Karen Wong, O.D. and Marissa Koopman, O.D.

Title: Unraveling a case of downbeat and investigating its underlying neurologic etiologies

Abstract Downbeat nystagmus is a neuro-ophthalmic sign that is associated with serious neurologic disorders. The primary care optometrist must be able to identify key characteristics of downbeat nystagmus and be aware of its clinical implications.

I. Case History: • Patient demographic: 53-year-old Caucasian female • Chief complaint: blurry vision in extreme lateral gazes, vertical , difficulty reading, oscillopsia, loss of balance, and impaired memory for the past six months • Ocular history: no significant ocular history • Medical history: history of melanoma, colon , 3-5 years of , mild concussion to the occipital lobe, and newly diagnosed midline cerebellar ataxia • Medications: amlodipine, bupropion, folic acid, hydrocodone, lisinopril, , tramadol, trazodone, and vitamin D3

II. Pertinent findings • Clinical findings: best-corrected visual acuities are 20/25 in each eye; cover test revealed a small left hypertropia and esotropia; extraocular motility exhibited absence of restrictions but a vertical nystagmus with greatest amplitude and frequency in both lateral gazes and in down gaze; her ocular health was unremarkable. • Physical findings: gait instability, patient ambulated with a cane. Laboratory studies: drug abuse panel was positive for ethyl alcohol, hydrocodone, and opiates; elevated thiamine levels (414 mmol/L); presence of anti-retinal auto-antibodies indicating potential for photoreceptor autoimmune damage; cancer screening was clear. • Radiology studies: Magnetic Resonance Angiogram (MRA) results were unremarkable. Magnetic Resonance Imaging (MRI) showed signs of cerebral and cerebellar atrophy.

III. Differential diagnosis: • Nystagmus is an oscillation of the eyes in a specific wave-form, direction, amplitude, and frequency with the potential of a null point.1 • Primary diagnosis: downbeat nystagmus (DBN) due to vertical direction, increased frequency in lateral and down gazes, and conjugacy in wave-form. Etiologies include Wernicke-Korsakoff Syndrome and Paraneoplastic Cerebellar Degeneration.2, 3, • Secondary diagnoses: gaze-evoked nystagmus and infantile nystagmus.4, 5

IV. Diagnosis and discussion: • DBN is the most common type of acquired nystagmus that optometrists can encounter. Its etiology is generally localized to a lesion in the , but its pathophysiology is still not fully understood. However, it is hypothesized that lesions to the flocculus within the cerebellum disinhibits the superior vestibular nucleus causing spontaneous upward ocular drift and compensating downward saccades.6 • Etiologies include: cerebellar infarcts (91%), cerebellar degeneration (73%), developmental anomalies to the and/or cerebellum (73%) (i.e. Arnold Chiari Malformation), (67%), and toxicity to the cerebellum (2%) (i.e. alcohol, opioids, barbiturates). In rare cases, downbeat nystagmus can be attributable to closed-head trauma or paraneoplastic syndromes.1 • DBN elicits vague symptoms of blurry vision, dizziness, loss of balance, and difficulty reading. A careful evaluation of fixation, pursuits, saccades, and the characteristics of the nystagmus in different gazes and upon convergence should be recorded. DBN secondary to cerebellar damage increases in amplitude and frequency in lateral gazes (81%), in down gaze (85%), and when converging (64%). 99% of patients with downbeat nystagmus exhibit saccadic intrusions during pursuits, slowed OKN, and suppression of VOR—all signs of cerebellar damage.1 • Diagnosing the etiology of DBN requires through medical history and assessment of neurological symptoms related to cerebellar damage.1 • Given the patient’s profile, her primary diagnosis is DBN secondary to Wernicke-Korsakoff Syndrome, a condition that results from cerebellar damage due to chronic alcohol intake, which inhibits the body from properly absorbing thiamine (vitamin B1).1 The condition is marked with the classic triad of memory impairment, gait ataxia, and ocular motor disorders.2

V. Treatment, management: • Prismatic spectacle correction for diplopia • Timely neuro-ophthalmology referral for MRI o Potential medical treatment: 10mg of 4-aminopyridine: decreases DBN by reversing the disinhibition of upward ocular drift caused by lesions to the Purkinje cells within the flocculus of the cerebellum.7 • Treatment of Wernicke-Korsakoff Syndrome: alcohol abstentious and high doses of thiamine.8

VI. Conclusion • Presence of DBN prompts detailed case history and ocular motility testing, such as fixation, pursuits, and saccades. • Wernicke-Korsakoff Syndrome is a diagnosis of exclusion; further evaluation is needed. • Potentially life-threatening etiologies of DBN need to be ruled out before considering treatment.

1) Yee RD. Downbeat Nystagmus: Characteristics and Localization of Lesions. Trans Am Ophthalmol Soc 1989;87:984-1032. 2) Jung YC, Chanraud S, Sullivan EV. Neuroimaging of Wernicke's Encephalopathy and Korsakoff's Syndrome. Neuropsychol Rev 2016;2:170-180. 3) Grewal DS, Fishman GA, Jampol LM. Autoimmune Retinopathy and Antiretinal Antibodies: A Review. Retina, The Journal of Retinal and Vitreous Diseases 2014;34:827-845. 4) Rett, D. Gaze-evoked nystagmus: A Case Report and Literature Review. Optometry 2007;78:460- 4. 5) Abel LA. Infantile Nystagmus: Current Concepts in Diagnosis and Management. Clin Exp Optom 2006;89:57-65. 6) Pierrot-Deseilligny C, Milea D. Vertical Nystagmus: Clinical Facts and Hypotheses. Brain 2005;128:1237-46. 7) Kalla R, Spiegel R, Claassen J, et al. Comparison of 10-pm Doses of 4-Aminopyridine and 3,4- Diaminopyridine for the Treatment of Downbeat Nystagmus. J Neuro-Ophthalmol 2001;31:320- 25. 8) Paparrigopoulos T, Tzavellas E, Karaiskos D, et al. Complete Recovery from Undertreated Wernicke-Korsakoff Syndrome Following Aggressive Thiamine Treatment. In Vivo 2010;24:231- 33.