Downbeat nystagmus (DBN) is a distinctive ocular motor finding most commonly associated with cerebellar or brainstem dysfunction—particularly involving the flocculus, paraflocculus, or vestibulocerebellum. Patients typically report oscillopsia, imbalance, and unsteadiness that worsens with downgaze, head movement, or walking. DBN may present idiopathically, but is often linked to degenerative ataxias (such as spinocerebellar ataxias), structural lesions (e.g., Arnold-Chiari malformation, cerebellar atrophy), or medication-induced causes (e.g., lithium, anticonvulsants). There is no definitive cure, but several pharmacological agents have demonstrated partial symptomatic benefit.
Medications
4-Aminopyridine (4-AP)
4-Aminopyridine, a voltage-gated potassium channel blocker, has emerged as a leading pharmacologic treatment for DBN and cerebellar ataxia. By enhancing cerebellar Purkinje cell excitability, 4-AP may restore inhibitory tone to vestibular pathways and suppress pathological nystagmus. In clinical studies, 4-AP (typically dosed at 5–10 mg TID) significantly reduced the slow-phase velocity of DBN and improved oscillopsia-related disability. Benefits on gait and balance are more modest but occasionally reported. Higher doses (>20 mg/day) increased risk of seizures, so close titration and monitoring are essential. More common side effects include numbness/tingling as well as increased dizziness. A sustained-release formulation (fampridine) is also used off-label, particularly in patients with concurrent multiple sclerosis-related symptoms.
Acetazolamide
Acetazolamide, a carbonic anhydrase inhibitor, is traditionally used in episodic ataxia type 2 (EA2), where it can suppress both ataxia and DBN. The mechanism is believed to involve modulation of neuronal excitability through pH and ion channel shifts in cerebellar neurons. Acetazolamide is typically started at 250 mg BID, with titration up to 500–1000 mg/day in divided doses based on response and tolerability. While effective in genetically confirmed EA2, its utility in idiopathic DBN or other ataxic syndromes is less predictable. Side effects include paresthesias, fatigue, nephrolithiasis, and electrolyte disturbances, especially hypokalemia, which necessitates periodic monitoring of serum electrolytes and renal function. Despite these limitations, acetazolamide remains a first-line agent in EA2-related DBN.
Gabapentin
Gabapentin, an anticonvulsant with calcium channel-modulating properties, has been trialed off-label for DBN and cerebellar ataxia. Although evidence is limited to small series and anecdotal reports, some patients experience reduced oscillopsia and improved gait stability, particularly in cases where symptoms have a sensory or central neuropathic component. It is generally started at 300 mg once daily and titrated to 900–1800 mg/day in divided doses. Gabapentin is generally well tolerated, with dizziness and sedation being the most common side effects. It may be a reasonable adjunct in patients unable to tolerate or respond to potassium channel blockers or acetazolamide.
Baclofen
Baclofen, a GABA-B receptor agonist, has been used occasionally in DBN, particularly when coexisting spasticity, stiffness, or vertical ocular oscillations suggest brainstem involvement. The rationale is based on GABAergic dysfunction within the vestibular and cerebellar circuits. Though evidence is sparse, some patients may benefit from baclofen’s centrally acting muscle-relaxant effects. Doses typically start at 5 mg BID and can be titrated up to 30–60 mg/day, depending on tolerance. Sedation, weakness, and dizziness are common dose-limiting side effects. Baclofen may be particularly helpful in patients with DBN secondary to multiple sclerosis or other demyelinating conditions.
Riluzole
Riluzole, a glutamate modulator approved for the treatment of amyotrophic lateral sclerosis (ALS), has shown potential neuroprotective effects in cerebellar degeneration. A few exploratory studies and case reports have evaluated its use in cerebellar ataxia and DBN, with mixed results. Riluzole is typically dosed at 50 mg twice daily. In small cohorts, it has been associated with a slowed progression of gait ataxia and modest improvements in balance, although its effect on DBN itself appears to be limited. It is generally well tolerated, but liver function tests should be monitored periodically. Given its mechanism and tolerability, riluzole may be considered in progressive degenerative ataxias where other treatments have failed, though its role remains investigational.
Authors: Jake Sossamon, MD, and Kristen Steenerson, MD
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