Journal of Neuro-Ophthalmology:
Therapy for Nystagmus
Thurtell, Matthew J MBBS, FRACP; Leigh, R John MD
Department of Neurology, University Hospitals Case Medical Center, Cleveland, Ohio; and Neurology Service and Daroff-Dell'Osso Ocular Motility Laboratory, Veterans Affairs Medical Center, Cleveland, Ohio.
Supported by the National Institutes of Health R01-EY06717, the Office of Research and Development, the Medical Research Service, the Department of Veterans Affairs, and the Evenor Armington Fund.
Address correspondence to Dr. R. John Leigh, MD, Department of Neurology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106-5040; E-mail: email@example.com
Pathological forms of nystagmus and their visual consequences can be treated using pharmacological, optical, and surgical approaches. Acquired periodic alternating nystagmus improves following treatment with baclofen, and downbeat nystagmus may improve following treatment with aminopyridines. Gabapentin and memantine are helpful in reducing acquired pendular nystagmus due to multiple sclerosis. Ocular oscillations in oculopalatal tremor may also improve following treatment with memantine or gabapentin. The infantile nystagmus syndrome (INS) may have only a minor impact on vision if “foveation periods” are well developed, but symptomatic patients may benefit from treatment with gabapentin, memantine, or base-out prisms to induce convergence. Several surgical therapies are also reported to improve INS, but selection of the optimal treatment depends on careful evaluation of visual acuity and nystagmus intensity in various gaze positions. Electro-optical devices are a promising and novel approach for treating the visual consequences of acquired forms of nystagmus.
Rational therapy of nystagmus rests on several basic principles (1). A clear percept of an object requires that its image be held steadily within about 0.5 degrees of the center of the fovea. For objects with higher spatial frequencies, such as Snellen optotypes, retinal image slip should be less than 5 degrees per second.
Patients with infantile nystagmus syndrome (INS), formerly called congenital nystagmus, often have a brief epoch of stillness called the “foveation period” during each cycle of the nystagmus, which is sufficient to provide clear vision (Fig. 1). It appears that they can suppress the visual consequences of rapid image motion at times other than during the foveation period, and therefore seldom complain of oscillopsia (2).
There are 3 gaze-holding mechanisms that promote clear vision. Visual fixation mechanisms reduce eye drifts that take the eyes away from the target and suppress unwanted saccades. The vestibulo-ocular reflex (VOR) generates eye movements to compensate for head perturbations at short latency, being especially important for stabilizing gaze during locomotion. An eccentric gaze-holding mechanism is important to withstand the elastic pull of the orbital fascia that tends to bring the eye back to the center position. Malfunction of each of these gaze-holding mechanisms, as well as other abnormal inputs to the ocular motor system, may cause drifts of the eye away from the target (slow phases) with interspersed corrective quick phases (saccades) that constitute pathological nystagmus.
Based on these principles, one goal of therapy is to abolish abnormal ocular oscillations and leave normal gaze-holding eye movements intact. For example, treatments to stop the eyes from moving altogether, such as botulinum toxin injections, may abolish the ocular oscillations, but provide no net improvement, since patients then complain of blurred vision when they move their head (due to absent VOR) and diplopia (due to absent vergence, which normally aligns the eyes). Treatments that suppress the abnormal ocular oscillations without affecting normal eye movements are therefore preferred. Furthermore, some forms of nystagmus, such as the gaze-evoked nystagmus common with drug intoxications and cerebellar disease (1,3), do not usually cause sufficient visual disturbance to require treatment. It should be noted that inappropriate saccades, including intrusions and oscillations, may also impair vision, but treatments for these are reviewed elsewhere (1,4-6).
We will review, in turn, drug treatments for pathological nystagmus, optical devices that negate the visual consequences of ocular oscillations, and surgical procedures. We will briefly discuss botulinum toxin and alternative methods to treat nystagmus (Table 1). We caution that although many treatments have been proposed for nystagmus, few have been evaluated with controlled clinical trials (7-9).
Nystagmus of Peripheral Vestibular Imbalance
This form of nystagmus usually resolves over the course of a few days. Medications, mainly used to treat associated vertigo, nausea, and vomiting, are helpful only during the acute phase of the illness (1,10). Nystagmus associated with benign paroxysmal positional vertigo is better treated with repositioning procedures, such as the Epley maneuver (11), than with medications.
