Increasing Velocity Slow Phases in Acquired Nystagmus

Clinical Correspondence Increasing Velocity Slow Phases in Acquired Nystagmus Tatiana Bakaeva, MD, PhD, Ninad Desai, MBBS, Weiwei Dai, MSEE, John-Ross Rizzo, MD, MSCI, Janet C. Rucker, MD A 29-year-old woman with a history of ovarian cancer 3 years previously reported a 2-year history of oscillopsia and progressive imbalance. Cancer treatment included hysterectomy, bilateral salpingo-oophorectomy, and cisplatin and etoposide chemotherapy. After treatment, she developed chemotherapy-induced peripheral neuropathy with imbalance. She was stable and ambulating with a walker for 1 year, at which time she developed oscillopsia and increased imbalance. Brain MRI was normal and her neurologist initiated plasmapheresis for a presumptive paraneoplastic syndrome. Her condition continued to worsen. Evaluation 2 years later revealed visual acuity of 20/ 40 in the right eye and 20/30 in the left eye. Color vision, pupils, visual fields, and fundi were normal. She had downbeat nystagmus (DBN) in primary gaze that increased in lateral downgaze, decreased in upgaze and with convergence, and was unchanged by head or supine position. Saccades were hypermetric. Smooth pursuit was impaired, especially downward. Strength was 4/5 in distal extremities. Sensation was decreased to all modalities to the knees bilaterally. Reflexes were absent. She was able to stand with a wide-based stance, but unable to walk. Eye movement recordings (magnetic scleral search coil) revealed saccadic hypermetria with occasional hypometria. Saccade amplitude and peak velocity/duration "main sequence" relationships were normal. Smooth pursuit gain was reduced (diagonal target moving sinusoidally at 0.3 Hz; horizontal gain 20.46, vertical gain 20.36). DBN with exponentially increasing velocity slow phases was present (Fig. 1). Departments of Neurology (TB, ND, WD, J-RR, JCR), Rehabilitation Medicine (J-RR) and Ophthalmology (JCR), New York University School of Medicine, New York, New York; and Department of Electrical and Computer Engineering (WD), New York University Tandon School of Engineering, New York, New York. The authors report no conflicts of interest. Address correspondence to Janet C. Rucker, MD, Neuro-Ophthalmology Division, NYU School of Medicine, 240 East 38th Street, 20th Floor, New York, NY 10016; E-mail: [e-mail] Bakaeva et al: J Neuro-Ophthalmol 2018; 38: 479-482 Brain MRI with gadolinium and chest, abdomen, and pelvic computed tomography (CT) were normal. Serum CA-125, anti-Hu, Yo, and Ri antibodies were negative. Cerebrospinal fluid analysis was normal, including cytology, with exception of positive anti-Hu antibodies. Electromyography revealed a generalized sensory neuronopathy. Body fluoro-deoxy-glucose positron emission tomography (FDG-PET) was not tolerated. She was treated with IVIg without benefit. Exploratory laparotomy was refused. Annual chest, abdomen, and pelvic CTs were negative for the next 2 years. She became bed-bound due to truncal instability. FDG-PET with coregistered pelvic CT ultimately revealed 2 enlarged metabolically active lymph nodes (Fig. 2A). CT-guided biopsy revealed small cell carcinoma (Fig. 2B). Pathologic review of her original 13-cm ovarian mass was identical and recurrent small-cell undifferentiated ovarian carcinoma was diagnosed. Our patient's course presented several unusual and diagnostically challenging features. These included: anti-Hu antibody association with ovarian cancer ultimately explained by unusual small-cell ovarian cancer; paraneoplastic antibodies detected only in the cerebrospinal fluid; a 4-year duration between paraneoplastic syndrome onset and recurrent cancer diagnosis; and increasing velocity DBN slow phases. This last finding is the focus of the ensuing discussion. Jerk nystagmus, which may be acquired or congenital, is comprised slow eye drifts (slow phases) from desired gaze position, followed by fast corrective saccades (fast phases). It is the slow phases that represent the pathologic portion of the movement and perpetuate the nystagmus. The velocity profile of slow phases may be linear or exponentially decreasing or increasing. Acquired jerk nystagmus typically has linear or decreasing velocity slow phases, with linear forms arising from asymmetric vestibular tone and decreasing velocity forms arising from dysfunction of gaze-holding neural integration networks. Jerk congenital (i.e., infantile) nystagmus (CN), by contrast, is characterized by specific features that allow for differentiation from acquired nystagmus, including exponentially increasing velocity slow phase 479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Vertical eye movement recording traces of eye vs target position (by convention, an upward deflection represents an upward movement): (A) smooth pursuit demonstrating impaired smooth pursuit gain with superimposed