Introduction

Nystagmus is often encountered in ophthalmology practice, having a prevalence of about 24 per 10,000 in the general population.[1] Unlike physiologic nystagmus, where the slow phases of nystagmus minimize retinal image slip, the slow phases of pathologic nystagmus cause retinal image slip. Retinal image slip of greater than 5 degrees per second produces a decline in visual acuity, partly because the image of the object of interest no longer lies on the fovea, and illusory motion of the visual environment known as oscillopsia.[2,3] Saccadic intrusions and oscillations can also cause visual symptoms, such as difficulty reading, since they take the eye off target so that the image of the object of interest no longer lies on the fovea.[2]

Goals of Treatment

The goal of treatment is to reduce visual symptoms (e.g., blurred vision, oscillopsia) by reducing the speed of nystagmus slow phases or by suppressing saccadic oscillations. Treatments that stop the eyes from moving altogether (e.g., botulinum toxin injections into the extraocular muscles) are not ideal, because they cause oscillopsia during head movements (due to loss of the vestibulo-ocular reflex) and diplopia (due to loss of vergence eye movements).[2] Thus, treatments that suppress the abnormal eye movements without affecting normal eye movements are preferred. Note that some types of nystagmus (e.g., gaze-evoked) and saccadic intrusions (e.g., square-wave jerks) do not usually give visual symptoms and, thus, do not require specific treatment.

General Approaches to Treatment

Treatments for nystagmus that have been proposed include medical, optical, surgical, and other miscellaneous treatments (Table 1); few of these have been evaluated in prospective masked clinical trials.[2,4] Likewise, a variety of treatments for saccadic oscillations have been proposed; few have been evaluated in prospective masked clinical trials.[2] Most treatments aim to suppress the abnormal eye movements without affecting normal eye movements, whereas others aim to negate the visual consequences of the abnormal eye movements. Choice of treatment depends on the type of nystagmus or saccadic oscillation and its characteristics. While some patients will derive benefit from one treatment approach, others require a combination of treatments.[2,4]

Treatment of Acquired Forms of Nystagmus

Medical treatments are usually the most effective for treating acquired forms of nystagmus. Optical, surgical, and other treatments can also be helpful. The dosing and common side-effects of medical treatments for acquired forms of nystagmus are summarized in Table 2.[5]

Peripheral Vestibular Nystagmus

Nystagmus can result from peripheral vestibular diseases, such as vestibular neuritis, Ménière’s disease, and benign paroxysmal positional vertigo. In most cases, the nystagmus is short-lived or intermittent. The associated vertigo, nausea, and vomiting are often more distressing to the patient than are the visual symptoms from the nystagmus. Consequently, the patient is best managed with treatments directed towards the underlying disorder.[6]

Peripheral Vestibular Nystagmus

Downbeat Nystagmus

Downbeat nystagmus is common and often causes disabling visual symptoms (e.g., vertical oscillopsia). Many affected patients seek treatment. Clonazepam, a GABAA-agonist, has been shown to improve downbeat nystagmus in two uncontrolled trials.[7,8] Baclofen, a GABAB-agonist, was thought to suppress downbeat nystagmus,[9,10] but did not produce a consistent benefit in a double-masked trial.[11] Gabapentin, now thought to act as an α2δ-1 calcium channel antagonist[12] and N-methyl-D-aspartate (NMDA) receptor antagonist,[13] did not consistently improve downbeat nystagmus in the same trial.[11] Anticholinergics have been suggested as a potential treatment.[14] However, a prospective double-masked trial showed that trihexyphenidyl produced only a modest improvement with significant side-effects.[15]

Recent trials have demonstrated that the aminopyridine potassium channel blockers are effective for downbeat nystagmus. 3,4-diaminopyridine and 4-aminopyridine have been shown to suppress downbeat nystagmus, although they are more effective in patients with cerebellar degenerations and less effective in those with focal cerebellar lesions.[16,17] 4-aminopyridine appears to be more effective than 3,4-diaminopyridine.[18] Both drugs are well tolerated, although they can cause seizures (usually in patients with a predisposition to epilepsy who are given high dosages) and cardiac arrhythmias in patients with QT interval prolongation. The mechanism by which they suppress downbeat nystagmus is unclear, although they might work by altering the firing of cerebellar Purkinje cells.[19] 3,4-diaminopyridine has been shown to modulate the gravity-dependence of downbeat nystagmus and, thus, might suppress the nystagmus by modulating otolithic pathways.[20] An extended-release formulation of 4-aminopyridine is available in the US and is approved for the treatment of gait difficulties in multiple sclerosis (MS) patients.[21] At present, the aminopyridines are first-line treatment for downbeat nystagmus (see Table 2 for recommended dosing). In those who do not respond, a trial of clonazepam could be considered (Table 2). Surgery (e.g., tenotomy and reattachment) can be considered for treating severe intractable oscillopsia in patients with downbeat nystagmus, either alone or in combination with medical therapy,[22] but clinical trials are yet to be performed.

