Neuro-Ophthalmology Symposium

Educational Objectives

The goal of this program is to improve the management of neuro-ophthalmologic disorders. After hearing and assim­ilating this program, the participant will be better able to:

1.   Diagnose and treat arteritic and nonarteritic anterior ischemic optic neuropathy.

2.   List the advantages and disadvantages of corticosteroid therapy for myasthenia gravis.

3.   Describe a technique for predicting generalization of myasthenia gravis that utilizes the orbicularis oculi mus­cle.

4.    Identify the various waveforms of nystagmus in adults and infants.

5.   Recommend appropriate diagnostic testing and treatment for the different forms of nystagmus.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Arnold is a consultant for Pfizer. Drs. ten Hove and Fletcher and the planning committee reported nothing to disclose. In his lecture, Dr. Fletcher presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Arnold was recorded at Annual Clinical Conference, held January 9-10, 2009, in Kansas City, MO, and sponsored by the Kansas City Society of Ophthalmology and Otolaryngology. Drs. Fletcher and ten Hove spoke at Practical Pearls in Neuro-Ophthalmology, held September 25-26, 2009, in Toronto, ON, and presented by the Department of Ophthalmology and Vision Sciences and the Division of Neurology, Faculty of Medicine, University of Toronto. The Audio-Digest Founda­tion thanks the speakers and the sponsors for their cooperation in the production of this program.

Advances in Ischemic Optic Neuropathy

Anthony C. Arnold, MD, Professor and Chief of Neuro-Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles

Anterior Ischemic Optic Neuropathy (AION)

Characteristics: patients usually >50 yr of age; rapid onset; painless loss of visual field (VF) with or without loss of visual acuity (VA); afferent pupillary defect; altitudinal loss of VF in 50% to 80% of patients, with optic disc edema (often with flame hemorrhages) at or preceding onset of visual loss; acute optic neuropathy without altitudinal loss of VF (eg, arcuate defect or diffuse loss of VF) could also be AION

Temporal arteritis: affects 5% to 10% of patients with AION (mean age 70 yr)

Signs and symptoms: jaw claudication, temporal tenderness or pain, malaise, and joint pain; high erythrocyte sedi­mentation rate (ESR; ie, 70 mm/hr to >100 mm/hr); severe visual loss (<20/200); distinctively pale (chalk-white) disc edema; flame hemorrhages; may see cotton wool patches adjacent to disc or elsewhere in retina; peripapil­lary choroidal ischemia may blur architecture of disc; AION associated with cilioretinal artery occlusion indi­cates temporal arteritis

Pathogenesis: arteritis occurs in ciliary arteries, with inflammation, thrombosis, occlusion of arteries, and ischemic infarct of optic nerve head

Diagnosis: fluorescein angiography  —  poor filling of disc and choroid around nerve observed after »1 min; in non­arteritic AION (NAION), choroid fills normally but nerve does not; ESR  —  some patients have normal ESR; C-reactive protein (CRP)  —  not influenced by age or other factors and more specific than ESR; ESR >47 mm/hr plus CRP >2.45 mg/dL (upper limit of normal »0.8 mg/dL) highly specific for temporal arteritis in AION; biopsy  —  gold standard; positive result establishes diagnosis, but negative result does not rule out diagnosis; 3% to 5% false-negative rate (for various reasons) seen with unilateral biopsy

Treatment: 1 g/day intravenous (IV) methylprednisolone or 1 mg/kg per day oral prednisone; possible to delay bi­opsy for £10 days after starting corticosteroid therapy; treat to prevent visual loss in fellow eye (occurs at rate of 80% to 95% if not treated);  affected eye occasionally improves; treatment lasts 6 to 12 mo, and tapering difficult; biopsy increases confidence in diagnosis and supports necessity of intensive corticosteroid therapy

Nonarteritic Form (NAION)

Background: 90% to 95% of AION; patients younger, with no systemic symptoms, lower ESRs (mean »40 mm/hr), and less severe visual loss (>20/200); in static form, patients have discrete episode of visual loss, then stabilize; in progressive form (25%), patients have multiple episodes of segmental or steady visual loss before stabilizing; early treatment may help progressive form

