Ординатура / Офтальмология / Английские материалы / Neuro-Ophthalmology_Kidd, Newman, Biousse_2008

the optic neuritis treatment trial.68 The condition known as autoimmune optic neuropathy is discussed following lupus.

Thyroid associated autoantibodies have been noted in some cases of optic neuritis and in the opticospinal form of MS in Japan69; these antibodies were found in 5 of 14 patients with the opticospinal form of MS and in 1 of 32 with the classical form of MS. The prevalence of thyroid antibodies in non-neurologic controls is not stated, and the report predates the recent controversy over the

relevance of neuromyelitis optica IgG (NMO-IgG) in the optic-spinal form of MS in Japanese patients.70,71 Optic neuritis is not, however, noted in a series

of Hashimoto encephalitis or steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT).72

The occurrence of an optic neuropathy associated with paraneoplastic antibodies seems to be rare with few cases in the literature; most are associated with small cell lung cancer. The pathology of one case revealed a widespread lymphocytic infiltration and fibrosis of the meninges extending to the optic nerves and chiasm as well as other cranial nerves.73 In one case the optic neuropathy presented with

disc swelling and improved spontaneously, in the other two a progressive predominately central field loss developed with optic atrophy.74,75 All three cases have

been associated with a cerebellar syndrome.

More recently an association has been shown between optic neuritis and the paraneoplastic antibody collapsin response-mediated protein 5 (CRMP-5). A series of 15 patients has been reported by one center76 in which 18 previous case reports (including the 3 noted previously) are also referenced. All had developed a subacute visual loss with swollen optic discs. Five were seen to have coexisting retinitis, and 9 had vitritis. Fluorescein angiography revealed leakage from the swollen disc and also peripheral parts of the retina, and 4 who had had vitrectomy showed a reactive vitreous lymphocytosis. All had other neurologic signs during the disease course with white matter lesions on MRI. The optic neuropathy often became bilateral. The CSF was moderately active and all had oligoclonal bands; CRMP-5 was found in all CSF samples tested. Most patients had small cell lung carcinoma, others had thyroid and renal carcinoma. Although CRMP-5 is found in association with thymoma, no patient with this disorder has been shown to have a CRMP-5 associated optic neuritis.

OPTIC NEURITIS FOLLOWING VACCINATION

The prevalence of this complication is difficult to ascertain because many cases are unlikely to be reported. There are case reports of optic neuritis following influenza vaccinations,77,78 measles, mumps, rubella (MMR),79 diphtheria, tetanus, pertussis (DTP),80 bacille Calmette-Guerin (BCG),81 and hepatitis B.82 Most cases are bilateral, and the prognosis with and without treatment with corticosteroids seems to be good.

DEVIC’S SYNDROME

Devic described a neurologic syndrome comprising the association of an optic neuropathy with transverse myelitis. The clinical phenotype may be seen in conjunction with a variety of immune-mediated disorders such as systemic lupus erythematosus, Sjo¨gren’s syndrome, antiphospholipid antibodies and anti-neutrophil cytoplasmic

antigen (ANCA), toxins such as clioquinol, as well as various viruses and other infections such as tuberculosis and mycoplasma.83 Those that arise without such associations may be considered to have Devic’s syndrome.

Devic’s syndrome is considerably more common in females84,85 and occurs at any age. The disease may arise as a monophasic illness, in which it is more com-

mon that both optic nerve and cord involvement arise synchronously, or a relapsing one, in which repeated attacks occur85,86 and in which the severity

of the neurologic impairment at onset is on average less severe. The optic neuropathy may be unilateral and sequential or bilateral and synchronous and develops before or after the cord lesion with equal frequency.