This type of nystagmus is largely a feature of diseases affecting the vestibulocerebellum. Several hypotheses have been proposed for its pathogenesis, most invoking an up-down asymmetry that affects the inhibition of projections of the vertical semicircular canals, vertical smooth pursuit, or otolithic influences (1). Many medications have been reported to improve downbeat nystagmus, including the GABAA agonist clonazepam (12,13) and the GABAB agonist baclofen (14,15). However, a double-masked comparison of baclofen and gabapentin showed that neither drug produced a consistent improvement and that, in some patients, the nystagmus was made worse (16).
An interest in using anticholinergic agents was generated by the observation that intravenous scopolamine reduces downbeat nystagmus (17). However, a controlled trial of the oral anticholinergic agent trihexyphenidyl produced only modest improvement and side effects that were poorly tolerated (18).
The potassium channel blockers 3,4-diaminopyridine and 4-aminopyridine are promising for the treatment of downbeat nystagmus. Both medications have been shown to suppress downbeat nystagmus in some patients (19-22). Although they are generally well tolerated, they can cause seizures. How do they suppress nystagmus? Because potassium channels are abundant on cerebellar Purkinje cells, the aminopyridines may increase their discharge. The enhanced Purkinje cell activity could then restore normal levels of inhibition of vertical vestibular eye movements, leading to suppression of the nystagmus (22). However, 4-aminopyridine suppresses upbeat nystagmus in some patients (23), and it may occasionally cause downbeat nystagmus to convert to upbeat nystagmus (24). Alternatively, 4-aminopyridine could modulate otolithic mechanisms that influence vertical nystagmus (24). Whatever the mechanism, many patients are likely to benefit from treatment with 4-aminopyridine, which is generally better tolerated than 3,4-diaminopyridine (21,25,26).
This form of nystagmus usually occurs with brainstem lesions. Although it may produce pronounced visual symptoms during the acute period, upbeat nystagmus often resolves spontaneously or converts to downbeat nystagmus. There are few clinical trials evaluating pharmacological treatments for this form of nystagmus, although 1 recent study has shown that it may be suppressed with memantine (8). Treatments similar to those for downbeat nystagmus, such as the aminopyridines (23), are also worth considering in patients with persistent upbeat nystagmus.
Periodic Alternating Nystagmus
This form of nystagmus consists of spontaneous horizontal nystagmus that reverses direction approximately every 100-120 seconds. The acquired form of periodic alternating nystagmus (PAN) is a rare but well understood form of central vestibular nystagmus. A monkey model has been produced following surgical lesions of the cerebellar nodulus and ventral uvula (27). Such lesions may cause excessive vestibular responses (velocity storage), which, in turn, stimulate adaptive mechanisms that cause the ocular oscillations (28). The nystagmus of most patients (and the monkey model) is decreased following treatment with the GABAB agonist baclofen (29-32). Improvement following treatment with memantine has also been reported (33). The infantile form of PAN, which has a more variable cycle length, probably has a different pathogenesis and only occasionally improves with baclofen treatment (34-37).
Acquired Pendular Nystagmus Associated With Multiple Sclerosis
This form of nystagmus usually causes visual impairment and oscillopsia, for which most affected patients seek therapy. These patients often have coexisting internuclear ophthalmoparesis and impaired visual function due to optic neuropathy. Indeed, the amplitude of the nystagmus is often greater in the eye with poorer vision, prompting the hypothesis that delays in visual pathway conduction give rise to the oscillations (38). However, other investigations have suggested that an instability in the gaze-holding mechanism (neural integrator) may be responsible (39-41). Suspicion of neural integrator dysfunction led to the testing of medications with presumed effects on GABA-mediated and glutamate-mediated mechanisms (41,42). In early studies, GABAergic agents, such as clonazepam, valproate, and isoniazid, were found to decrease the nystagmus in some patients (43,44). In a multicenter double-masked study of 15 patients with acquired pendular nystagmus (APN) (16), gabapentin, an anticonvulsant initially thought to have GABAergic action, was compared to baclofen, a GABAB agonist. Visual acuity improved significantly with gabapentin, but not with baclofen. Gabapentin reduced median eye speed in all 3 planes, but baclofen did so only in the vertical plane. In 10 of the 15 patients, the suppression of nystagmus with gabapentin was substantial, and 8 patients chose to continue taking the drug. However, some patients in the study showed no response to either medication. An important side effect of gabapentin was increased ataxia. Three subsequent trials, 1 comparing gabapentin with the anticonvulsant Vigabatrin (45) and the other 2 comparing it with memantine (8,9), have confirmed that gabapentin is an effective treatment for APN. Vigabatrin, which is more purely GABAergic than gabapentin, was ineffective in the first of these trials (45), suggesting that gabapentin suppresses APN by a non-GABAergic mechanism. Gabapentin is now known to exert its effect by binding to the calcium channel subunit α2δ-1 (46).
Memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist that has been used for more than 25 years in Germany as a therapy for a variety of neurological symptoms, including treatment of spasticity in multiple sclerosis (MS), was recently approved by the United States Food and Drug Administration at a dose of 20 mg/d for the treatment of memory failure in Alzheimer disease. At doses of 40 mg/d, memantine has been reported to reduce or abolish APN in patients with MS (8,9,47). Memantine also shows some antagonistic effects at 5-hydroxytryptamine and nicotinic acetylcholine receptors (48). Memantine may reduce nystagmus in some patients in whom gabapentin has proven ineffective (8,9,49). However, at doses of 30 mg/d, patients with MS may develop blurred vision, fatigue, severe headache, increased muscle weakness, or gait instability (50), so that gabapentin may be the preferred treatment when APN is due to MS.
While recent clinical trials have compared the relative efficacy of gabapentin and memantine for APN (8,9), further trials are required to determine if combinations of gabapentin and memantine have an additive effect and to establish whether these drugs may be useful adjuncts to surgical treatments for APN, as suggested in case reports (51,52). The same is true for other medications that have been reported to suppress nystagmus in individual patients with APN, but have not been studied in controlled trials (Table 1).
Previously called oculopalatal myoclonus, oculopalatal tremor (OPT) usually develops in the weeks following brainstem or cerebellar strokes that interrupt projections from the deep cerebellar nuclei. These projections run in the superior cerebellar peduncle, bending (but not synapsing) near the red nucleus, before descending in the central tegmental tract to contact the inferior olivary nuclei (53). In health, inferior olivary neurons, which possess gap junctions (connexins) on their dendrites, discharge asynchronously. Following degenerative hypertrophy of the inferior olives, gap junctions also develop on the cell bodies of olivary neurons (54), producing electrotonic coupling between them. Thereafter, ensembles of inferior olivary neurons begin to fire in synchrony at a frequency of about 2 Hz and serve as “pacemakers” projecting via climbing fibers to the cerebellum, where maladaptive learning takes place (55,56). The entire process results in spontaneous oscillations of the eyes, palate, and other branchial muscles at a frequency of about 2 Hz.
Nystagmus may be the only clinical manifestation of OPT. Some patients show partial suppression of their nystagmus with gabapentin (16) or memantine (Fig. 2) (8). However, neither drug noticeably suppresses the palatal tremor, which is usually asymptomatic. While the nystagmus of OPT can respond dramatically to gabapentin or memantine in occasional patients (8), it is generally more refractory to treatment than is APN secondary to MS.
The hypertrophied inferior olivary nucleus of patients with OPT also shows increased acetylcholinesterase activity (57), prompting trials of anticholinergic agents. Some patients with pendular nystagmus may show a response to trihexyphenidyl (58,59), but a clinical trial of this medication showed only modest effects (18). A discrepancy between the effects of intravenous scopolamine (17) and oral trihexyphenidyl in certain pendular forms of nystagmus might be due to the more selective antagonism of muscarinic receptors by trihexyphenidyl (60). Intravenous scopolamine clouds consciousness and is not a practical therapy for pendular forms of nystagmus. Furthermore, transdermal scopolamine is not a reliable therapy for pendular forms of nystagmus and can make the nystagmus worse or induce confusion (61).
Novel therapies for OPT may target the unusual electrotonic coupling of the inferior olivary neurons by connexins (62-64). These connexins can be inhibited by certain antimalarial agents (65). Other medications reported to aid patients with OPT are listed in Table 1.
Familial Episodic Vertigo and Ataxia Type 2
Nystagmus in this disorder, which is due to a calcium channelopathy, usually responds to acetazolamide (66-68), although associated cerebellar symptoms are occasionally made worse (69). The potassium channel blocker 4-aminopyridine is also an effective treatment for episodic ataxia type 2 in some patients (70). Some patients with spinocerebellar ataxia type 6 who have episodic attacks of vertigo and nystagmus benefit from acetazolamide (71). Studies of animal models for these channelopathies are likely to produce a clearer rationale for therapy (72).