Presentation: mild to moderate disc edema and hyperemia, with subsequent development of pallor; significant focal peripapillary arteriolar narrowing during acute swollen phase; crowded disc in fellow eye; some patients show ele­vated capillary dilatation and telangiectasia on surface of nerve (sometimes confused with hemangioma) that disap­pears over time; crowded nerve predisposes to AION

Course: generally stable; study showed >40% of patients had spontaneous improvement (by 3 lines) of VA, but not of VF; disc edema generally resolves in 6 to 8 wk; follow-up critical because those that do not resolve may be due to alternative cause (eg, atypical inflammation or meningioma of optic nerve sheath)

Management: confirm NAION; evaluate for risk factors; provide prognostic information; provide balanced counsel about unproven therapies; consider prophylactic measures for fellow eye

Risk factors: hypertension, diabetes, hyperlipidemia, and smoking; nocturnal hypotension  —  if significant, may cause hypoperfusion of optic disc; other factors  —  association of prothrombotic factors, hypercoagulability state, and levels of homocysteine with AION not proven; carotid stenosis  —studies found no significant incidence of ca­rotid stenosis in patients with NAION

Investigational therapies: NAION thought to occur at cribriform plate of nerve head, where swelling compromises microvasculature and causes more infarction; decompression of optic nerve sheath  —  failed in Ischemic Ocular Neuropathy Trial; transvitreal radial optic neurotomy  —  involves pars plana vitrectomy and opening of scleral ca­nal (sclerotomy); risk slightly greater than with orbitotomy; study showed 10 lines improvement in VA in 6 of 7 pa­tients, with no major complications; further study showed significantly improved VA in 8 patients compared to controls; procedure also used for central retinal vein occlusion; intravitreal injections  —  injection of vascular endo­thelial growth factor (VEGF) inhibitor or triamcinolone to reduce vasogenic edema of disc produced no change in VF, but some improvement in VA (possibly because of macular improvement); may not affect retrolaminar process of AION

Prognosis: »15% rate of involvement of fellow eye after 5 yr; per 2001 study by speaker and another from Emory University, rate  40% in patients <50 yr of age after 1 yr

Prophylaxis: utility of aspirin prophylaxis unproven, but widely used because patients with NAION have increased risk for other vascular events

Myasthenia Gravis

Martin ten Hove, MD, Associate Professor and Deputy Head of Ophthalmology, Queen’s University, Kingston, ON

Progression to generalized myasthenia: »40% of patients present with purely ocular disease (ie, extraocular move­ments, ptosis, and weakness of orbicularis); generalization to systemic or bulbar weakness occurs (usually in £3 yr) in »80%; studies report widely varying rates of generalization (13%-95%)

Corticosteroid therapy: case-control series found substantial reduction in rates of generalization; nicotinic striated skeletal muscle receptor subjected to antibodies that block and destroy it; ocular cases may remain ocular because skeletal muscles have many more receptors; steroids ameliorate diplopia and ptosis and preserve nicotinic recep­tors; drawbacks  —  steroids may mask but not prevent generalization; in 40% to 60% of patients, possible that treat­ing and exposing to toxicity associated with steroids unnecessary

Risk for generalization: no tests or parameters (eg, level of antibodies to acetylcholine receptor, age) reliably predic­tive; single fiber electromyography (EMG)  —  if normal, likelihood that disease will not generalize increases by 60% to 80%

Orbicularis oculi muscle: proposed indicator of muscle strength; easily accessible and often involved in purely ocu­lar cases; unlike extraocular and levator muscles, not influenced by central mechanisms (eg, fusional mecha­nisms, reticular activating system); baseline strength not influenced by training or premorbid occupation

Treatment: inhibitors of cholinesterase, cell cycle, and T cells; B cell depeleters; first line  —  corticosteroids (short-term) and azathioprine (long-term); no data guiding when to taper, how aggressively to use agents, or how to deter­mine when patient reaches pharmacologic remission

Remission: rates 10% to 30% (more common in women); lasts ³6 mo; thymectomy  —  controversial in absence of thymoma; may increase remission rates to 30% to 45%

Exacerbation: early detection can prevent hospitalization and need for respiratory support