Downbeat Nystagmus

Upbeat Nystagmus

Upbeat nystagmus can produce vertical oscillopsia, but the nystagmus resolves spontaneously; long-term treatment is only required if it is persistent. There have been very few clinical trials evaluating proposed treatments. One uncontrolled trial reported a benefit with baclofen.[9] A prospective double-masked cross-over trial reported reduction of upbeat nystagmus or upbeat components of nystagmus with memantine, a non-competitive NMDA receptor antagonist, but not with gabapentin.[23] In another study, 4-aminopyridine suppressed upbeat nystagmus in one patient.[24] A trial of memantine, 4-aminopyridine, or baclofen could be considered in patients with visual symptoms from persistent upbeat nystagmus (see Table 2 for recommended dosing).

Upbeat Nystagmus

Torsional Nystagmus

Torsional nystagmus can cause disabling oscillopsia. However, there have been very few clinical trials evaluating proposed treatments. A double-masked cross-over trial reported a modest reduction with gabapentin, but little response to memantine, in a single patient.[23] While further studies are required to identify medications that suppress torsional nystagmus, a trial of gabapentin could be considered in patients with visual symptoms from persistent torsional nystagmus (see Table 2 for recommended dosing).

Torsional Nystagmus

Seesaw Nystagmus

Acquired seesaw nystagmus is rarely encountered, but can give rise to disabling oscillopsia. Several small studies have suggested that pendular seesaw nystagmus can be suppressed by alcohol or clonazepam in individual patients.[25-27] A double-masked cross-over trial reported that the jerk form (hemi-seesaw nystagmus) can be suppressed with gabapentin or memantine.[23] Treatment with clonazepam, gabapentin, or memantine could be considered in patients with visual symptoms from persistent seesaw nystagmus (see Table 2 for recommended dosing).

Seesaw Nystagmus | alternative Seesaw Nystagmus

Periodic Alternating Nystagmus

Patients with acquired periodic alternating nystagmus often complain of oscillopsia. Several non-randomized and non-controlled studies have reported complete suppression of the nystagmus with baclofen.[28-30] The efficacy of baclofen in treating periodic alternating nystagmus has been confirmed in primates.[31] A benefit from memantine has been reported in a patient whose nystagmus was refractory to baclofen.[32] At present, baclofen is considered first-line treatment for acquired periodic alternating nystagmus, while memantine could be tried in those patients who do not respond to baclofen (see Table 2 for recommended dosing).

Periodic Alternating Nystagmus

Acquired Pendular Nystagmus in Multiple Sclerosis

Acquired pendular nystagmus (APN) can occur in patients with multiple sclerosis (MS) and causes disabling visual symptoms. The hypothesis that it arises due to instability of the ocular motor neural integrator led to testing of drugs thought to have effects on GABA- and glutamate-mediated mechanisms. GABAergic drugs (e.g., clonazepam, valproate, and isoniazid) were found to help some patients in early studies.[33,34] The effects of gabapentin, which was initially thought to have GABAergic effects, were compared with those of baclofen in a double-masked study including patients with APN.[11] Visual acuity improved with gabapentin, but not baclofen, and only gabapentin reduced median nystagmus slow phase speed. However, some patients had no response to gabapentin or reported severe side-effects (e.g., ataxia). Gabapentin was subsequently compared with vigabatrin, which is known to be purely GABAergic.[35] Gabapentin suppressed APN, but vigabatrin did not, suggesting that gabapentin might suppress APN by a non-GABAergic mechanism; gabapentin is now thought to exert its effect via the α2δ-1 calcium channel subunit[12] and NMDA receptors.[13] Two recent prospective masked trials have confirmed that gabapentin is often effective in suppressing APN in MS, but not all patients respond.[23,36]

Several prospective masked trials have demonstrated that memantine can suppress APN in patients with MS when given in doses of 40-60mg per day.[23,36,37] It can reduce APN in those patients who do not respond to gabapentin.[23,37] However, patients with MS can develop a reversible exacerbation of MS symptoms when receiving 30mg or more of memantine per day[38] and, thus, gabapentin may be the preferred initial treatment for APN in MS (see Table 2 for recommended dosing). There is a potential role for combining drug therapies (e.g., gabapentin and memantine), but no clinical trials have been conducted to date. Surgery (e.g., tenotomy and reattachment) might also be effective in suppressing APN in patients with severe intractable oscillopsia,[22] but should not be routinely recommended as clinical trials are yet to be performed.

