Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

14

1

Optic Neuritis and Multiple Sclerosis

serious and costly treatment. This topic remains debated and recommendations vary among countries [44].

IVIG has also been suggested to facilitate recovery in chronic optic neuritis [61, 62, 63, 72, 73]; however, IVIG administration does not significantly reverse persistent visual loss [48].

Summary for the Clinician

■Evidence from recent randomized, pla- cebo-controlled trials supports early intervention with immunomodulatory agents in high-risk patients with clinically isolated syndromes to decrease the risk of subsequent development of MS [4, 28].

■The decision to treat high-risk optic neuritis patients with immunomodulatory agents should be individualized.

1.4 Pediatric Optic Neuritis

The natural history and management of optic neuritis in children is different than in adults [11]. The data on pediatric optic neuritis are scarce and controversial, and are primarily based on small retrospective chart reviews [12, 45], and on one longitudinal study [37]. These limited studies suggest:

•Mean age of onset: around 10 years

•2/3 female

•2/3 have disc edema (compared to 1/3 of adults)

•2/3 have bilateral involvement

•2/3 have a history of a preceding febrile illness within 2 weeks of onset

•Those with unilateral involvement may have a greater tendency to develop subsequent MS, but also carry a better visual prognosis than those with bilateral involvement

•Subsequent development of MS is less than in adults, and those who do develop MS are older (mean age 12 years) at the onset of optic neuritis

Summary for the Clinician

■In children, data are lacking regarding both the effects of intravenous methylprednisolone on visual recovery and the effects of immunomodulatory agents on the subsequent development of MS.

■Based on the studies done in adults, it would seem reasonable to offer IV steroids in cases with severe visual loss (especially when bilateral), and to consider immunomodulatory agents when the brain MRI is abnormal [4].

References

1.Achiron A, Kishner I, Sarova-Pinhas I et al (2004) Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, pla- cebo-controlled trial. Arch Neurol 61:1515–1520

2.Arnold AC (2005) Evolving management of optic neuritis and multiple sclerosis. Am J Ophthalmol 139:1101–1108

3.Atkins EJ, Biousse V, Newman NJ (2006) The natural history of optic neuritis. Rev Neurol Dis 3:45–55

4.Balcer L (2006) Optic neuritis. New Engl J Med 354:1273–1280

5.Barkhof F, Filippi M, Miller DH et al (1997) Isolated demyelinating syndromes: comparison of different magnetic resonance imaging criteria to predict conversion to clinically definite multiple sclerosis. Brain 120:2059–2069

6.Beck RW, Cleary PA, Anderson MM Jr. et al (1992) A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 326:581–588

7.Beck RW, Cleary PA, Trobe JD et al (1993) The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 329:1764–1769

8.Beck RW, Arrington J, Murtagh FR et al (1993) Brain MRI in acute optic neuritis: experience of the Optic Neuritis Study Group. Arch Neurol 8:841–846

feron β-1a for early multiple sclerosis: CHAMPS trial subgroup analyses. Ann Neurol 51:481–490

10.Bermel R, Puli S, Rudick R et al (2005) Gray mater MRI T2 hypointensity predicts longitudinal atrophy in multiple sclerosis. Arch Neurol 62:1371–1376

11.Boomer JA, Siatkowski RM (2003) Optic neuritis in adults and children. Semin Ophthalmol 18:174–180

12.Brady KM, Brar AS, Lee AG et al (1999) Optic neuritis in children: clinical features and visual outcome. J AAPOS 3:98–103

13.Brex P, Ciccarelli O, O’Riordan J et al (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:156–164

14.Brusaferri F, Candelise F (2000) Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials. J Neurol 247:435–442

15.CHAMPIONS Study Group (2006) IM interferon β-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 66:678–684

16.CHAMPS Study Group (2001) Interferon β-1a for optic neuritis patients at high-risk for multiple sclerosis. Am J Ophthalmol 132:463–471

17.Cole SR, Beck RW, Moke PS et al (1998) The predictive value of CSF oligoclonal banding for MS 5 years after optic neuritis. Neurology 51:885–887

18.Comi C, Filippi M, Barkhof F et al (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study (ETOMS). Lancet 358:1586–1582

19.Dalton CM, Brex PA, Miszkiel KA et al (2003) New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes. Ann Neurol 53:673–676

20.Dalton CM, Brex PA, Miszkiel KA et al (2003) Spinal cord MRI in clinically isolated optic neuritis. J Neurol Neurosurg Psychiatry 74:1587–1580