This form of nystagmus may be suppressed by alcohol (73,74) and clonazepam (75). We have observed improvement of hemiseesaw nystagmus in single patients treated with gabapentin or memantine (8).
This ocular motor disorder, which consists of slow-and sometimes symptomatic-vertical oscillations in an eye with visual loss (1), may be improved with gabapentin (76).
Nystagmus of Early Childhood
The nystagmus of some patients with INS has improved with gabapentin or memantine. In a randomized, controlled, double-masked trial comparing the 2 medications, nystagmus intensity and visual acuity improved in both treatment groups (77). However, there was only a small effect in patients with abnormal afferent visual system function or structure compared to those with normal afferent visual systems. INS may also be reduced by smoking cannabis (78,79).
Gene therapy holds the potential for treatment of nystagmus associated with retinal disorders. For example, in an animal model of Leber congenital amaurosis, successful gene therapy restored vision and reduced the associated nystagmus (80-83).
Correction of refractive error is worthwhile in most patients with infantile or acquired forms of nystagmus and may produce an appreciable improvement in vision (84,85). Contact lenses may suppress INS (86), suggesting a mechanism beyond refractive correction (discussed further in the final section of this review). The main therapy for latent nystagmus (fusional maldevelopment nystagmus syndrome) consists of measures to improve vision, such as patching for amblyopia (87).
Patients whose nystagmus is suppressed by convergence may benefit from wearing spectacle prisms that require convergence for single vision of far targets (88). Adequate convergence may be produced by a pair of 7 prism-diopter base-out prisms with −1 diopter spherical power added to compensate for the accommodation that accompanies the induced convergence (89). (The spherical correction may not be required in individuals with presbyopia.) With base-out prisms, some individuals with INS experience an improvement of vision that is sufficient to qualify them for a driving license. Occasional patients with acquired nystagmus may benefit from prisms (90). Those whose nystagmus is worse during near viewing may respond to base-in prisms, which reduce convergence effort (91). Patients with INS whose nystagmus is of lower amplitude when the eyes are placed in an eccentric null position rarely report a benefit from conjugate prisms that shift gaze.
An alternative approach has been to develop optical devices that negate the visual effects of the nystagmus. One approach consists of using high-plus spectacle lenses in combination with high-minus contact lenses (92). The underlying principle is that stabilization of images on the retina can be achieved if the power of the spectacle lens focuses the primary image close to the center of rotation of the eye. However, such images are defocused, requiring a contact lens to extend the focus back onto the retina. Because the contact lens moves with the eye, it does not negate the effect of retinal image stabilization due to the spectacle lens. With such high-positive spectacle lens and high-negative contact lens combinations, it is possible to negate about 90% of the visual effects of eye movements (93). However, this approach impairs all eye movements, including the VOR and vergence, so that it is only useful when the patient is stationary and viewing monocularly. Other disadvantages are that the field of view is limited and patients with ataxia may have difficulty inserting the contact lens. Gas-permeable or even soft contact lenses may, however, achieve lesser degrees of image stabilization that are beneficial to the patient (94,95). Thus, in selected patients, this approach may prove useful for limited periods of time, such as for the duration of a movie.
A more recent approach is to develop an electro-optical device that measures the ocular oscillations and negates their effects (96). This approach is best suited for pendular nystagmus, which can be electronically distinguished from normal eye movements, such as voluntary saccades. Figure 3 summarizes the image-shifting optics that are being used to develop a portable battery-driven device (97,98), a prototype of which is shown in Figure 4.
Surgical procedures for the treatment of nystagmus have mainly been developed for patients with INS. The Anderson-Kestenbaum operation aims to move the attachments of the extraocular muscles, so that the null point is shifted to the straight-ahead gaze position (99,100). Selection of patients who will benefit most entails measuring visual acuity and nystagmus intensity in different gaze positions (101). The surgeon can then calculate what is required surgically to shift the position of the null point (102,103). The Anderson-Kestenbaum procedure not only shifts and broadens the null zone, it decreases nystagmus intensity outside of the null zone, and may improve head posture (104-106).
A second surgical approach, suitable for patients whose nystagmus suppresses with convergence, aims to diverge the eyes, thereby requiring the patient to converge during far viewing (107,108). Some surgeons have reported that combining the Anderson-Kestenbaum operation with a divergence procedure may produce a better visual outcome than either alone (102,107,109).