The majority of patients suffer optic neuropathies on both sides, although simultaneous involvement is most uncommon. Rather, the second eye would become involved hours or days after the first; very rarely would there be weeks or months apart. Characteristically, the loss of vision would be acute and severe, in contrast to Leber’s hereditary optic neuropathy, in which a slow progression of symptoms arises. Forty percent deteriorate to NPL. Pain occurs but is less com-

mon than in MS or in granulomatous optic neuropathies. The field defects tend to be central.83,86 Disc appearances also vary from normal appearances at onset

to severe swelling with peripapillary hemorrhage. Over time, all cases exhibit a gradual atrophy. Most recover to some degree, often after the first week and continuing over several weeks, although some are left without light perception. With repeated attacks of optic neuritis, a permanent visual deficit accrues.

The CSF is usually highly active with raised protein and often hundreds or even thousands of white cells. There may be a polymorph leucocytosis. Glucose levels are not reduced, and the prevalence of oligoclonal bands is low at around 30%.84,85 On repeated testing, oligoclonal bands tend to become absent.

Recently, an antibody against central nervous system (CNS) endothelial tissues, NMO-IgG, has been associated with 73% of patients tested with a clinical diagnosis of Devic’s syndrome87 and 58% of patients with the opticospinal form of MS prevalent in Japan. NMO-IgG binds to the abluminal surface of microvessels, pia, subpia, and Virchow-Robin sheaths, at the aquaporin-4 (AQP4) water channel.88

MRI of the brain shows a lesion within one or both optic nerves that enhances, and the remainder of the brain is normal in the majority of cases. Those who have a relapsing disease course tend to acquire brain lesions that are typical of those seen in MS. Recently, it has been shown intriguingly that high signal abnormalities arise on fluid attenuated inversion recovery (FLAIR) sequences around the third and

adjacent to the fourth ventricles without clinical accompaniment; these occur in regions of high density of aquaporin-4 channels89,90 (Fig. 7–10). The cord scans

are without exception abnormal and show cord swelling in the acute phase (Fig. 7–10), with long and large cord lesions that extend over several cord segments.

The pathology is one of diffuse swelling and softening over the affected segments, occasionally the entire cord or optic nerve.91 Histologic examination reveals extensive macrophage infiltration with myelin and axonal loss, necrosis, and cavitation. Both white and gray matter structures are affected. In chronic cases, there is extensive gliosis, cystic cavitation, and profound atrophy. The vessels show thickening and hyalinization.

Immunopathologic studies show complement activation and a prominent neutrophil and eosinophil but sparse lymphocyte infiltration. Vascular changes with thickening and hyalinization occur in active and inactive lesions with

Figure 7–10 Devic’s syndrome. A, Axial FLAIR magnetic resonance imaging (MRI) showing high signal adjacent to the fourth ventricle. B, T2-weighted sagittal MRI of the cervical cord showing a long lesion extending between C3 and D1 with cord swelling.

prominent perivascular deposition of immunoglobulin. The pattern therefore is one of a humoral immune disorder with early involvement of the vessels.

The diagnosis remains a clinical one with much overlap between classical descriptions of the disease and other inflammatory and immune-mediated disorders, and only patients with rather classical descriptions may be labeled thus

TABLE 7–4 New Diagnostic Criteria for Devic’s Syndrome

Definite NMO Optic neuritis Acute myelitis

At least two of three supportive criteria

Contiguous spinal cord MRI lesion extending over more than 3 vertebral segments Brain MRI not meeting diagnostic criteria for multiple sclerosis

NMO-IgG seropositive status

MRI, magnetic resonance imaging; NMO, neuromyelitis optica.

From Wingerchuck DM, et al: Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1466–1467.

with confidence. This year new diagnostic criteria for Devic’s syndrome have been suggested92 (Table 7–4).

Treatment

No randomized controlled trial of any treatment in this condition has been published. The literature points out that steroids often are used, and many authors use immunosuppression in an attempt to reduce number of attacks in the relapsing form. There is one report of a significant benefit over an 18-month treatment period with azathioprine93 and more recently also with mitoxantrone.94 Plasma exchange is also advocated.95 One paper used intravenous immunoglobulin (IVIG) in two patients whose attacks stopped during treatment,96 and another reported the use of rituximab in eight patients in whom the frequency of attacks was dramatically reduced.97

Prognosis

The rate of relapse in the nonmonophasic form is on average high, with the majority of patients suffering attacks more than once per year,98 leading to a stepwise decline in neurologic function over a short time. Incomplete recovery both to vision and to spinal cord function usually means a high level of residual neurologic impairment and disability.