downbeat nystagmus; (B) saccades demonstrating saccadic hypermetria, particularly for upward saccades, with superimposed downbeat nystagmus; and (C) primary gaze demonstrating downbeat nystagmus; (D) magnified fragment from (C) during central fixation demonstrating downbeat nystagmus with an exponentially increasing velocity slow phase waveform. Slow phases are represented by gray bars and fast phases of nystagmus in the nonshaded regions. waveforms, historically thought pathognomonic for CN. The first report of increasing velocity slow phases in acquired nystagmus was in a patient similar to ours, with paraneoplastic cerebellar degeneration and DBN secondary to ovarian cancer (1). Additional cases of increasing velocity DBN slow phases have since been reported in patients with Chiari malformation (2), ankylosing spondylitis with a high cervical bone lesion (3), Wernicke encephalopathy (4) as well as in flocculectomized monkeys (5). Subsequent reports also have documented increasing velocity slow phase waveforms in acquired torsional nystagmus (6-8). Several pathogenetic mechanisms are proposed for DBN, including central vestibular tone asymmetry through vestibulocerebellar connections with semicircular canals (9-11) and otolith organs (12,13) or an imbalance in vertical smooth pursuit tone (14). A novel hypothesis invoking brainstem neural integrator instability was proposed on discovery of increasing velocity slow phase waveforms in some patients. The neural integrators are a network of neurons including the medial vestibular 480 nucleus/nucleus prepositus hypoglossi for horizontal eye movements and the interstitial nucleus of Cajal for vertical eye movements that maintain eccentric eye position. The cerebellar flocculus plays an important role in improving performance of neural integration and steady gaze-holding (15), possibly through a positive feedback loop through which output can be either decreased (leading to "leaky" neural integration and decreasing velocity slow phase nystagmus) or increased (leading to "unstable" neural integration and increasing velocity slow phase nystagmus) (1,11). For DBN with increasing velocity slow phases, increased gain in the upward integrator driving the eyes up is postulated. Computer modeling supports this hypothesis by replication of rapidly shifting slow phase velocity waveforms (alternating between increasing, decreasing, and linear slow phase velocity DBN over short periods) through short-term gain manipulation in the neural integrators and their cerebellar feedback loops (3). Induction of increasing velocity slow phase nystagmus waveforms in monkeys has been demonstrated Bakaeva et al: J Neuro-Ophthalmol 2018; 38: 479-482 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A. Fluoro-deoxy-glucose position emission tomography-computed tomography reveals 2 enlarged metabolically active left inguinal lymph nodes (arrows) in axial (left), sagittal (center), and coronal (right) scans. B. Left inguinal lymph node biopsy: metastatic ovarian small-cell undifferentiated carcinoma (hematoxylin & eosin, ·40; inset, ·100). through chemical lesions in regions of the neural integrators thought to receive cerebellar floccular afferent input (16). An additional feature of interest in our patient was DBN dampening with convergence. CN is also typically lessened with near viewing (17), whereas convergence in acquired vertical jerk nystagmus may decrease or increase nystagmus intensity (18), or reverse its direction (19). A potential mechanism for convergence effects may relate to near target-viewing modulation of vestibular reflexes (20). Alternatively, in vertical nystagmus, convergence may directly influence upward and downward neural integrator balance (i.e., leading either to reduction in upward integrator drive or increased activity in the downward integrator to dampen DBN). In summary, increasing velocity slow phases in jerk nystagmus are not pathognomic for CN, may be underrecognized in acquired nystagmus, and should prompt neurological evaluation when newly developed in adults. Clinical significance and diagnostic specificity of increasing velocity slow phases in acquired nystagmus are presently unclear and quantitative recordings were not critical to our patient's diagnosis. However, detailed study of nystagmus waveforms is essential to advance understanding of physiologic mechanisms and to guide future progress in the treatment of patients with nystagmus. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: T. Bakaeva, N. Desai, W. Dai, and J. Rucker; b. Acquisition of data: W. Dai and J. Rucker; c. Analysis and interpretation of data: W. Dai, J.-R. Rizzo, and J. Rucker; Category 2: a. Drafting the manuscript: T. Bakaeva, N. Desai, W. Dai, and J. Rucker; b. Revising it for intellectual content: J.-R. Rizzo and J. Rucker; Category 3: a. 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