A third approach involves large recessions (weakening) of the horizontal rectus muscles, which may cause improvement of vision and head posture (110-115). However, experimental procedures to weaken the extraocular muscles induce adaptive changes that restore muscle force (116). Such changes might cause the nystagmus to increase in severity following an initial improvement. Thus, controlled studies are required to evaluate the long-term effects of this recession approach.
An observation of Dell'Osso (117), that some suppression of nystagmus and broadening of the null zone follows almost every surgical procedure for INS, led to the suggestion that simply detaching the muscles, dissecting the perimuscular fascia, and reattaching them (“tenotomy and reattachment”) at the same site on the globe might suppress INS. Experimental studies using a canine model support this hypothesis (118). The operation may have its effects by disrupting extraocular proprioceptive feedback signals (119). Recent work has shown that the brain not only receives proprioceptive inputs from extraocular muscles (120), but appears to use that information at a cortical level (121). Clinical trials have indicated that some patients treated with tenotomy and reattachment show improvement in some measures of visual and ocular motor function following horizontal rectus surgery (122-124), but not all reports agree (125).
Aside from the need to conduct masked trials, other challenges to evaluate the effectiveness of surgical therapies for INS arise from the inherent variability of the nystagmus waveform and the complex relationship between waveform and visual acuity in any 1 individual. Thus, measurements of the duration of the foveation period from eye movement records (126) may appear to improve more with surgery than do conventional measurements of visual acuity, which is highly variable in INS. Carefully selected patients with INS may benefit from surgical treatments that are geared to their individual visual and ocular motor findings: 1) if there is a narrow eccentric null zone, then the Anderson-Kestenbaum operation should be considered; 2) if the nystagmus is greatly reduced with convergence, then a bilateral medial rectus recession procedure often damps the nystagmus; and 3) if neither of these conditions apply, then tenotomy and reattachment may help some patients by broadening the null zone. Patients with INS and associated afferent visual system abnormalities, such as oculocutaneous albinism, are less likely to benefit from surgery (127).
Extraocular muscle surgery has also been tried as a treatment for acquired nystagmus, either alone or in combination with medication therapy, sometimes with success (52,128-131). However, formal clinical trials are needed to determine whether surgery has a role in the treatment of acquired nystagmus.
Botulinum toxin has been injected into the extraocular muscles or retrobulbar space to temporarily reduce or abolish acquired nystagmus (132,133). Although some patients have reported improved vision (134-137), common side effects include ptosis and diplopia, which are usually more troublesome to the patient than were the visual consequences of the nystagmus itself. Less often, botulinum toxin has been used to treat infantile or latent nystagmus (138,139).
Another drawback of botulinum toxin treatment for nystagmus is that it also impairs normal eye movements (140,141). Compromised function of the VOR causes patients to complain of blurred vision or oscillopsia when they walk. In patients who habitually view with their injected (paretic) eye, adaptive changes may take place such that the nystagmus increases in the noninjected eye (135).
Thus, botulinum toxin may abolish nystagmus and improve vision in some patients and may be acceptable to patients who are prepared to view monocularly. However, its limited period of action and side effects limit its therapeutic value.
OTHER TREATMENT APPROACHES
After the observation that wearing contact lenses may suppress INS (86), it was documented that electrical stimulation or vibration over the forehead may suppress the oscillations in some patients (142). Such effects may be exerted via the trigeminal system, which receives afferent (proprioceptive) signals from the extraocular muscles (143). Acupuncture to the neck muscles may suppress INS in some patients, perhaps by a similar mechanism (144,145). Biofeedback has also been reported to help some patients with this condition (146,147), but without sustained effects (148). At present, a definite benefit from any of these treatments is yet to be demonstrated via controlled trials.
As more becomes known about the pharmacology of the ocular motor system, new medications may emerge for the treatment of acquired and infantile forms of nystagmus. Ideally, these drugs should be evaluated in controlled masked trials. Better understanding of the proprioceptive control of eye movements may make it possible to hone surgical treatments, such as tenotomy and reattachment (149), or even develop medication therapies that act at the insertions of the extraocular muscles (119). Since INS appears to be genetically determined in many individuals (150), specific treatment directed toward the abnormal protein or channel may be effective. Gene therapy offers great promise for those individuals with hereditary retinal disorders that are associated with nystagmus (83). In refractory acquired forms of nystagmus, electro-optical devices may negate the visual consequences of the nystagmus if individualized digital filtering of nystagmus waveforms can be achieved and the devices can be miniaturized (97).
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