BEHC¸ET’S SYNDROME

Behc¸et’s syndrome is an uncommon systemic disorder of unknown etiology characterized by recurrent oral and genital ulceration and panuveitis. Constitutional symptoms comprising malaise, fatigue, and loss of weight are common. Skin involvement, characterized by erythema nodosum, pustular eruptions, or pseudofolliculitis, occurs, and there is an oligoarthropathy of large joints such as the knees, ankles, and shoulders. Involvement of the lungs, gastrointestinal tract, and kidneys is rare. Thrombosis is common, and vasculitis may be associated with the development of arterial aneurysms. There is an association with HLA-B51, particularly in patients with Mediterranean and Japanese ancestry. Other genetic susceptibility factors, such as factor V Leiden gene mutations and mutations within the TNFa gene, are likely to allow the condition to develop in patients genetically susceptible, when the immune system is triggered by certain, presumed infective, antigenic stimuli.99

Figure 7–11 Behc¸et’s syndrome. Fundus photograph of a patient with an occlusive retinal vasculitis of the inferior quadrant. (Courtesy of Mr. Miles Stanford.)

The eyes are affected in around 70% of cases.100 The ophthalmic complications include an anterior uveitis (classically with the development of hypopyon) and a retinal vasculitis in which retinal vein occlusion may arise as a result of inflammation (Fig. 7–11), macular edema and optic disc ischemia may arise, and cataract, cystoid macular edema, glaucoma, and optic atrophy may eventually develop. Scleritis and vitritis may also occur.101 Optic neuropathy may arise as a consequence of retinal vasculitis in the condition, and the ocular complications are a much more common cause of visual impairment than neurologic complications.

Neurologic complications arise in 5% to 10% of cases and involve either the development of inflammation within the brain, brainstem, spinal cord, roots, or muscle or as a consequence of a venous sinus thrombosis.102 Most complications arise as single events, others follow a relapsing-remitting course and less often a progressive course may be followed leading to severe neurologic impairment and disablement. Intracranial hypertension may develop not associated with discernible venous sinus thrombosis.

Isolated optic neuropathy is extremely rare with only a handful of published case reports, although the prevalence of reports is increasing. The majority of cases have developed a subacute painless unilateral optic neuropathy of varying

but often mild severity associated with a central field defect and optic disc swelling without hemorrhage or retinal vasculitis.102–108 There are three reports

of bilateral synchronous optic neuropathy.109–111

As with other forms of neurologic Behc¸et’s syndrome, the initial manifestations may be neurologic.102,112 Imaging may be normal or associated with high

signal lesions within the optic nerve on dedicated optic nerve imaging.106 CSF tends not to be active unless there is evidence for inflammation elsewhere within the nervous system. Oligoclonal bands are absent.

Treatment with intravenous corticosteroids has resulted in improvements in visual acuity in most cases. There is no report of relapsing optic neuropathy, but in the case of neurologic complications elsewhere, patients treated with immune suppression do tend to have a less often relapsing disease course.

CELIAC DISEASE

Celiac disease may be associated with neurologic complications, and the neurologic syndromes may be associated with anti-gliadin antibodies in the absence of the gastrointestinal disorder; peripheral neuropathy, myopathy, cerebellar ataxia,

brainstem encephalitis, and an encephalopathy with seizures and calcification have been reported. There is a recent report of two cases who presented with a Devic phenotype in whom optic neuropathy was seen: in the first case, the bilateral optic neuropathy occurred synchronous with the cord lesion, and in the second a unilateral optic neuropathy of poor recovery had arisen a year before the development of the cord lesion.113 There is another report of a patient with ANCA antibodies and celiac disease who presented with bilateral optic neuritis.114

INFLAMMATORY BOWEL DISEASE

Case reports of optic neuropathy in ulcerative colitis and Crohn’s disease are rare.115–118 Patients present with signs of an optic neuropathy and disc swelling.