Acquired Pendular Nystagmus in Multiple Sclerosis

Acquired Pendular Nystagmus in Oculopalatal Tremor

The nystagmus of oculopalatal tremor (OPT) often causes severe intractable oscillopsia. Several studies have evaluated the effect of anticholinergic agents on the nystagmus of OPT. Although individual patients can respond to trihexyphenidyl,[39,40] it was only modestly effective in a prospective masked trial.[15] A prospective double-masked trial comparing intravenously-administered scopolamine, benztropine, and glycopyrrolate found that scopolamine reduced the nystagmus of OPT, whereas benztropine was less effective, and glycopyrrolate had no effect.[14] However, treatment with intravenous scopolamine resulted in significant side-effects and is not practical for day-to-day treatment. Transdermal scopolamine was also found to be unreliable, given that it can make the nystagmus worse in some patients or cause significant side-effects.[41] Two prospective double-masked cross-over trials have demonstrated that gabapentin and memantine can suppress the nystagmus of OPT.[11,23] Although the nystagmus of OPT is often more refractory to treatment with gabapentin and memantine than is APN due to MS, a trial of therapy is worthwhile (see Table 2 for recommended dosing). There is a potential role for combined drug therapies (e.g., gabapentin and memantine) or surgical therapy (e.g., tenotomy and reattachment), but these treatment approaches have not been evaluated in clinical trials.

Tretament of Congenital Forms of Nystagmus

Treatment for congenital forms of nystagmus depends on the severity of visual symptoms, severity of any associated afferent visual system anomalies, and the characteristics of the nystagmus itself.[2,4] Some patients do not have visual symptoms, especially if “foveation periods” are well developed, and most do not complain of oscillopsia.[42] Those with impaired vision might have so due to afferent visual system anomalies (e.g., optic nerve or foveal hypoplasia),[2] such that suppression of the nystagmus does not produce a significant improvement in vision. However, patients with visual symptoms with intact afferent visual systems can benefit from treatments that suppress the nystagmus.[2,4]

Infantile Nystagmus Syndrome

Infantile nystagmus can be treated using optical, surgical, and medical approaches.[2,4] Optical treatments are simple, safe, and may be all that is required to improve vision. Correction of refractive error alone might bring about an appreciable improvement in vision.[43,44] Use of contact lenses might be preferred over spectacle lenses, because contact lenses often suppress infantile nystagmus by an uncertain mechanism.[45] Spectacle lenses are preferred in patients whose nystagmus suppresses with convergence, because prism can be added to induce convergence, and thereby suppress the nystagmus and improve visual acuity, during viewing of far targets.[46] Sufficient convergence can be produced by a pair of 7 diopter base-out prisms with -1 diopter sphere added to compensate for the accompanying accommodation.

Several surgical procedures can be considered for treatment of infantile nystagmus. The Anderson-Kestenbaum procedure aims to move the attachments of the extraocular muscles, so that the null point of the nystagmus is shifted to the straight ahead position.[47,48] The Anderson-Kestenbaum procedure also leads to decreased nystagmus intensity outside of the null zone and may improve head posture.[49-51] However, selection of patients who will benefit requires measurement of visual acuity and nystagmus in different gaze positions. Cüppers’ divergence procedure can be effective in patients whose nystagmus suppresses with convergence; the procedure diverges the eyes, so that the patient is required to converge during far viewing.[52,53] In some patients, combining the Anderson-Kestenbaum and Cüppers’ divergence procedures can produce a better outcome than either procedure alone.[53] Another surgical approach involves large recessions of the horizontal rectus muscles,[54-58] sometimes in combination with other procedures,[59] to produce suppression of the nystagmus. However, the nystagmus can increase following an initial improvement, due to adaptive changes. It has been observed that some suppression of the nystagmus and broadening of the null zone follows almost all surgical procedures for infantile nystagmus, which led to the suggestion that merely detaching the muscles, dissecting the perimuscular fascia, and re-attaching them at the same site (“tenotomy and reattachment”) might suppress the nystagmus.[60] Studies in a canine model support this hypothesis.[61] Clinical trials indicate that some patients treated with tenotomy and reattachment show improvement in some measures of visual and ocular motor function following horizontal rectus surgery,[62-64] but not all reports agree.[65] Since the operation may have its effects by disrupting extraocular proprioceptive feedback signals, variations on the original procedure have been proposed.[66] Carefully selected patients with infantile nystagmus can benefit from surgical treatments that are tailored to their individual visual and ocular motor findings: (1) if there is a narrow eccentric null zone, then the Anderson-Kestenbaum procedure could be considered; (2) if the nystagmus is reduced with convergence, then Cüppers’ divergence procedure could be considered; and (3) if neither of these conditions apply, then tenotomy and reattachment could be considered. Patients with infantile nystagmus and afferent visual system anomalies (e.g., oculo-cutaneous albinism) are less likely to benefit from surgical intervention.[67]

