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 are classified as Class C.
Supranuclear Ocular Motor Disorders
Downbeat Nystagmus (DBN)
No studies on the natural course of DBN are available. In non-placebo-controlled-studies with a limited number of patients, administration of the gamma-aminobutyric acid (GABA)-A agonist clonazepam (0.5 mg per os [p.o.] three times daily) (Currie & Matsuo, 1986), the GABA-B agonist baclofen (10 mg p.o. three times daily) (Dieterich et al., 1991), and gabapentin (probably calcium channel blocker) (Averbuch-Heller et al., 1997) had positive effects and reduced DBN. Intravenous injection of the cholinergic drug physostigmine (acetylcholine [Ach]-esterase inhibitor) worsened DBN 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 (Barton, Huaman, & Sharpe, 1994). 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 (Pedersen et al., 1980; Spooner & Baloh, 1981; Liebenberg et al., 2005; personal observation). Recent placebo-controlled studies have suggested that the potassium channel blockers 3,4-diaminopyridine (3 x 20 mg/day) and 4-aminopyridine (3 x 10 mg/day) may be effective in reducing DBN (Strupp et al., 2003) and in improving the vestibulo-ocular reflex (VOR) and smooth pursuit (Kalla et al., 2004). A further study in 11 patients with DBN because of cerebellar degeneration confirmed this effect and showed that 3,4-diaminopyridine especially reduce the gravity-independent velocity bias (Sprenger et al., 2006). As DBN is generally less pronounced in upward gaze, base-down prisms sometimes help to reduce oscillopsia during reading in some patients.
Treatment with baclofen (5–10 mg p.o. three times daily) resulted in an improvement in several patients (Dieterich et al., 1991). There are some observations that 10 mg 4-aminopyridine three times a day reduces upbeat nystagmus (Glasauer et al., 2005).
Alcohol had a beneficial effect (1.2 g/kg body weight) in two patients (Frisèn & Wikkelso, 1986; Lepore, 1987), but this cannot be recommended as treatment, as did clonazepam (Carlow, 1986). Recently, Averbruch-Heller et al. (1997) reported on three patients with a seesaw component to their pendular nystagmus, who improved on gabapentin.
Periodic Alternating Nystagmus (PAN)
In general, PAN does not improve spontaneously. Several case reports of acquired as well as congenital PAN describe a positive effect of baclofen, a GABA-B agonist, in a dose of 5–10 mg p.o. three times daily (Carlow, 1986; Halmagyi, Rudge, & Gresty, 1980; Larmande & Larmande, 1983; Isago, Tsuboya, & Kataura, 1985; Nuti et al., 1986; Comer, Dawson, & Lee, 2006). Furthermore, phenothiazine and barbiturates have been found to be effective in single cases (Isago, Tsuboya, & Kataura, 1985; Nathanson, Bergman, & Bender, 1953). Recently, also memantine was described as effective (Kumar et al., 2009). PAN because of bilateral visual loss resolves if vision is restored (Cross, Smith, & Norton, 1982; Jay, Williams, & De Chicchis, 1985). In a case of PAN associated to a Chiari-malformation, a surgical decompression resolved the PAN (Al-Awami et al., 2005).
Non-vestibular Supranuclear Ocular Motor Disorders
Acquired Pendular Nystagmus (APN)
Most reports (case reports or case series) state that anticholinergic treatment with trihexyphenidyl (20–40 mg p.o. daily) is effective (Herishanu, & Louzoun, 1986; Jabbari et al., 1987), but in a double-blind study by Leigh et al. (1991), 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, Barton et al. (1994) found in a double-blind trial that scopolamine (0.4 mg intravenous [i.v.]) decreased the nystagmus in all five tested patients with APN. However, there are even observations that scopolamine may make the pendular nystagmus worse in some patients (Kim, Averbuch-Heller, & Leigh, 2001). In three other patients, the combination with lidocaine (100 mg i.v.) decreased nystagmus (Gresty, Ell, & Findley, 1982; Ell et al., 1982). Recently, Starck et al. (1997) reported an improvement in three of 10 patients who received a scopolamine patch (containing 1.5 mg scopolamine, released at a rate of 0.5 mg/day). The same authors failed to observe further improvement when scopolamine and mexiletine (400–600 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 (15–60 mg p.o. daily). Two patients responded to clonazepam (3 x 0.5–1.0 mg p.o. daily), a GABA-A agonist (Starck et al., 1997). In a further crossover study, Starck and coworkers (2010) showed that memantine as well as gabapentin was able not only to reduce the nystagmus but also to improve visual acuity. Two other groups have reported benefit with GABA-ergic drugs. Traccis et al. (1990) showed improvement in one of three patients with APN and cerebellar ataxia because of multiple sclerosis (MS) when treated with isoniazid (800–1000 mg p.o. daily) and glasses with prisms that induced convergence. This observation was not confirmed by other investigators (Leigh et al., 1994). Gabapentin substantially improved the nystagmus (and visual acuity) in 10 of 15 patients (Averbuch-Heller et al., 1997). Gabapentin was superior to vigabatrin in a small series of patients (Bandini et al., 2001). Interestingly, Mossman et al. (1993) described two patients who benefited from intake of alcohol but not from other substances. Recently, a beneficial effect of cannabis was also reported (Schon et al., 1999; Dell'Osso, 2000).