Around half the cases have an associated pain, and a further half have signs of ocular inflammation, predominately an anterior granulomatous-type uveitis. Inflammatory ocular complications are said to arise in around 5% of patients

with Crohn’s disease119 and include conjunctivitis, episcleritis, iridocyclitis, and retinal vasculitis. Two cases of neuroretinitis have been described.116,120

VOGT-KOYANAGI-HARADA SYNDROME

Vogt-Koyanagi-Harada (VKH) is a rare disorder that is more common in darkskinned people of African and Asian ancestry. It consists of a viral-type prodrome with an aseptic meningitis and hearing problems including tinnitus. This is a result of an immune-mediated attack of melanin-containing cells of the meninges and cochlea. An anterior granulomatous uveitis then develops, sometimes associated with a vitritis, disc swelling, and multiple serous retinal detachments. As the uveitis subsides, depigmentation develops leading to vitiligo, alopecia, and poliosis of the eyelids, eyebrows, and hair. This depigmentation also involves the choroid leading to a mottled “sunset glow” fundus in which can

be seen multiple Dalen-Fuchs nodules in the inferior peripheral retina.121 Optic neuropathy is most uncommon; only three cases have been reported,122–124 and

the authors of one point out correctly that it is uncertain whether the signs of the optic neuropathy reflect optic disc involvement or (perhaps more likely) ischemia of the disc as a consequence of choroidal involvement by the inflammatory disease.123

Connective Tissue Disorders and Systemic Vasculitis

LUPUS

Systemic lupus erythematosus is an uncommon multisystem disease associated with ANA and anti-DNA antibody. The skin, joints, kidneys, lungs, nervous system, and eyes are all affected. The anti-phospholipid antibody arises commonly, although it may be no more prevalent than in other connective tissue diseases.125 Neurologic complications arise in around 20%126 and include encephalopathy with seizures and psychosis, vascular disorders, transverse

myelitis, including (quite commonly) a Devic’s syndrome phenotype, optic neuropathy, and headache disorders. There is a closer association between neurologic complications in lupus and the presence of anti-phospholipid antibodies.127

The ocular manifestations arise predominately in the retina, with the development of cotton wool spots, often associated with retinal arteriolar dilatation.128 Intraretinal hemorrhages may also occur.129 Retinal artery and vein occlusion may also occur. More rarely, a progressive arteriolar vaso-occlusive disease develops, in which extensive hemorrhage and neovascularization may follow. Involvement of anterior structures is less common; scleritis, episcleritis, and orbital involvement may occur, but an anterior uveitis is rare.130

The optic neuropathy that may arise in lupus may be acute or chronic and progressive. In the acute form, patients present in a manner typical of a demyelinating optic neuritis with periocular pain and pain on eye movement leading to a subacute visual loss. The disc may be swollen or normal. There appears

not to be a relationship between the development of an optic neuropathy and the presence of retinal vasculitis,131,132 with only one published report in which

the two conditions coexist.133 Generally, there is a central field defect that is scotomatous or arcuate, but altitudinal defects may also be seen. These patients

seem more likely to have involvement of other areas of the nervous system at the same or other times,128,132,136 although other series do not show this.135,136

The simultaneous development of a bilateral optic neuritis has been seen in three cases, most of whom were children.137,138 Chiasmal involvement has also been seen.139,140 Imaging investigations show enlargement of the affected nerve or chiasm with gadolinium enhancement.136,140

Untreated, the patients are less likely to improve than those with a demyelinating optic neuritis. The pathology is one of infarction associated with arteriolar

fibrinoid necrosis.138 More recently, however, it has been noted that patients often improve following administration of corticosteroids137,139 and immune

suppression141 including oral methylprednisolone, methotrexate, chlorambucil, and azathioprine, but in refractory and steroid-unresponsive cases, pulsed IV cyclophosphamide has been shown to be beneficial.134