Testing: scoring systems include quantitative myasthenia gravis score (QMGS), myasthenia gravis quality of life score, manual muscle test (incorporated into QMGS), single-fiber EMG, and antibodies; useful at different stages of disease (eg, vital capacity score relevant only in myasthenic crisis, and dynamometers require significant in­volvement to show weakness); orbicularis oculi  —  candidate for early detection marker; circular muscle; exerts vertical force on upper and lower lids to effect closure; speaker developed instrument that measures closing pres­sure with reproducibility within 2% to 3%; demonstrated stable strength over time in normal individuals (with some decline at >60 yr of age); measurements differentiated between normal individuals and patients with all stages of myasthenia; showed increase in strength over time with treatment; may help identify patients at low risk for generalization (do not require corticosteroids) as well as those who need aggressive treatment

Nystagmus

William A. Fletcher, MD, Professor, Departments of Clinical Neurosciences and Surgery, University of Cal­gary, AB

Background: rhythmic biphasic oscillation of eyes, defined by presence of slow phase; jerk nystagmus  —  second part of oscillation rapid; sinusoidal pendular nystagmus  —  second part slow

Infantile Onset

Syndromes: congenital or infantile nystagmus; fusional maldevelopment nystagmus (latent or manifest latent form); spasmus nutans

Congenital: incidence 1 in 1000 to 1 in 6000; causes 5% to 10% of visual impairment in children; usually not inher­ited; in study of 224 patients, 110 had idiopathic nystagmus, 33% had albinism, and <10% had ocular anomalies (eg, retinal dystrophies, aniridia, optic nerve hypoplasia); study found nystagmus remained undetected in 1 in 6 patients at 6 mo of age

Waveforms: 12 subtypes; jerk type shows exponentially increasing velocity in slow phase; patients with albinism may have dynamic null or periodic alternating types; most patients have prominent horizontal component, but 25% have vertical and/or torsional components, and 4% have purely torsional or vertical waveforms; decreases with convergence and increases with fixation or anxiety; null zone near primary position in most patients; »25% of patients show compensatory turning or nodding of head; patients have median VA of 20/50 and cannot drive; 40% notice occasional oscillopsia (may indicate decompensated strabismus or progressive visual loss due to ret­inal degeneration or other causes); often have reversed optokinetic nystagmus (OKN), reversed smooth pursuit, and strabismus

Management: refer patient to ophthalmologist for evaluation of ocular abnormalities and retinal dystrophies; elec­troretinography (ERG) recommended for most patients >1 yr of age; magnetic resonance imaging (MRI) unnec­essary unless abnormality detected in fundus; cycloplegic refraction required because many have ³2 diopters of astigmatism; fit patients with contact lenses early to improve VA and decrease intensity of nystagmus; base-out prisms may induce convergence; pharmacologic  —  decreased amplitude and some improvement in VA achieved with gabapentin and memantine; surgical  —  procedures include tenotomy and rectus recessions; unnecessary for most patients

Latent form: nystagmus beats in both eyes towards seeing eye when one eye covered or dissociated; esotropia and fixation with one eye seen in manifest latent form; patients often have strabismus, amblyopia, and dissociated verti­cal deviation, but may not have visual symptoms

Acquired Spontaneous Forms

Peripheral vestibular (jerk nystagmus): in patient with left vestibular neuronitis, unidirectional right-beating nys­tagmus worsened on rightward gaze (Alexander’s law) and improved on leftward gaze; if fixation removed, nystag­mus increased; torsional component often seen; decreased input from labyrinth confirmed by head-thrust test showing corrective saccade; head-thrust test not completely reliable for distinguishing patients with vertigo due to central lesions (eg, cerebellar infarct, brainstem infarct) from those with peripheral lesions; peripheral vestibular nystagmus can occur with central lesions

Downbeat (central nystagmus): often inconspicuous in primary position, but appears in lateral gaze; usually wors­ens when patient looks downward; most common causes include cerebellar degeneration, Chiari malformation, vascular disease, and multiple sclerosis (MS); Munich study  —  40% of patients showed no findings on MRI or other tests, 1 patient had brainstem lesion, 36% had bilateral vestibular loss shown by head-thrust or caloric test­ing; also occurs in patients with spinocerebellar ataxia type 6; »33% had peripheral neuropathy

