EDITORIAL 1 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.1.1 on 1 January 2003. Downloaded from

Eye movement disorders arise is an instability in the adaptive ...... mechanisms that normally govern the performance of the VOR; the best under- stood example is periodic alternating Drug treatments for eye movement nystagmus. disorders Treatment of nystagmus caused by peripheral vestibular imbalances R J Leigh, R L Tomsak Nystagmus caused by peripheral ves- ...... tibular imbalance resolves spontane- ously over the course of a few days Advances in the treatment of eye movement disorders because of central adaptive mecha- nisms.5 Drug treatments play only a minor role, mainly to control attendant PATHOGENESIS OF ABNORMAL of to and fro sinusoidal oscillation; this and . A range of neuro- EYE MOVEMENTS AND THEIR form of nystagmus is often visually transmitters has been identified within VISUAL CONSEQUENCES disabling and presents an important the vestibular system,6 although drugs The modern rationale for the treatment therapeutic challenge. with , , and of abnormal eye movements rests on Nystagmus is different from inappro- properties remain the current concepts of the neurobiology of priate saccades that intrude on steady most popular (table 1). Current ap- 2 ocular motility and vision.1 In order to fixation. Saccades produce brief, high proaches emphasise using these “ves- see clearly the details in our visual world, speed movement of images upon the tibular sedatives” only for 24 to 48 images must be held quite still upon the retina, but this does not normally inter- hours, if vertigo and nausea are severe.5 retina, especially the central, foveal part, fere with stable clear vision. Only when After this time, exercises are encouraged which has the highest density of pho- inappropriate saccades repeatedly misdi- to accelerate the brain’s ability to correct toreceptors. In order to read, which con- rect the fovea will vision be impaired— the imbalance. cerns detection of high spatial frequen- for example, during reading. cies, image motion should ideally be less We now know a good deal about the Treatment of nystagmus caused by than about 5°/s.2 If image drift substan- anatomical and physiological substrates central vestibular imbalances tially exceeds this limit, visual acuity will for the three gaze holding mechanisms, It has been possible to identify several and the neural machinery that generates decline and the illusion that the world is 12 mechanisms leading to downbeat nys- moving (oscillopsia) may be experi- saccades. Less is known about the tagmus, and to develop animal models.2 enced. Normally, three main mecha- pharmacological substrate for eye move- For example, the vestibular cerebellum is nisms hold gaze (the line of sight) ments, but recent findings have sug- known to govern, by inhibitory path- gested possible treatments for abnormal steady, so that our view of the world is 3 ways, the central projections of the ante- clear and stable.2 The first is the eye movements. However, as will be rior canals (which generate upward eye vestibulo-ocular reflex, by which the seen, success with any drug may turn out movements) but not central projections motion detectors of the inner ear initiate to be more complicated than originally of the posterior canals (which generate supposed, and empirical trials have con- 2 eye movements to compensate for head downward eye movements). Thus ves- tributed as much as drug selection based perturbations, such as occur during tibular cerebellar lesions, such as the on animal studies. Table 1 summarises locomotion. The second mechanism is Chiari malformation, will remove inhibi- drugs reported to suppress the more “visual fixation,” which has two compo- tion from anterior canal projections, common forms of abnormal eye move- http://jnnp.bmj.com/ nents: the detection of retinal image drift causing the eyes to drift up (and leading ments. Other types of treatment, includ- and programming of corrective eye to downbeat nystagmus). Projections ing optical methods and botulinum movements, and the suppression of from the cerebellar cortex to the vestibu- toxin, are summarised elsewhere.2 The unwanted eye movements that take the lar nuclei use the transmitter clinical features of pathological nystag- eye away from the target. The third γ-aminobutyric acid (GABA). Thus mus and saccadic abnormalities have mechanism depends on a neural net- GABAergic agents might be expected to recently been reviewed, with video work that makes it possible to hold the suppress downbeat nystagmus. Similar examples.4 eyes at an eccentric position (for exam- considerations apply to upbeat nystag- on October 1, 2021 by guest. Protected copyright. ple, in lateral gaze). Malfunction of any Pathogenesis and treatment of mus, which can in some cases be related of these three mechanisms may cause vestibular forms of nystagmus to lesions that selectively affect central the eyes to drift away from the object of The vestibulo-ocular reflex (VOR) de- projections of the anterior versus the regard; corrective, quick phases (sac- pends on motion detectors in the inner posterior canals.2 In other cases of cades) may then redirect the fovea ear that respond to angular and linear upbeat nystagmus, involvement of med- towards the target. Thus a definition of head accelerations. The organisation of ullary structures important in the gaze nystagmus is repetitive to and fro invol- the peripheral vestibular system—with a holding mechanism, discussed below, untary eye movements that are initiated resting neural discharge rate even with may be required. by slow drifts of the eye. the head stationary, and reciprocal push- Clonazepam is reported to reduce It is important to differentiate patho- pull contributions from the two ears— downbeat nystagmus from a variety of 78 logical nystagmus from physiological nys- predisposes to the development of causes. The GABAB agonist baclofen is tagmus. During rotation of the head and imbalances.2 Thus sudden loss of neural reported to reduce downbeat nystagmus body in space, both vestibular nystagmus activity from one ear (a peripheral imbal- and associated oscillopsia.9 However, a and optokinetic nystagmus act to reduce ance) will be misinterpreted as head double blind comparison of baclofen and motion of images of the world on the rotation leading to vertigo and nystag- gabapentin showed that neither drug retina, and so to preserve clear vision. mus. Imbalances of vestibular “tone” can produced consistent improvement, and During pathological nystagmus, however, also occur on a central basis, leading to in some patients the nystagmus was drifts of the eyes away from the target downbeat, upbeat, and torsional forms of made worse.10 The drug degrade vision. In one pathological form, nystagmus. A third mechanism by which (an este- pendular nystagmus, the eye drifts consist pathological vestibular nystagmus can rase inhibitor), given intravenously,