21.De Stefano N, Narayanan S, Francis GS et al (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65–70

22.Ebers GC (1985) Optic neuritis and multiple sclerosis. Arch Neurol 42:702–704

Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis. J Neurol Neurosurg Psychiatry 68:156–161

24.Francis DA, Compston DA, Batchelor JR, McDonald WI (1987) A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up. J Neurol Neurosurg Psychiatry 50:758–765

25.Frederiksen JL (1998) Can CSF predict the course of optic neuritis? Mult Scler 4:132–135

26.Freedman M, Kappos L, Polman C et al (2006) Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT): clinical outcomes. Neurology 66:S02.001

27.Frohman E, Racke M (2000) To treat or not to treat? The therapeutic dilemma of idiopathic monosymptomatic demyelinating syndromes. Arch Neurol 58:930–932

28.Frohman E, Frohman T, Zee D et al (2005) The neuro-ophthalmology of multiple sclerosis. Lancet Neurol 4:111–121

29.Ghezzi A, Martinelli V, Torri V et al (1999) Longterm follow-up of isolated optic neuritis: the risk of developing multiple sclerosis, its outcome, and the prognostic role of paraclinical tests. J Neurol 246:770–775

30.Jacobs LD, Kaba SE, Miller CM et al (1997) Correlation of clinical, MRI and CSF findings in optic neuritis. Ann Neurol 41:392–398

31.Jacobs LD, Beck RW, Simon JH et al (2000) The effect of intramuscular interferon beta 1a treatment initiated at the time of a first acute clinical demyelinating event on the rate of development of clinically definite multiple sclerosis. N Engl J Med 343:898–904

32.Jin YP, de Pedro-Cuesta J, Huang YH, Söderström M (2003) Predicting multiple sclerosis at optic neuritis onset. Mult Scler 9:135–141

33.Kaufman DI, Trobe JD, Eggenberger ER et al (2000) Practice parameter: the role of corticosteroids in the management of acute monosymptomatic optic neuritis. Neurology 54:2039–2044

34.Korteweg T, Tintoré M, Uidehaag B et al (2006) MRI criteria for dissemination in space in patients with clinically isolated syndromes: a multicentre follow-up study. Lancet Neurol 5:221–227

35.Kurtzke JF (1985) Optic neuritis or multiple sclerosis. Arch Neurol 42:704–710

16

1

62.Rodriguez M, Miller DJ (1994) Immune promotion of central nervous system remyelination. Prog Brain Res 103:343–355

63.Rodriguez M, Miller DJ, Lennon VA (1996) Immunoglobulins reactive with myelin basic protein promote CNS remyelination. Neurology 46:538–545

64.Roed HG, Langkilde A, Sellebjerg F et al (2005) A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology 65:804–810

65.Rolak LA, Beck RW, Paty DW et al (1996) Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treatment trial. Neurology 46:368–372

66.Sandberg-Wolheim M, Bynke H, Cronqvist S et al (1990) A long term prospective study of optic neuritis: evaluation of risk factors. Ann Neurol 27:386–393

67.Sellebjerg F, Nielsen HS, Frederiksen JL et al (1999) A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 52:1479–1484

68.Söderström M, Jin YP, Hillert J, Link H (1998) Optic neuritis, prognosis for multiple sclerosis from MRI, CSF, and HLA findings. Neurology 50:708–714

References 17

69.Sorensen PS, Wanscher B, Jensen CV et al (1998) Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 50:1273–1281

70.Tintoré M, Rovira A, Martinez MJ et al (2000) Isolated demyelinating syndromes: comparison of different diagnostic MRI criteria to predict conversion to clinically definite multiple sclerosis. Am J Neuroradiol 21:702–706

71.Tintoré M, Rovira A, Rio J et al (2005) Is optic neuritis more benign than other first attacks in multiple sclerosis? Ann Neurol 57:210–215

72.Van Engelen BG, Hommes OR, Pinckers A et al (1992) Improved vision after intravenous immunoglobulin in stable demyelinating optic neuritis. Ann Neurol 32:834–835

73.Van Engelen BG, Miller DJ, Pavelko KD et al (1994) Promotion of remyelination by polyclonal immunoglobulin and IVIg in Theiler’s virus induced demyelination and in MS. J Neurol Neurosurg Psychiatry 58 [Suppl. 1]:65–68

74.Weinshenker BG, Bass B, Rice GP et al (1989) The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 112:133–146