Treatment: aminopyridines  —  controlled trial showed 2,3-aminopyridine effective in only 50% of patients, as deter­mined by slow-phase velocity; in recent study, only patients with idiopathic cerebellar atrophy had good response

Upbeat (central nystagmus): lesions may occur over entire brainstem (eg, crossing ventral tegmental tract, area of nucleus intercalatus in midline of medulla, brachium conjunctivum); many causes, including Wernicke’s syndrome

Pendular: most common type; acquired form has rapid 2 to 3 Hz oscillation; rotary-type trajectory common; often worse in one eye; dissociated; patients have blurred vision and oscillopsia; internuclear ophthalmoplegia and other cerebellar findings common; 90% have MS

Treatment: blinded crossover study comparing gabapentin to memantine showed improved VA and amplitudes in 17 of 20 eyes with both medications; 4 of 11 patients reported subjective improvement with 40 mg memantine, and 4 additional patients reported improvement with 60 mg; 5 of 11 patients reported improvement with gabap­entin; mild side effects occurred with gabapentin in 80% of patients and with higher dose of memantine

Oculopalatal tremor: synchronous or asynchronous vertical oscillation of eyes and palate; caused by lesion of den­tato-rubro-olivary tract (Mollaret’s triangle); usually in central pons affecting central tegmental tract; produces in­ferior olivary hypertrophy on MRI; caused by stroke or demyelination trauma; in asymmetric form, one eye oscillates at greater amplitude

Suggested Reading

Antonio-Santos AA, Eggenberger ER: Medical treatment options for ocular myasthenia gravis. Curr Opin Ophthalmol 19:468, 2008; Argyriou AA et al: Myasthenia gravis initially presenting with pseudo-internuclear ophthalmoplegia. Neurol Sci 30:387, 2009; Atkins EJ et al: Translation of clinical studies to clinical practice: survey on the treatment of nonarteritic anterior ischemic op­tic neuropathy. Am J Ophthalmology 148:809, 2009; Beran DI, Murphy-Lavoie H: Acute, painless vision loss. J La State Med Soc 161:214, 2009; Chatzistefanou KI et al: The ice pack test in the differential diagnosis of myasthenic diplopia. Ophthalmology Sep 8, 2009 [Epub ahead of print]; DelMonte DW, Bhatti MT: Ischemic optic neuropathy. Int Ophthalmol Clin 49:35, 2009; Hayreh SS: Ischemic optic neuropathy. Prog Retin Eye Res 28:34, 2009; Hayreh SS: Pathogenesis of nonarteritic anterior ischemic optic neurop­athy. Arch Ophthalmol 127:1082, 2009; Hertle RW: Nystagmus in infancy and childhood. Semin Ophthalmol 23:307, 2008; Hertle RW: Does eye muscle surgery improve vision in patients with infantile Nystagmus syndrome? Ophthalmology 116:1837, 2009; Ho SF, Dhar-Munshi S: Nonarteritic anterior ischaemic optic neuropathy. Curr Opin Ophthalmol 19:461, 2009; Kerr NM et al: Non-arteritic anterior ischaemic optic neuropathy: a review and update. J Clin Neurosci 16:994, 2009; Kupersmith MJ: Ocular myasthe­nia gravis: treatment successes and failures in patients with long-term follow-up. J Neurol 256:1314, 2009; Luchanok U, Kaminski HJ: Ocular myasthenia: diagnostic and treatment recommendations and evidence base. Curr Opin Neurol 21:8, 2008 Luneau K et al: Ischemic optic neuropathies. Neurologist 14:341, 2008; McLean RJ, Gottlob I: The pharmacological treatment of nystagmus: a review. Expert Opin Pharmacother 10:1537, 2009; Scherer RW et al: Visual fields at follow-up in the Ischemic Optic Neuropathy Decompression Trial: evaluation of change in pattern defect and severity over time. Ophthalmology 115:1809, 2008; Strupp M et al: Aminopyridines for the treatment of cerebellar and ocular motor disorders. Prog Brain Res 171:535, 2008; Wagner J et al: Prognosis of idiopathic downbeat nystagmus. Ann N Y Acad Sci 1164:479, 2009.