www.jnnp.com 2 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.1.1 on 1 January 2003. Downloaded from

Table 1 Summary of current drug treatments for nystagmus*

Vestibular forms of nystagmus Peripheral imbalance , , prochlorperazine, ondansetron for relief of attendant vertigo and nausea; resume activities as soon as able Central imbalance • Downbeat nystagmus Clonazepam, baclofen, trihexyphenidyl; acetazolamide (for nystagmus associated with episodic ataxia type II) • Upbeat nystagmus Baclofen Central instability • Periodic alternating nystagmus Baclofen

Nystagmus associated with visual system disorder • Seesaw nystagmus Baclofen, clonazepam, , gabapentin

Nystagmus from disorders of the gaze holding mechanism • Acquired pendular nystagmus In association with disease of central myelin: gabapentin, , clonazepam, trihexyphenidyl, ; cannabis, alcohol As part of the syndrome of oculopalatal tremor (“myoclonus”): gabapentin, valproate trihexyphenidyl

Saccadic intrusions and oscillations • Square wave jerks • Opsoclonus and ocular flutter Clonazepam, popranolol, gabapentin, corticosteroids, intravenous immunoglobulin, plasma exchange

Miscellaneous abnormal movements • Superior oblique myokymia Gabapentin, carbamazepine, popranolol • Ocular neuromyotonia Carbamazepine

