NANOSNET

Very delicious case!!

The pattern you describe, gaze-evoked nystagmus in all cardinal positions with subtle low-frequency downbeat in primary, still reads like a vestibulocerebellopathy to me, most consistent with floccular or parafloccular dysfunction, and possibly nodulus or uvula depending on positional features. It would be helpful to know the rest of the ocular motor and vestibular exam to tease localization, including pursuit quality, saccadic accuracy and rebound, VOR cancellation, head impulse findings, positional testing, fixation dependence, and whether the downbeat increases with head position or eccentric gaze.

RE: etiology, I think about two parallel possibilities. One is unmasking, meaning the vaccine temporally revealed an otherwise inevitable hereditary or sporadic cerebellar process. The other is triggering, meaning the vaccine initiated an immune-mediated cerebellar syndrome that can be antibody-negative on smaller panels and early structural MRI. If you have not already done so, I would ensure an expanded autoimmune cerebellopathy and movement disorders panel is sent, such as the Mayo movement or ataxia panels, since they include newer autoimmune cerebellar targets that may not be captured on standard screens, including septin-related antibodies. Septin-associated syndromes can behave more like degenerative cerebellar disease, so serial volumetric cerebellar imaging can sometimes provide clues even when the first MRI looks normal.

Given his age and phenotype, I also keep germ cell biology on the radar. In a 30 to 31 year old male with a cerebellar ocular motor syndrome, it is worth ensuring we are not missing seminoma or even a regressed germ cell process that can be associated with paraneoplastic antibodies such as KLHL11, even when initial imaging and systemic symptoms are unrevealing.

If conventional MRI stays negative, functional imaging can occasionally be the only window into the physiology. We had a 21 year old male with a similar presentation after a COVID vaccine in 2021. He had oscillopsia and gait impairment with a normal initial MRI brain, and a mildly inflammatory LP early on. PET/CT was the only study that showed focal floccular hypermetabolism. He was treated with steroids and IVIG and his gait and oscillopsia improved, though when I last checked in summer 2025 he still had residual 2 to 3 degrees per second downbeat that was not visually impairing. He uses 4-AP situationally, particularly on sleep-deprived or high-stress days, to maintain crisp vision. Despite extensive serial workup, including whole-exome and mitochondrial testing repeated two years apart, everything remained unrevealing. That experience has made me more willing to consider PET or SPECT when the clinical localization is cerebellar but MRI remains normal.

Lastly, the most common vestibular syndrome I see post COVID infection and post vaccine is vestibular migraine. It can produce slow-phase velocities above the typical symptomatic threshold with variable nystagmus morphologies, both during attacks and between attacks, as reported in PMID: 33938251. Downbeat plus gaze-evoked nystagmus would likely be a forme fruste. I would ask carefully about pre-vaccine migraine history, motion sensitivity, photophobia, phonophobia, episodic dizziness or vertigo, and triggers, recognizing headaches may be absent. If the history fits, a trial of migraine vitamins or a CGRP agent can be reasonable.

On treatment logistics, if you go down the 4-AP or dalfampridine path for downbeat, I generally space dosing about every 4 to 5 hours during awake hours. On day one, I often have the patient send a baseline eye video pre-dose, then short videos every hour with a visual acuity or oscillopsia check with each recording. That helps determine the response curve and when to place the second dose. Also, since many patients do not perceive oscillopsia below about 3 degrees per second  because of compensation and retinal blur thresholds, it is worth confirming the true slow-phase velocity and real-world triggers if he is very symptomatic. A pragmatic alternative or adjunct is gabapentin, which can be milder, cheaper, and may help if a migraine phenotype is present even without prominent headache.