The seemingly separate condition of “auto-immune optic neuritis,” coined by Dutton and colleagues,142 in which subacute or progressive optic neuropathy develops in association with ANAs in the absence of systemic clinical evidence for lupus is not currently understood and may reflect a series of separate immune-mediated disorders in which autoantibodies are formed in a nonspecific way. The majority of the patients are female. In Dutton’s series of three cases, the condition was bilateral in two (although a previous optic neuropathy of undetermined etiology had arisen some years before), and all three showed ANAs. In one, there was an associated retinal vasculitis, in the second there was serologic evidence for mixed connective tissue disease with ANA and anti-RNP, and in the third both ANA and anti-DNA antibodies were present without systemic features of lupus, except that a polymyositis developed some time later. Each was treated with corticosteroids, and in general a reasonable visual recovery took place in each case. Following relapse of the disorder in each case, an immune-suppres- sive agent was added, and a short-term follow-up suggested that no further symptoms had arisen. A more comprehensive series published by Kupersmith and colleagues143 some time later reported 14 patients with recurrent optic

neuropathies in association with ANAs. In their series, 75% had bilateral optic neuropathies, although seldom had this occurred synchronously. Twenty-five percent of their cases also had other neurologic impairments. Patients had failed to improve following conventional corticosteroid therapy for a presumed demyelinating optic neuritis, but the majority improved when “megadose” intravenous methylprednisolone was given (5 to 14 g over 5 to 7 days). Around a third of these cases were seen to relapse on steroid withdrawal. This series was never followed to define what the risk of developing lupus or another connective tissue disorder was, and I am not certain how prevalent this disorder is. I personally have encountered only one such case.

There is also an association between the antiphospholipid antibody syndrome without lupus and optic neuropathy. There are no comparative data, but it is my impression that optic neuropathy is more common in lupus without antiphospholipid antibodies than in that associated with antiphospholipid antibodies and in the primary antiphospholipid antibody syndrome. One recent review cites 10 cases, although there is a mixture of ischemic optic neuropathy and other forms, including a slowly progressive bilateral optic neuropathy.144 A vaso-occlu-

sive ischemic retinopathy is common, with around 80% showing retinal venous tortuosity and 25% showing ischemic changes.145,146

¨

SJOGREN’S SYNDROME

Sjo¨gren’s syndrome is an immune-mediated condition in which a lymphocytic infiltration of lacrimal and salivary glands leads to xerostomia and xerophthalmia. There is an association between the disorder and the autoantigens SS-A(Ro) and SS-B (La). The syndrome may occur as a primary disorder or in conjunction with other connective tissue diseases, particularly lupus, rheumatoid arthritis, and scleroderma.

In patients with primary Sjo¨gren’s syndrome, a series of neurologic manifestations may arise, including peripheral neuropathy and ganglionopathy, isolated cranial neuropathy, myositis, transverse myelitis, and encephalomyelitis (which may

be relapsing-remitting and mimic MS on imaging). Optic neuritis is uncommon with around 28 cases reported,147–149 although it arose in 13 of 82 cases reported recently

from France.150 Two were associated with a Devic’s phenotype in this series. Treatment both for an optic neuritis and for the Devic phenotype involves

corticosteroids and immunosuppression. The prognosis appears to be good with treatment, with a greater risk of residual visual impairment on relapse than after the first attack.

MIXED CONNECTIVE TISSUE DISEASE

This disorder shows features of lupus, systemic sclerosis, polymyositis, and rheumatoid arthritis in association with the autoantibodies ANA, extractable nuclear antigens (ENA), and rheumatoid factor.

Neurologic complications appear to be less common than in other connective tissue disorders, but there is a report of a relapsing bilateral optic neuropathy that was unresponsive to treatment with steroids and cyclophosphamide associated with anti-SS-A and anti-RNP antibodies.151 Optic neuropathy occurs more often in association with a Devic’s syndrome; in one case,152 high-dose steroids