*For details see refs 2 and 3. causes worsening of downbeat probably has a different pathogenesis, synchronous depression and extorsion of nystagmus.9 Conversely, the anticholin- usually does not respond to baclofen.) the other eye in the first half cycle, ergic drug scopolamine reduces down- The initial suggestion was that baclofen followed by change in direction during beat nystagmus when given intra- worked as treatment for PAN because it the next half cycle.2 Seesaw nystagmus 11 venously, but oral anticholinergic is a GABAB agonist and so compensated may arise because crossing visual inputs agents such as trihexyphenidyl12 produce for loss of inhibitory inputs from the (from the temporal visual field) are no only a modest improvement which is cerebellum.214 However, baclofen also longer available to “calibrate” ocular offset by substantial side effects. Thus at has other effects that may be more responses to head roll. Individual pa- present the drug treatment of downbeat important with oral administration, tients with seesaw nystagmus have been nystagmus is unsatisfactory. such as effects on glutamate.3 reported to benefit from clonazepam and Upbeat nystagmus is occasionally sup- alcohol.71516 pressed by clonazepam,9 but it often Pathogenesis and treatment of resolves spontaneously over a few nystagmus caused by disorders of Pathogenesis and treatment of months. Torsional nystagmus is rare, and visual fixation nystagmus caused by disorders of http://jnnp.bmj.com/ there are few data available on its Disorders of the anterior visual pathways the gaze holding mechanism treatment. Nystagmus in familial epi- that degrade vision often cause nystag- In order for us to be able to hold the eyes sodic vertigo and ataxia type 2 is often mus. This is probably a result of two steadily at an eccentric position (for downbeat and responds to acetazola- separate mechanisms: deprivation of example, turned into right lateral gaze), mide and calcium channel blockers.13 motion vision information that can be the brain must programme a tonic used to programme eye movements to contraction of the extraocular muscles, Treatment of nystagmus caused by compensate for drifts of the eyes away otherwise the orbital tissue would pull instability of vestibular mechanisms from the target; and loss of visual signals back the eyes towards the centre.2 This Periodic alternating nystagmus (PAN) is that are essential for “calibration” of the gaze holding mechanism (sometimes on October 1, 2021 by guest. Protected copyright. a horizontal jerk nystagmus that reverses normal ocular motor responses. Thus called the neural integrator for eye direction approximately every two retinal disorders such as Leber’s congeni- movements) depends on several compo- minutes.2 This uncommon form of ac- tal amaurosis cause continuous nystag- nent structures that, together, constitute quired nystagmus occurs with lesions mus from birth.2 a network of neurones. For horizontal affecting the nodulus and uvula of the Occasionally, nystagmus and ocular gaze, key structures are the medial cerebellum—either experimental or drifts cause oscillopsia even when there vestibular nucleus and adjacent nucleus clinical. PAN probably arises from an is residual vision, and gabapentin may prepositus hypoglossi (MVN-NPH). For abnormality affecting a form of help some of these patients with pendu- vertical gaze, a key structure is the inter- “memory” for persistent vestibular lar nystagmus (personal observations). stitial nucleus of Cajal (INC). Both are stimuli referred to as “velocity storage.” Optic nerve demyelination in multiple probably governed by a brain stem– The nodulus and uvula appear to govern sclerosis may be associated with ac- cerebellar circuit that includes the cell velocity storage, and when these struc- quired pendular nystagmus, but it re- groups of the paramedian tracts, which tures are lesioned, velocity storage is mains uncertain whether loss of visual are spread throughout the brain stem, prolonged. Adaptive mechanisms that input is the main reason for this visually and receive a “copy” of all premotor eye attempt to hold velocity storage in check disabling oscillation, which is discussed movement commands.17 The paramedian cause an oscillating vestibular imbal- further below. tract cell groups project to the vestibular ance, manifest as PAN. Baclofen is effec- Chiasmal lesions are associated with cerebellum which, in turn, projects back tive treatment in most cases of acquired seesaw nystagmus, which consists of eleva- to the MVN-NPH and to the INC. In PAN. 14 (A congenital form of PAN, which tion and intorsion of one eye and patients with multiple sclerosis and

