propose a complementary hypothesis for pendular SSN that requires the additional interruption of internuclear signals of the AOS and preservation of the interstitial nucleus of Cajal (INC) with its efferent projections (Fig. 3). To elucidate the pathophysiology of the dissociated vertical oscillations (in the pitch plane) that are the hallmark Yat-Ming Woo et al: J Neuro-Ophthalmol 2018; 38: 65-69 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 2. Proposed pathways involved in the pathophysiology of pendular seesaw nystagmus. Double-hit hypothesis (compromise of the visuovestibular adaptive mechanism for the VOR): First hit: compression of the chiasm (CHM) causes loss of bilateral temporal visual fields and retinal error miscalibration of the VOR leading to nystagmus in the roll plane. Second hit: compression of the medial terminal nucleus (MTN) causes interruption of retinal error signals in the pitch plane: a) interruption of inhibitory afferent gamma-aminobutyric acidergic neurons to the interstitial nucleus of Cajal (INC) with subsequent vertical (pitch plane) and torsional (roll plane) nystagmus as exhibited in previous INC stimulation studies; and b) disinhibition of the VOR due to decreased cerebellar Purkinje fiber inhibitory signaling to the vestibular nuclei. ION, inferior olivary nucleus; VOR, vestibulo-ocular reflex; III, third nerve nucleus, IV, fourth nerve nucleus; VI, sixth nerve nucleus. Adapted from (16). of pendular SSN, further understanding of AOS anatomy is required (14,17,19). Three paired AOS terminal midbrain nuclei receive visual signals from the contralateral retina through fibers of the accessory optic tract that are then relayed to the ipsilateral ION (14-16,19). Rabbit electrical microstimulation studies have revealed that each pair of AOS terminal nuclei processes visual information regarding one of 3 cardinal rotational axes (14). In particular, the medial terminal nucleus (MTN) processes retinal error signals in the pitch plane (14,15). The MTN is anatomically located in the ventral midbrain, bordered laterally by the cerebral peduncle and in close proximity to the interpeduncular cistern (19). Of the 3 terminal nuclei of the AOS, the MTN is the most vulnerable to anterior compression (Figs. 1, 2). Compression of the MTN could result in a lack of transmission of retinal frameshift error signals in the pitch plane leading to vertical nystagmus. The sparing of the more posteriorly located dorsal and lateral terminal nuclei at the pretectal region may explain why pendular SSN lacks a horizontal movement component. The INC, located at the dorsomedial midbrain tegmentum, is an important constituent of the "eye movement neural integrator," a distributed network of neurons that combines ocular velocity signals and encodes them into position commands (18). The INC is believed to be responsible for generating vertical and torsional eye position signals and has extensive afferent and efferent pathways to the Yat-Ming Woo et al: J Neuro-Ophthalmol 2018; 38: 65-69 vestibular nuclei that are conveyed through the medial longitudinal fasciculus (7,18,20). Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the central nervous system, and GABAergic neurons were discovered to be predominantly active in governing AOS internuclear signaling relative to excitatory stimulation (15). Injury to the MTN could lead to disinhibition of the INC, and several reports have emphasized the importance of its preservation for pendular SSN to develop (4,5,7,21). Stereotactic lesioning of the INC in a patient was observed to abolish pendular SSN while electric stimulation evoked its exacerbation (7). Our hypothesis is supported by our patient's MRI findings that demonstrated sparing of the posteriorly located INC, with tumor compression of the optic chiasm and the anterior interpeduncular region of the midbrain. Although an explanation for the 180° out-of-phase dissociated vertical eye movement observed in pendular SSN is lacking, a phylogenetic theory was proposed. Dysfunction of the AOS with subsequent disinhibition of the INC could represent an unmasking of an atavistic VOR pathway mediating vertical eye movement observed in lateral-eyed animals (17). Lateral-eyed animals (in contrast to frontal in humans) normally have dissociated binocular vision, that is, when the head is tilted in the roll plane, one