The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C) are defined at the end of the "Major Recommendations" field.
All treatment recommendations available in the literature are classified as Class C only.
Supranuclear Ocular Motor Disorders
Central Vestibular Disorders
Downbeat Nystagmus
No studies on the natural course of downbeat nystagmus are available. In non-placebo-controlled studies with a limited number of patients, administration of the gamma-aminobutyric acid-A (GABA-A) agonist clonazepam (0.5 mg orally [p.o.] three times daily), the GABA-B agonist baclofen (10 mg p.o. three times daily), and gabapentin (probably calcium channel blocker) had positive effects and reduced downbeat nystagmus. Intravenous injection of the cholinergic drug physostigmine (Ach-esterase inhibitor) worsened downbeat nystagmus in five patients. This effect was partially reversed in one patient by the anticholinergic drug biperiden, suggesting that anticholinergic drugs might be beneficial, as was shown in a double-blind study on intravenous scopolamine. In isolated patients with a craniocervical anomaly, a surgical decompression by removal of part of the occipital bone in the region of the foramen magnum was beneficial. Recent placebo-controlled studies have suggested that the potassium channel blocker 3, 4-diaminopyridine may be effective in downbeat nystagmus. As downbeat nystagmus is generally less pronounced in upward gaze, base-down prisms sometimes help to reduce oscillopsia during reading.
Upbeat Nystagmus
Treatment with baclofen (5 to 10 mg p.o. three times daily) resulted in an improvement in several patients.
Seesaw Nystagmus
Alcohol had a beneficial effect (1.2 g/kg body weight) in two patients, as was clonazepam. Recently, one study reported on three patients with a seesaw component to their pendular nystagmus, who improved on gabapentin.
Periodic Alternating Nystagmus
In general, periodic alternating nystagmus does not improve spontaneously. Several case reports describe a positive effect of baclofen, a GABA-B agonist, in a dose of 5–10 mg p.o. three times daily. Furthermore, phenothiazine and barbiturates have been found to be effective in single cases. Periodic alternating nystagmus due to bilateral visual loss resolves if vision is restored.
Non-Vestibular Supranuclear Ocular Motor Disorders
Acquired Pendular Nystagmus
Most reports (case reports or case series) state that anticholinergic treatment with trihexyphenidyl (20 to 40 mg p.o. daily) is effective, but in a double-blind study only one of six patients showed improvement from this oral treatment, whereas three patients showed a decrease in nystagmus and improvement of visual acuity during treatment with tridihexethyl chloride (a quaternary anticholinergic that does not cross the blood-brain barrier). In contrast, other authors found in a double-blind trial that scopolamine (0.4 mg intravenously [i.v.]) decreased the nystagmus in all five tested patients with acquired pendular nystagmus. However, there are even observations that scopolamine may make the pendular nystagmus worse in some patients. In three other patients the combination with lidocaine (100 mg i.v.) decreased nystagmus. Recently, an improvement was reported in three of 10 patients who received a scopolamine patch (containing 1.5 mg scopolamine, released at a rate of 0.5 mg per day). The same authors failed to observe further improvement when scopolamine and mexiletine (400 to 600 mg p.o. daily) were given in combination. The most effective substance in their study was memantine, a glutamate antagonist, which significantly improved the nystagmus in all nine tested patients (15 to 60 mg p.o. daily). Two patients responded to clonazepam (3 x 0.5 to 1.0 mg p.o. daily), a GABA-A agonist. Two other groups have reported benefit with GABA-ergic drugs. One study showed improvement in one of three patients with acquired pendular nystagmus (APN) and cerebellar ataxia due to multiple sclerosis (MS) when treated with isoniazid (800 to 1000 mg p.o. daily) and glasses with prisms that induced convergence. This observation was not confirmed by other investigators. Gabapentin substantially improved the nystagmus (and visual acuity) in 10 of 15 patients in another study. Gabapentin was superior to vigabatrin in a small series of patients. Interestingly, a study described two patients who benefited from intake of alcohol but not from other substances. The necessary blood levels were 20 to 35 mmol/L. Recently, a beneficial effect of cannabis was also reported.
Practically, treatment should start with memantine in a dosage of 15 to 60 mg p.o. or alternatively 300 to 400 mg gabapentin three times daily. If there is no or only a small effect, benzodiazepines like clonazepam (0.5 to 1.0 mg p.o. three times daily) can be tried. Further possibilities are scopolamine patches or trihexyphenidyl. However, side effects are a major limitation of anticholinergic therapy.
Opsoclonus and Ocular Flutter
In addition to therapy for any underlying process such as tumor or encephalitis, treatment with immunoglobulins or prednisolone may be occasionally effective. Four of five patients with square-wave oscillations, probably a related fixation disturbance, showed an improvement on therapy with valproic acid. In single cases an improvement has been observed during treatment with propranolol (40 to 80 mg p.o. three times daily), nitrazepam (15 to 30 mg p.o. daily), and clonazepam (0.5 to 2.0 mg p.o. three times daily). One study reported a dramatic improvement in one patient after the administration of 200 mg thiamine i.v.; no further descriptions of the patient are given in the paper.
Nuclear and Infranuclear Ocular Disorders
Superior Oblique Myokymia
Spontaneous remissions, which can last for days up to years, are typical of superior oblique myokymia but there are several reports that anticonvulsants, especially carbamazepine, have a therapeutic effect. Carbamazepine (200 to 400 mg p.o. three or four times daily) or, less often, phenytoin (250 to 400 mg p.o. daily) are recommended. Gabapentin has also been reported to be effective. Long-term studies on the continued effectiveness of these drugs are not available. One study described a decrease in the efficacy of the treatment after a month in some patients. Beta-blockers, even topically, have been reported to be effective.
In chronic cases that did not improve with anticonvulsants, tenotomy of the superior oblique muscle has been performed, but usually it necessitates inferior oblique surgery as well. Surgical decompression of the IVth nerve has also been reported to be beneficial but may result in superior oblique palsy.
Practically, treatment should be started with carbamazepine (200 to 400 mg p.o. three to four times daily) or phenytoin (250 to 400 mg p.o. daily). The side effects and the risk of such therapy are the same as when used to treat trigeminal neuralgia.
Paroxysmal Vestibular Episodes
As initial therapy, an anticonvulsant [carbamazepine (slow release formulation) 2 x 200 to 800 mg p.o. daily; phenytoin 250 to 400 mg p.o. daily, lamotrigine 100 to 400 mg p.o. daily] should be given. In general, a positive response to antiepileptic drugs can be achieved with low dosages. If the symptoms do not cease, a surgical approach may be considered. There are no satisfactory follow-up studies, and the diagnostic criteria have not yet been fully established.
Definitions:
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