www.jnnp.com EDITORIAL 3 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.1.1 on 1 January 2003. Downloaded from acquired pendular nystagmus, magnetic double blind study comparing gabapen- and are a sign of midline cerebellar resonance imaging often shows lesions tin with baclofen in a group of 15 disease (affecting the fastigial nucleus).2 that may be affecting the paramedian patients, nystagmus decreased and There is currently no effective drug tract cell groups.18 visual acuity improved significantly with treatment. Experimental inactivation of the gabapentin, but not with baclofen.10 Both of these oscillations are distinct MVN-NPH by discrete injections of mus- Other drugs with presumed GABAergic from saccadic oscillations without an cimol, which increases normal GABA effects, such as clonazepam and val- intersaccadic interval, which typically inhibition and thereby decreases neuro- proate, also help some patients.7 These occur at a frequency of 15–30 Hz. When nal activity, disrupts horizontal gaze clinical observations, combined with the the latter occur only in the horizontal holding, causing severe gaze evoked effects of pharmacological inactivation plane, they are called ocular flutter; nystagmus.19 20 Local injection of NMDA on the gaze holding mechanism noted when they have horizontal, vertical, and (N-methyl-D-aspartate) agonists and above, led to a “GABAergic hypothesis” torsional components, they are called antagonists into this region also causes for acquired pendular nystagmus.10 How- opsoclonus.2 Flutter and opsoclonus gaze evoked nystagmus.20 Pharmacologi- ever, the more purely GABAergic drug occur in four main clinical settings: cal inactivation of the INC with musci- vigabatrin is ineffective as a treatment.25 parainfectious brain stem encephalitis mol produces failure of eccentric vertical Furthermore, memantine—a drug with (including multiple sclerosis), paraneo- and torsional gaze holding.21 Pharmaco- NMDA blocking, AMPA (α-amino-3- plastic syndromes, metabolic-toxic logical inactivation of the paramedian hydroxy-5-methyl-4-isoxalone- states, or idiopathic. tract cell groups also results in failure of propionic acid) receptor modulation, and Recovery of opsoclonus associated 22 gaze holding, as do surgical lesions of action—is also effective with brain stem encephalitis may be 2 the vestibular cerebellum. How can for acquired pendular nystagmus in speeded by intravenous immuno- these data be used to select drug multiple sclerosis.24 Thus it seems that globulin.29 In opsoclonus associated treatment for abnormal eye movements? suppression of this form of nystagmus with cancer, treatment of the tumour Gaze evoked nystagmus is seldom probably occurs through glutamate itself often does not ameliorate the visually disabling unless severe, because blocking mechanisms (a property that neurological syndrome. In children with patients’ eye drifts are minor when the gabapentin possesses). Gabapentin is neural crest tumours, opsoclonus may eyes are close to central position. On the also effective in some patients with ocu- respond to corticosteroids, intravenous other hand, instability of the neural net- lopalatal tremor.10 It is generally well tol- immunoglobulin, or chemotherapy.30 work could cause nystagmus either with erated but can make ataxia worse. Some Plasmapheresis and intravenous immu- drifts away from the centre position patients do not respond at all to gaba- noglobulins sometimes proved effective (reported with cerebellar disorders) or, pentin, but many do obtain some relief in adults. Symptomatic treatment of the conceivably, acquired pendular nystag- from their visual symptoms. saccadic oscillations is unsatisfactory, mus. This latter idea—that acquired Agents with cholinergic effects are although propranolol, verapamil, clon- pendular nystagmus arises from an less effective as treatment for acquired azepam, and gabapentin have been instability in the gaze holding pendular nystagmus. Although intra- reported to suppress them in individual mechanism—has gained some experi- 231 23 venous scopolamine may suppress the patients. mental support, and has prompted oscillations,11 neither transdermal scopo- trials of drugs with effects on GABAergic lamine or oral agents such as trihexy- TREATMENT OF MISCELLANEOUS and glutamate receptors. Nonetheless, phenidyl benefit more than the occa- OTHER ABNORMAL EYE more than one mechanism is probably sional patient.12 26 Recently, smoking MOVEMENTS THAT DISRUPT responsible for acquired pendular nys- cannabis (but not taking oral prepara- VISION tagmus, and we discuss it separately tions) was reported to help one patient Patients suffering from superior oblique below. 27 http://jnnp.bmj.com/ with multiple sclerosis, a finding that myokymia complain of brief recurrent epi- Treatments for acquired pendular opens up new possibilities for developing sodes of monocular blurring of vision, or 2 nystagmus treatments, provided social constraints tremulous sensations in one eye. The Acquired pendular nystagmus is encoun- allow this. attacks consists of monocular spasms of tered in at least three clinical settings: small torsional–vertical rotations that can first, in association with disorders of TREATMENT OF SACCADIC sometimes be detected by looking for the central myelin such as multiple sclerosis, INTRUSIONS AND OSCILLATIONS movement of a conjunctival vessel, as the Several types of inappropriate saccadic patient announces the onset of symp-

