Downbeat Nystagmus Is Abolished by Alcohol in Nonalcoholic Wernicke Encephalopathy

Abstract

Background and Objectives

Lesions of the cerebellar flocculus cause enduring downbeat nystagmus (DBN) with unrelenting oscillopsia. Unlike most patients with DBN, the flocculus is structurally spared in nonalcoholic Wernicke encephalopathy (nWE) with chronic DBN. The objective was to study the effects of alcohol in nWE.

Methods

We recorded eye movements of a unique patient with nWE under controlled alcohol consumption who said his oscillopsia disappeared with a few drinks of alcohol.

Results

His DBN was markedly diminished by alcohol (by 77.4%), although he remained alert with normal saccades.

Discussion

This striking observation may be caused by the differential effect of alcohol on the perihypoglossal complex and the paramedian tract neurons, which control the level of activity in the flocculus, with opposite (inhibition and excitation, respectively) effects. The finding suggests new ideas about the treatment and pathophysiology of DBN with a structurally intact cerebellum.

PRACTICAL IMPLICATIONS

Oscillopsia due to DBN in nonalcoholic Wernicke encephalopathy can be abolished by alcohol.

Downbeat nystagmus (DBN) is commonly caused by structural lesions of the cerebellar flocculus.^1,2 Thiamine deficiency in Wernicke encephalopathy (WE) frequently causes vertical nystagmus. Early in WE, upbeat nystagmus (UBN) often predominates, but later, it changes to chronic DBN. Importantly, the flocculus is structurally spared in non-alcoholic Wernicke's encephalopathy (nWE) with chronic DBN. Kattah et al. suggested that this transition may reflect different susceptibility and recovery patterns in WE of 2 flocculus-projecting structures: the perihypoglossal complex (PHC, inhibitory) and the medullary paramedian tract neurons (PTNs, excitatory).^3,4 In this study, we describe a unique patient with nWE with initial UBN and later DBN and severely disabling oscillopsia. The patient said his unrelenting oscillopsia disappeared with a few drinks of alcohol. We recorded his eye movements under controlled alcohol consumption as this unusual response suggests new ways to think about the pathophysiology and potential drug therapies for DBN.

Case

The 54-year-old patient developed nWE due to malnutrition after treatment for a squamous cell carcinoma in the neck. He did not drink alcohol regularly nor had any previous neurologic disorders. Because of inflammation of his mouth from radiation therapy, he could not eat, requiring parenteral nutrition. Three months after therapy, he noticed blurred vision, and an examination showed UBN. WE was diagnosed with markedly reduced thiamine levels (9 µg/L; normal range: 24–99 µg/L). Cranial MRI scans obtained 1 week after the patient noticed vertical oscillopsia showed bilateral, symmetric, high-signal intensity alterations on axial fluid attenuated inversion recovery images in paraventricular structures in the medial thalamus, mesencephalon, and medulla compatible with WE. The lesions likely involved the prepositus hypoglossii nuclei and possibly the medial vestibular nuclei underneath the IV ventricle in the paramedian dorsal medulla. These areas anatomically correspond to the region of the PHC and PTNs. The cerebellum was normal.

After thiamine substitution (62 µg/L), he slowly recovered. His oscillopsia decreased over months but eventually intensified again as his nystagmus changed from UBN to DBN. Remarkably, he noticed that his oscillopsia disappeared when drinking alcohol socially.

The patient consented to compare his DBN before and after controlled alcohol consumption. He took no regular medications and was not on any medications during the alcohol test. The study was approved by our ethics committee. His eye movements were recorded using a video-based tracker (EyeLink II) and a laser target projected on a screen 120 cm away before and 30 minutes after drinking 80 mL of 96% ethanol diluted in soda (equaling approximately 1 bottle of wine). The breath alcohol content was 0 before and 0.8‰ after drinking.

Comparing DBN before and with alcohol, Figure 1 shows the strong reduction of DBN (vertical = green) while a small (0.6°/s ± 0.6) horizontal (blue traces) gaze-evoked nystagmus emerged (Videos 1 and 2 ). The effect on the nystagmus in specific eye positions is shown in the box plots of Figure 2 (baseline mean slow-phase velocity reduction: 77.4% ± 21.0, range: 47.5%–100%). With alcohol, DBN averaged over all gaze positions markedly decreased from 13.7°/s ± 5.2 without alcohol to 4.6°/s ± 2.9 with alcohol (T(10) = 8.25, p < 0.001). Note the striking decrease of DBN in gaze straight ahead (center).

Figure 1. Modulation of DBN by Alcohol.

Vertical (green) and horizontal (blue) eye position traces on leftward gaze before (upper row) and after (lower row) alcohol consumption (target = dashed line). Although DBN is markedly reduced by alcohol, it induces a small horizontal gaze-evoked nystagmus. DBN = downbeat nystagmus.