2.1 Introduction

Ischemic syndromes of the optic nerve (ischemic optic neuropathy, ION) are classified according to: (1) the location of the ischemic damage to the nerve and (2) the etiologic factor, if known, for the ischemia. Anterior ischemic optic neuropathy (AION) includes syndromes involving the optic nerve head, with visible optic disc

edema. Posterior ischemic optic neuropathy (PION) incorporates those conditions involving the intraorbital, intracanalicular, or intracranial portions of the optic nerve, with no visible edema of the optic disc. While several specific etiologic factors have been identified in ION, the most critical for initial management is the vasculitis of giant cell, or temporal, arteritis (GCA); therefore, ION is typically classified as either arteritic (usu-

20

2

Ischemic Optic Neuropathies

ally due to GCA) or nonarteritic. Nonarteritic ION is most often idiopathic, but specific etiologies such as systemic hypotension are occasionally identified.

2.2Anterior Ischemic Optic Neuropathy

Anterior ischemic optic neuropathy (AION) typically presents with the rapid onset of painless unilateral visual loss developing over hours to days. An altitudinal visual field defect (typically inferior) is the most common pattern of loss (Fig. 2.1), but arcuate scotomas, cecocentral defects, and generalized depression are also frequently seen (Fig. 2.2). Visual acuity is decreased if the field defect involves fixation, but may be normal if an arcuate pattern spares the central region. The pupil in the affected eye demonstrates the presence of a relative afferent pupillary defect (RAPD) unless pre-existing or concurrent optic neuropathy in the fellow eye results in abnormal pupillary reactivity, which obscures the signs of the RAPD. The optic disc is edematous at onset; the edema may be pallid, but it is not uncommon to see disc hyperemia, particularly in the nonarteritic form. The disc most often is diffusely swol-

len, but a segment of more prominent edema is frequently present (Fig. 2.3). Flame hemorrhages are commonly located adjacent to the disc, and peripapillary retinal arteriolar narrowing may occur. Retinal arteriolar emboli are only rarely associated.

2.2.1Arteritic Anterior Ischemic Optic Neuropathy

2.2.1.1 Clinical Presentation

Giant cell arteritis (GCA) is the cause for arteritic anterior ischemic optic neuropathy (AAION) in a relatively small minority (5.7%) of cases [20], with an estimated annual incidence in the United States of 0.57 per 100,000 over the age of 60 [33]. The mean age of onset for AAION is 70 years, with only rare occurrence under the age of 60. Giant cell arteritis occurs more frequently in women and with increasing age. It is most common in Caucasians and is unusual in African American and Hispanic patients [33].

Arteritic AION usually occurs in association with other systemic symptoms of the disease.

Headache (most common), jaw claudication, and temporal artery or scalp tenderness are most

Fig. 2.3.  Fundus photograph of optic disc in AION. The disc is edematous, with a segment of more prominent hyperemic edema superiorly, pallor inferiorly

specific for the disorder. The headache is often severe, constant, and disabling. True jaw claudication, with muscular cramping and fatigue progressing with continued chewing activity, has high specificity for temporal arteritis. Claudication may also occur in muscles of the neck or tongue. The syndrome of polymyalgia rheumatica (PMR), including malaise, anorexia, weight loss, fever, proximal joint arthralgia and myalgia, is frequently reported. This constellation of systemic symptoms and hematologic inflammatory markers, but without temporal artery or ocular involvement, may lead to arteritis in some cases. In contrast, so-called occult GCA, without overt systemic symptoms and sometimes without abnormal blood testing, may occur; in Hayreh’s recent report, 21.2% of patients with GCA and visual loss had no systemic symptoms of the disease [26].

In addition to systemic symptoms, certain associated local signs may aid in the diagnosis of AAION, including induration of the tempo-

22

2

Ischemic Optic Neuropathies

ral region, decreased or absent temporal artery pulse, and cord-like firmness or nodularity of the temporal artery.

Arteritic AION typically presents with severe visual loss (visual acuity <20/200 in 57.8%–76.5% of cases) [1, 10, 41, 52] developing rapidly over hours to days. In one series 21% of cases had no light perception [41]. While the initial presentation is often unilateral, bilateral simultaneous AION is more commonly arteritic than nonarteritic, and its occurrence raises suspicion for GCA. The persistent visual loss of AAION is preceded in 7%–18% of cases [1, 24, 41] by transient visual loss similar to that of carotid artery disease, although the episodes may be of shorter duration; these are only rarely associated with the nonarteritic form of AION (NAION) and are highly suggestive of arteritis. The pallid type of optic disc edema (Fig. 2.4) is seen more frequently in the arteritic than in the nonarteritic form; chalkwhite pallor with edema is seen in severe cases and is highly unusual in NAION. Cotton wool patches indicative of concurrent retinal ischemia may be seen. Retinal arterial occlusion may occur simultaneously with the optic neuropathy. In Hayreh’s recent series [24], cilioretinal artery occlusion occurred in 21.2%; this is a very unusual occurrence in NAION, and is highly suggestive of GCA. Peripapillary choroidal ischemia may be associated with the optic neuropathy, produc-