addiction, and a range of con- on October 1, 2021 by guest. Protected copyright. genital disorders of myelin formation; movements may intrude upon steady toms. They are more easily detected second, as part of the syndrome of fixation.2 Square wave jerks occur in during examination with an ophthalmo- oculopalatal tremor (“myoclonus”), healthy subjects, but are the prominent scope. The condition is usually benign and which typically develops months after a finding in progressive supranuclear palsy might be triggered by mild damage to the brain stem stroke, and is associated with and some spinocerebellar atrophies. trochlear nerve with regeneration. Most, synchronised movements of the palate They are small conjugate saccades, rang- but not all, patients are helped by car- and other branchial muscles (hyper- ing from 0.5° to 5.0° in size, which take bamazepine, propranolol, or gabapentin.32 trophic olivary degeneration is also a the eye away from the fixation position Ocular neuromyotonia is characterised feature); and third, as a feature of Whip- and then return it there after a period of by episodes of diplopia that are usually ple’s disease affecting the nervous sys- about 200 ms. They seldom interfere precipitated by holding the eyes in tem, when the nystagmus is usually with vision, even if they are frequent, eccentric gaze, often sustained adduc- convergent–divergent and associated although it has been suggested that tion.33 These episodes are caused by with movements of the masticatory reading performance may be improved if involuntary, sometimes painful, contrac- muscles (oculomasticatory myorhyth- they are suppressed using methy- tion of one or more muscles innervated mia).2 It seems likely that different phenidate.28 Macrosaccadic oscillations by one oculomotor nerve. Most reported mechanisms underlie each form. consist of horizontal saccades that occur patients have undergone previous radia- The most effective treatments for in bursts, building up and then decreas- tion treatment to the parasellar region. acquired pendular nystagmus in associ- ing in amplitude, with intersaccadic The mechanism responsible for ocular ation with disorders of central myelin are intervals of about 200 ms. These oscilla- neuromyotonia is unknown, but ephap- gabapentin10 and memantine.24 In one tions are usually induced by a gaze shift tic neural transmission has been suggest.

www.jnnp.com 4 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.1.1 on 1 January 2003. Downloaded from