Figure 2. Box Plots of Slow Phase Velocities (°/s) of DBN.

Various vertical (upper left) and horizontal (upper right) gaze positions before (upper row) and after alcohol consumption (lower row); median (red bar) with upper and lower quartiles, whiskers = range to most extreme data points, outliers = “+”. DBN = downbeat nystagmus.

Video 1

DBN before alcohol: DBN on far viewing in gaze straight ahead and lateral gaze (no alcohol).Download Supplementary Video 1 ^{(8.9MB, mp4)} via http://dx.doi.org/10.1212/001138_Video_1

Video 2

DBN reduction by alcohol: DBN on far viewing in gaze straight ahead and lateral gaze bilaterally (with alcohol).Download Supplementary Video 2 ^{(13.3MB, mp4)} via http://dx.doi.org/10.1212/001138_Video_2

Before alcohol consumption, pursuit eye movements were normal (horizontal velocity gain: 0.92; vertical velocity gain: 0.8). The speed of horizontal saccades was normal with a peak velocity for a 15° movement of 366°/s. Vertical saccades were minimally slow with a peak velocity of 255°/s for a 15° movement. With alcohol, horizontal (velocity gain: 0.85) and vertical (velocity gain: 0.47) pursuits were reduced, but saccade velocity did not change (15°; horizontal saccades: 335.6°/s; vertical: 293.3°/s).

The patient was treated with various medications, such as fampridine (2 × 10 mg/d), acetyl-DL-leucine (3 × 1 g/d), zonisamide (300 mg/d), sodium oxybate (4.5 g/d, a structural analog of gamma amino-butyric acid [GABA]), baclofen (3 × 10 mg/d), and clonazepam (2 × 0.5 mg/d), but, in contrast to the striking effect of alcohol, he reported no improvement of blurred vision and oscillopsia.

Discussion

Structural cerebellar lesions of the flocculus often cause DBN.^1,2,5 The upward drift is caused by decreased activity of floccular Purkinje cells⁶ because they normally inhibit brainstem pathways that mediate upward slow phases. UBN in WE often turns into chronic DBN.⁴ A recent hypothesis attributes this transition to remote effects of impaired brainstem structures on the cerebellum and specifically a differential susceptibility and recovery from thiamine deficiency of the PHC and the PTNs in the medulla.^3,4 Because the PHC (inhibitory) and PTNs (excitatory) have functionally opposite effects on the cerebellar flocculus, changes over time in the relative function of both brainstem structures may alter the inhibition from the intact flocculus on the brainstem pathways that mediate upward slow phases of nystagmus. Consequently, less floccular inhibition could lead to an upward slow-phase bias and resulting DBN. Thus, functional and structural lesions² of the flocculus—here, due to deficient activation of the flocculus from an impaired PTN—could produce DBN. Although speculative, this hypothesis suggests that substances such as alcohol or medications may affect the extracerebellar structures that project to the flocculus and so indirectly alter activity in brainstem circuits for vertical gaze holding.

Alcohol has widespread effects on eye movements and elicits horizontal gaze-evoked nystagmus in healthy participants using the same dose.⁷ However, alcohol also diminishes acquired pendular nystagmus⁸ and see-saw nystagmus.⁹ Alcohol acts primarily inhibitory through its actions on GABA, glutamate, acetylcholine, calcium, and potassium channels. Of interest, clonazepam with its GABA-like properties has been shown to reduce DBN in some patients with DBN of noncerebellar origin¹⁰ but not in patients with DBN due to cerebellar degenerations.⁹ Unfortunately, GABA agents (e.g., natriumoxybat) and GABA_A-agonists (e.g., clonazepam) did not ameliorate DBN in our patient. In this study, we propose that alcohol acts on the PHC and PMT that influence activity in an intact flocculus toward restoring balance in vertical gaze holding. This hypothesis distinguishes DBN caused by nWE from the direct damage to the flocculus caused by most cerebellar diseases including chronic alcoholism.

The striking reduction of DBN with alcohol in our patient suggests targeted pharmacologic treatment of DBN in nWE and in other metabolic disorders when a functional lesion of the flocculus is suspected. GABA agents (e.g., natriumoxybat), GABA_A-agonists (e.g., clonazepam), medications that alter t-type low voltage calcium channel activity such as zonisamide, or benign nicotine analogs (because nicotine can produce UBN), at least theoretically, might lessen DBN.¹¹ Agents that influence the circuits that project to the cerebellum might be most effective. Indeed, patients with essential tremor, who may have subtle signs of ocular motor cerebellar dysfunction,¹² respond dramatically to alcohol.

Appendix. Authors

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.