Medical treatments of infantile nystagmus are less favorable, since they would need to be given life-long and can cause side-effects. A randomized, controlled, double-masked trial comparing gabapentin and memantine found that the nystagmus intensity and visual acuity improved in both treatment groups.[68] However, patients with afferent visual system anomalies derived only a small benefit. Recent studies have reported that infantile nystagmus might be suppressed with carbonic anhydrase inhibitors, including oral acetazolamide and topical brinzolamide.[69,70] Infantile nystagmus can also be reduced after smoking cannabis.[71] Lastly, gene therapy holds the potential for treatment of nystagmus associated with congenital retinal disorders. For example, in an animal model of Leber’s congenital amaurosis, successful gene therapy restored vision and reduced the associated nystagmus.[72-75]

Other Congenital Forms of Nystagmus

The treatment options for other congenital forms of nystagmus are limited. Treatment for latent nystagmus (fusional maldevelopment nystagmus syndrome) consists of measures to improve vision, such as correction of refractive error and treatment of amblyopia.[2,4] Spasmus nutans syndrome typically resolves spontaneously and does not require specific intervention.[2,4]

Treatment of Intractable Nystagmus

There are several treatment options for patients who do not respond to the approaches listed above. Optical devices that negate the visual effects of the nystagmus can be tried. One such approach consists of using high-plus spectacle lenses in combination with high-minus contact lenses.[2,4,76] While the visual effects of the nystagmus can be effectively negated using this approach, it is only useful when the patient is stationary and viewing monocularly, since the visual effects of normal eye movements are also negated.[77] Another approach involves use of an electro-optical device, which measures the ocular oscillations and incorporates image-shifting optics to negate, in real-time, their visual effects.[78] Electro-optical devices are best suited for patients with pendular forms of nystagmus, since the abnormal eye movements can be more easily distinguished from normal eye movements, but these devices remain experimental and are not yet commercially available. Treatments to stop the eyes from moving altogether, such as botulinum toxin injections into the extraocular muscles, can also be considered in patients with intractable nystagmus. While the injections can lead to reduced oscillopsia and improved visual acuity, patients often develop diplopia and ptosis.[79-84] Furthermore, normal eye movements are impaired and the treatment is only effective for several weeks to months, making botulinum toxin injections limited in therapeutic value.[2,4]

Treatment of Saccadic Oscillations

The treatment of saccadic oscillations depends on whether the patient has visual symptoms from the oscillations. Some forms of saccadic oscillation, such as square-wave jerks, do not cause visual symptoms and, thus, do not require specific treatment.[2] For saccadic oscillations that cause visual symptoms, medical treatments are most effective.[2]

Macrosaccadic Oscillations

Macrosaccadic oscillations often result in difficulty with reading, but there are few clinical trials investigating proposed treatments. Memantine reduced the frequency of the oscillations and improved reading ability in one family with macrosaccadic oscillations due to cerebellar ataxia and, thus, could be considered in patients with symptomatic macrosaccadic oscillations.[85]

Ocular Flutter and Opsoclonu

Ocular flutter and opsoclonus can produce oscillopsia. When due to brainstem encephalitis, treatment with intravenous immunoglobulin (IVIg), corticosteroids, azathioprine, or monoclonal antibodies directed against B-lymphocytes can speed recovery.[86-88] In adults with paraneoplastic opsoclonus, treatment of the underlying tumor can produce an improvement in the oscillations.[87] Plasmapheresis, IVIg, and immunoadsorption therapy can also be effective.[89-91] Opsoclonus in children with neural crest tumors often responds to corticosteroids[92] and sometimes to IVIg.[93] New therapies with monoclonal antibodies directed against B-lymphocytes may be effective.[88] Occasional patients gain a benefit from medications, such as gabapentin,[94] but formal clinical trials have not been conducted.

Ocular Flutter

Opsoclonus