Carbamazepine may prove effective 4 Serra A, Leigh RJ. The diagnostic value of integrator in monkey. Vision Res treatment.33 nystagmus. Spontaneous and induced 1999;39:4286–95. oscillations. J Neurol Neurosurg Psychiatry (in 21 Helmchen C, Rambold H, Fuhry L, et al. press). Deficits in vertical and torsional eye SUMMARY 5 Halmagyi GM, Cremer PD. Assessment and movements after uni- and bilateral treatment of . J Neurol Neurosurg inactivation of the interstitial nucleus of Cajal Drug treatments now exist for some Psychiatry 2000;68:129–34. of the alert monkey. Exp Brain Res forms of acquired nystagmus and other 6 Vidal P-P, Vibert N, Serafin M, et al. Intrinsic abnormal eye movements that disrupt physiological and pharmacological properties 1998;119:436–52. 22 Nakamogoe K, Iwamoto Y, Yoshida K. clear vision. Although some patients of central vestibular neurons. Adv Otorhinolarygol 1999;55:26–81. Evidence for brainstem structures participating obtain substantial improvement of visual 7 Currie JN, Matsuo V. The use of clonazepam in oculomotor integration. Science symptoms from drug treatment, many in the treatment of nystagmus-induced 2000;288:857–9. others do not. Better understanding of oscillopsia. Ophthalmology 23 Das VE, Oruganti P, Kramer PD, et al. 1986;93:924–32. Experimental tests of a neural-network model the molecular basis of eye movements is 8 Young YH, Huang TW. Role of clonazepam for ocular oscillations caused by disease of likely to indicate new pharmacological in the treatment of idiopathic downbeat central myelin. Exp Brain Res nystagmus. Laryngoscope 2001;111:1490–3. approaches. Anecdotal reports of agents 2000;133:189–97. 9 Dieterich M, Straube A, Brandt T, et al.The 24 Starck M, Albrecht H, Straube A, et al. Drug that quell abnormal eye movements have effects of baclofen and cholinergic drugs on provided useful suggestions for drug upbeat and downbeat nystagmus. J Neurol therapy for acquired pendular nystagmus in multiple sclerosis. J Neurol 1997;244:9–16. treatments, but require systematic follow Neurosurg Psychiatry 1991;54:627–32. 10 Averbuch-Heller L, Tusa RJ, Fuhry L, et al.A 25 Bandini F, Castello E, Mazzella L, et al. up. To date, published studies of masked double-blind controlled study of gabapentin Gabapentin but not vigabatrin is effective in controlled trials of drug treatments for and baclofen as treatment for acquired the treatment of acquired nystagmus in abnormal eye movements are few in nystagmus. Ann Neurol 1997;41:818–25. multiple sclerosis: how valid is the GABAergic 11 Barton JJ, Huaman AG, Sharpe JA. hypothesis? J Neurol Neurosurg Psychiatry number. Both basic scientists and clini- Muscarinic antagonists in the treatment of 2001;71:107–10. cal neurologists can contribute to ad- acquired pendular and down beat nystagmus: 26 Kim JI, Averbuch-Heller L, Leigh RJ. Evaluation a double blind, randomized trial of three vancement in this field. of transdermal scopolamine as treatment for intravenous drugs. Ann Neurol acquired nystagmus. J Neuro-ophthalmol 1994;35:319–25. ACKNOWLEDGEMENTS 12 Leigh RJ, Burnstine TH, Ruff RL, et al.The 2001;21:188–92. 27 Schon F, Hart PE, Hodgson TL, et al. RJL is supported by NIH grant EY06717, the effect of anticholinergic agents upon acquired nystagmus. A double-blind study of Suppression of pendular nystagmus by Office of Research and Development, Medical trihexyphenidyl and chloride. smoking cannabis in a patient with multiple Research Service, Department of Veterans Neurology 1991;41:1737–41. sclerosis. Neurology 1999;53:2209–10. Affairs, and the Evenor Armington Fund. 13 Baloh RW, Jen JC. Genetics of familial 28 Currie JN, Goldberg ME, Matsuo V, et al. episodic vertigo and ataxia. Ann NY Acad Dyslexia with saccadic intrusions: a treatable J Neurol Neurosurg Psychiatry 2003;74:1–4 Sci 2002;956:338–45. reading disorder with a characteristic 14 Halmagyi GM, Rudge P, Gresty MA, et al. oculomotor sign. Neurology 1986;36(suppl ...... Treatment of periodic alternating nystagmus. 1):134. Ann Neurol 1980;8:609–11. 29 Pless M, Ronthal M. Treatment of Authors’ affiliations 15 Cochin JP, Hannequin D, Do Marcolino C, et opsoclonus–myoclonus with high-dose R J Leigh, R L Tomsak, Department of al. Abolition par le clonazepam d’un Neurology, Veterans Affairs Medical Center, nystagmus en bascule intermittent. Rev Neurol intravenous immunoglobulin. Neurology and University Hospitals, Case Western Reserve (Paris) 1995;151:60–2. 1996;46:583–4. University, Cleveland, Ohio, USA 16 Frisén L, Wikkelso C. Posttraumatic seesaw 30 Russo C, Cohn SL, Petruzzi MJ, et al. nystagmus abolished by ethanol ingestion. Long-term neurologic outcome in children with Correspondence to: Dr R John Leigh, Neurology 1986;136:841–4. opsoclonus–myoclonus syndrome associated Department of Neurology, University Hospitals, 17 Büttner-Ennever JA, Horn AKE. Pathways with neuroblastoma: a report from the 11100 Euclid Avenue, Cleveland, Ohio from cell groups of the paramedian tracts to Pediatric Oncology Group. Med Pediatr 44106–5040, USA; [email protected] the floccular region. Ann NY Acad Sci Oncol 1997;28:284–8. 1996;781:532–40. 31 Moretti R, Torre RM, Antonello D, et al. 18 Lopez LI, Bronstein AM, Gresty MA, et al. REFERENCES Opsoclonus–myoclonus syndrome: gabapentin Clinical and MRI correlates in 27 patients with as a new therapeutic proposal. Eur J Neurol http://jnnp.bmj.com/ 1 Kaminski HJ, Leigh RJ, eds. The neurobiology acquired pendular nystagmus. Brain 2000;7:455–6. of eye movements: from molecules to 1996;119:465–72. 32 Tomsak RL, Kosmorsky GS, Leigh RJ. behavior. Ann N Y Acad Sci 19 Straube A, Kurzan R, Büttner U. Differential 2002;956:1–615. effects of bicuculline and muscimol Gabapentin attenuates superior oblique 2 Leigh RJ, Zee DS. The neurology of eye microinjections into the vestibular nuclei on myokymia. Am J Ophthalmol movements, 3rd ed. [Book/CD.] New York: simian eye movements. Exp Brain Res 2002;133:721–3. Oxford University Press, 1999. 1991;86:347–58. 33 Frohman EM, Zee DS. Ocular 3 Büttner U, Fuhry L. Drug therapy of 20 Arnold DB, Robinson DA, Leigh RJ. neuromyotonia: clinical features, physiological nystagmus and saccadic oscillations. Adv Nystagmus induced by pharmacological mechanisms, and response to therapy. Ann Otorhinolarygol 1999;55:195–227. inactivation of the brainstem ocular motor Neurol 1995;37:620–6. on October 1, 2021 by guest. Protected copyright.

www.jnnp.com