eye is turned superiorly and the other eye is displaced inferiorly with corresponding torsional movement to keep the eyes aligned 67 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 3. Anatomical location of the AOS terminal nuclei in the midbrain at the level of the superior colliculus. The MTN is part of the AOS located at the ventral midbrain. A large suprasellar tumor (e.g., a giant pituitary macroadenoma, dotted circle) may cause selective compression of the MTN sparing more dorsally located nuclei, such as the INC, LTN, and DTN. The MTN conveys vertical plane retinal error signals, and interruption of this pathway may cause miscalibration of the vestibulo-ocular reflex in this plane. AOS, accessory optic system; CN III, third nerve nucleus; INC, interstitial nucleus of Cajal; LTN; lateral terminal nucleus; MGB, medial geniculate body; mLF; medial longitudinal fasciculus; MTN, medial terminal nucleus; NOT-DTN, nucleus of the optic tract-dorsal terminal nucleus. Adapted from (16). along the horizon (17,22). The emergence of pendular SSN could reflect a regression to an older optokinetic system of our evolutionary predecessors and corroborates current understanding of the neurologic mechanism for infantile nystagmus (17). By contrast, jerk SSN typically occurs in patients with focal intrinsic lesions of the midbrain involving the INC or its afferent central graviceptive semicircular canal and/or otolithic projections from the vestibular nuclei (2). One widely accepted theory is that this results in an imbalance in vestibular input from the superior semicircular canals on both sides (3,23,24). Reported causes of jerk SSN include infarction, cavernoma, hypothalamic hamartoma, and multiple sclerosis of the INC or along its afferent pathways in the medial longitudinal fasciculus or medulla (3,25-28). Unlike pendular SSN, visual impairment is often absent in these patients and vestibular symptoms are more pronounced. Because the INC also has efferent projections to the cervical spinal cord, lesions may also cause a contraversive ocular tilt reaction, a type of postural synkinesis comprising of a head tilt to the contralateral side, ipsilateral hypertropia, and ocular counter-rolling (3,23,28,29). In summary, both forms of SSN are related to the impairment of vestibular responses initiated to maintain gaze stability during head rotation. Pendular SSN is associated with miscalibration of retinal error signals (due to a compromise of visuovestibular adaptive mechanisms), and jerk SSN results from an imbalance of afferent vestibular signals to the INC (2). Their clinical presentations and underlying TABLE 1. The two forms of SSN Pendular SSN Visual impairment Yes Characteristics of nystagmus SSN (torsion speed similar in each half-cycle) Associated localizing signs Bitemporal hemianopia (chiasm) Common etiology Parasellar tumors Side of lesion Midline Jerky SSN No Hemi-SSN (fast and slow phases for each half-cycle) Ocular tilt reaction (INC), INO (mLF), and vestibular signs Infarct Unilateral (quick phase ipsilateral to lesion) INC, interstitial nucleus of Cajal; INO, internuclear ophthalmoplegia; mLF, medial longitudinal fasciculus; SSN, seesaw nystagmus. 68 Yat-Ming Woo et al: J Neuro-Ophthalmol 2018; 38: 65-69 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation causes are distinct (Table 1). Our case report supports a double-hit hypothesis for pendular SSN involving a suprasellar lesion compressing the optic chiasm leading to bitemporal hemianopia as well as the MTN leading to a disinhibited VOR. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: Peter YM Woo, Saori Takemura, and Allen MY Cheong; b. Acquisition of data: Alberto Chu, Yung Chan, Hoi-Tung Wong, and Kwong-Yau Chan; and c. Analysis and interpretation of data: Peter YM Woo, Saori Takemura, and Allen MY Cheong. Category 2: a. Drafting the manuscript: Peter YM Woo, Saori Takemura, and Allen MY Cheong and b. Revising the manuscript for intellectual content: Peter YM Woo, Saori Takemura, and Allen MY Cheong. Category 3: a. Final approval of the completed manuscript: Peter YM Woo, Saori Takemura, Allen MY Cheong, and Kwong-Yau Chan. REFERENCES 1. Moura FC, Goncalves AC, Monteiro ML. Seesaw nystagmus caused by giant pituitary adenoma: case report. Arq Neuropsiquiatr. 2006;64:139-141. 2. 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