Practically, treatment should start with memantine in a dosage of 15–60 mg p.o. or alternatively 300–400 mg gabapentin three times daily. If there is no or only a small effect, benzodiazepines like clonazepam (0.5–1.0 mg p.o. three times daily) can be tried. Further possibilities are scopolamine patches or trihexyphenidyl.
Opsoclonus and Ocular Flutter
In addition to therapy for any underlying process such as tumour or encephalitis, treatment with immunoglobulins or prednisolone may be occasionally effective (Pless & Ronthal, 1996). Four of five patients with square-wave oscillations, probably a related fixation disturbance, showed an improvement on therapy with valproic acid (Traccis et al., 1997) or in patients with hereditary spinocerebellar ataxia on therapy with memantine 20 mg/daily (Serra et al., 2008). In single cases, an improvement has been observed during treatment with propranolol (40–80 mg p.o. three times daily), nitrazepam (15–30 mg p.o. daily) and clonazepam (0.5–2.0 mg p.o. three times daily) (overview in Carlow, 1986; Leopold, 1985). Nausieda et al. (1981) reported a dramatic improvement in one patient after the administration of 200 mg thiamine i.v.
In most cases, therapy is not necessary. Besides surgical interventions (Yee, Baloh, & Honrubia, 1982) only a few reports on medical treatment trials are reported. Baclofen (Pradeep et al., 2008), cannabis (McLean et al., 2007), and especially memantine and gabapentin are described. In a study with 47 patients, memantine (up to 40 mg) as well as gabapentin (up to 2400 mg) were shown to be superior to placebo and both also improved visual acuity (Hertle & Yang, 2006). A similar result was reported in a retrospective study of 23 patients with acquired as well as congenital nystagmus (Shery et al., 2006; Sarvananthan et al., 2006).
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 (200–400 mg p.o. three or four times daily) or, less often, phenytoin (250–400 mg p.o. daily) are recommended (Susac, Smith, & Schatz, 1973; Rosenberg & Glaser, 1983). Gabapentin has also been reported to be effective (Tomsak, Kosmorsky, & Leigh, 2002). Rosenberg and Glaser (1983) 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 (Tyler & Ruiz, 1990; Bibby et al., 1994). In chronic cases that did not improve with anticonvulsants, tenotomy of the superior oblique muscle was performed, but usually it necessitates inferior oblique surgery as well (Palmer & Shults, 1984; Brazis et al., 1994). Surgical decompression of the IV nerve has also been reported to be beneficial but may result in superior oblique palsy) (Samii et al., 1998; Scharwey et al., 2000). Practically, treatment should be started with carbamazepine (200–400 mg p.o. three to four times daily) or phenytoin (250–400 mg p.o. daily).
Paroxysmal Vestibular Episodes
As initial therapy, an anticonvulsant should be given (Brandt, 1999). Mean dosages of carbamazepine of about 600 mg/day and of oxcarbazepine of about 900 mg/day led to a reduction in the attack frequency of about 90% (Scharwey et al., 2000). 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 (Jannetta, Møller, & Møller, 1984). There are no satisfactory follow-up studies, and the diagnostic criteria have not yet been fully established.
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 for a Therapeutic Intervention
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.