Fig. 2.4.  Fundus photograph of optic disc in arteritic AION. The disc demonstrates prominently pale e­ dema

ing edema deep to the retina adjacent to the optic disc and exacerbating the visual loss [43]. It may also occur in a more widespread area, with or without optic disc involvement. The optic disc of the fellow eye in AAION most frequently is of normal diameter, with a normal physiologic cup [6, 35], as opposed to that in NAION, which tends to be small in diameter, with little or no physiologic cup.

Summary for the Clinician

■Arteritic AION presents with severe visual loss, pale optic disc edema, often with other signs of retinal vasculopathy, and in association with systemic symptoms including headache, jaw claudication, and temporal tenderness.

2.2.1.2 Pathophysiology

Histopathologic studies in AAION demonstrate vasculitis of the short posterior ciliary vessels supplying the optic nerve head, in addition to variable involvement of the superficial temporal, ophthalmic, choroidal, and central retinal arteries. Infiltration of the short posterior ciliary arteries by chronic inflammatory cells, with segmental occlusion of multiple vessels by inflammatory thickening and thrombus, has been documented. Autopsy studies have demonstrated ischemic necrosis predominantly involving the laminar and retrolaminar portions of the optic nerve supplied by these vessels and their distal tributaries.

Fluorescein angiographic data support involvement of the short posterior ciliary arteries in AAION. Delayed filling of the optic disc and adjacent choroid (Fig. 2.5) is consistently noted [16]. Extremely poor or absent filling of the choroid has been suggested as one useful factor in distinguishing arteritic from nonarteritic AION. Mack et al. [43] reported a mean choroid perfusion time (from first appearance to filling) of 69 s in patients with AAION, compared with 5.5 s in NAION; Siatkowski et al. [57] confirmed this finding with slightly different parameters, mean time from injection to choroid filling measur-

Fig. 2.5.  Fluorescein angiography in arteritic AION. Optic disc filling is poor and there is prominent nonperfusion of the nasal choroid

ing 29.7 s in AAION compared with 12.9 s in NAION.

2.2.1.3 Differential Diagnosis

The acute onset of severe visual loss in the setting of headache and optic disc edema, particularly when bilateral, requires consideration of alternative diagnoses, including acute optic neuropathy secondary to chronic papilledema (with or without intracranial mass), infiltrative optic neuropathy, and meningeal carcinomatosis involving the optic nerves. In cases of suspected AAION with negative workup or atypical course, neuroimaging should be performed to evaluate for intracranial mass or visible meningeal thickening and enhancement, and lumbar puncture should be considered to assess for evidence of elevated intracranial pressure or malignant cells.

2.2.1.4 Clinical Course

If untreated, AAION results in severe damage of the affected optic nerve. Recovery of useful vision after initial involvement is unusual, even with prompt therapy. In cases with unilateral presentation, estimates for development of AAION

in the fellow eye without therapy range from 54% to 95% [8, 41]. The optic disc edema typically resolves over 4–8 weeks, with resultant optic atrophy and generalized attenuation of retinal arterioles. Excavation of the optic disc occurs frequently after AAION, whereas this phenomenon is unusual in NAION. Danesh-Meyer et al. [14] reported optic disc cupping in 92% of 92 patients with AAION versus 2% of 102 patients with NAION. The excavation may be severe, mimicking glaucomatous damage, but the severity of the optic atrophy seen after AAION usually differentiates it from glaucomatous excavation.

2.2.1.5 Diagnostic Confirmation

The most important initial step in the management of AION is the assessment for evidence of GCA. A tentative diagnosis may be made on the basis of advanced age and typical clinical symptoms in conjunction with elevation of the erythrocyte sedimentation rate (ESR). Most cases of active GCA show markedly elevated ESR (mean 70 mm/h, often >100 mm/h). When the level is not extremely high, however, interpretation of the value becomes more difficult, as normative data are imprecise. As a rule, we recommend the clinically useful guideline that the upper level of normal, in mm/h, is calculated by dividing patient’s age by 2 in males, and the patient’s age plus 10, all divided by 2 in females. However, by these criteria, the level may be normal in up to 22% of patients with GCA. Conversely, the ESR rises with age, and levels above the listed upper limit of normal for the laboratory are common (up to 40% over 60 mm/h) in patients over 70 years without arteritis. In the Ischemic Optic Neuropathy Decompression Trial (IONDT), 9% of patients with NAION had ESR levels greater than 40 mm/h, with a range of 0–115 mm/h [31]. Moreover, the test is nonspecific, elevation confirming only the presence of any active inflammatory process or other disorder affecting red blood cell aggregation. In studies of cases in which biopsy of the temporal artery proved negative but the ESR was elevated, the most commonly associated diseases have been occult malignancy (most frequently lymphoma) in 18%–22%, other inflammatory disease in 17%–21%, and diabetes in 15%–20%. In these cases initially suspected of being GCA,

24

2

Ischemic Optic Neuropathies

internal medicine consultation to rule out other systemic disease is essential.

Additional blood abnormalities are common in GCA and may have prognostic value. Measurement of C-reactive protein (CRP), levels of which do not rise with age or anemia, may increase diagnostic accuracy and are currently recommended in conjunction with the ESR. Hayreh et al. [25] reported that a specificity of 97% for GCA was attained for AION patients with an ESR ≥47 mm/h and CRP >2.45 mg/dl (normally ≤0.5 mg/dl) from their laboratory. We currently recommend simultaneous measurement of both parameters in suspected cases of AAION. Fibrinogen is commonly elevated and may supplement CRP levels in increasing accuracy over the use of ESR alone. Thrombocytosis is seen in up to 50% of patients with GCA; its presence has been shown to be a marker for positive temporal artery biopsy and may be a predictor of visual loss. Liozon et al. [40] assessed 174 patients with GCA, correlating thrombocytosis with the development of permanent visual loss. Of 20 patients with permanent visual loss due to AAION, 13 (65%) had thrombocytosis. This feature may have implications for therapy (see below).

Giant cell arteritis is confirmed by positive temporal artery biopsy, which is strongly recommended in any case of suspected AAION. The certainty of biopsy-proven GCA provides support for long-term systemic corticosteroid therapy, which often is required for up to a year and may be associated with severe systemic complications. It also makes later decisions regarding the risk-benefit ratio of prolonged therapy more clear-cut. Negative biopsy, however, does not rule out GCA. False-negative biopsy may result from:

1.Discontinuous arterial involvement (“skip lesions”) undetected in 4%–5% due to an insufficient length (minimum 3–6 cm recommended) of specimen or insufficiently detailed step-sectioning.

2.Unilateral involvement with biopsy of the uninvolved temporal artery.

3.Improper handling of specimens.

4.Review by pathologist inexperienced in diagnosis of acute and healed arteritis.

The false-negative error rate for unilateral temporal artery biopsy has previously been estimated at

5%–11%. Hayreh et al. [25] more recently prospectively studied 76 patients who underwent contralateral biopsy due to high clinical suspicion after initially negative biopsy; 7 (9.2%) had evidence of active inflammation in the second biopsy. Boyev et al. [11] (3%), Danesh-Meyer et al. [13] (1%), Pless et al. [49] (5%), and Hall et al. [21] (5%) found varying rates of discordance between sides in bilateral biopsies. In the critical subset of patients who undergo contralateral biopsy after initially negative result (a sample biased toward the positive based on clinical parameters raising suspicion for GCA), studies with the greatest number of patients suggest a slightly higher discordance (2.8%–9.2%), but the difference is small. The data all suggest some degree of increased accuracy from bilateral biopsy samples, and considering the severe consequences of missed diagnosis, the relatively low risk of procedural complications, and the benefit of biopsy proof in the long-term management of these patients, we consider bilateral biopsy in all cases. The level of clinical suspicion guides these decisions.

Summary for the Clinician

■Diagnosis is confirmed by elevated ESR and CRP and by positive temporal artery biopsy.

2.2.1.6 Therapy

If GCA is suspected, therapy should be instituted immediately; initial treatment should not await diagnostic confirmation by temporal artery biopsy. Although chronic systemic corticosteroid therapy may reduce positive biopsy results in GCA, a delay of 7–10 days has no significant effect on results, and in some cases active inflammation may be detected after longer therapy. High-dose intravenous methylprednisolone at 1 g per day for the first 3–5 days is most often recommended, particularly when the patient is seen in the acute phase, since this mode of therapy produces higher blood levels of medication more rapidly than oral therapy. As these patients are