Brain, Vol. 126, No. 2, 276-284,
February 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg045
Chronic relapsing inflammatory optic neuropathy (CRION)
1 Neuro-ophthalmology Department, National Hospital for Neurology and Neurosurgery and 2 Medical Eye Unit, St Thomas’ Hospital, London, UK *Present address: Department of Clinical Neurosciences Royal Free Hospital, Pond Street, London NW3 2QG, UK
Correspondence to: Dr Elizabeth Graham, Consultant Medical Ophthalmologist, Medical Eye Unit, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK Email: elizabeth.graham{at}gstt.sthames.nhs.uk
Received October 31, 2001. Revised April 13, 2002. Second revision October 14, 2002. Accepted October 20, 2002.
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Summary |
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We describe the clinical characteristics and early natural history of a form of inflammatory optic neuropathy which is frequently bilateral and often painful, and is characterized by relapses and remissions. MRI scans of the brain are normal and those of the optic nerves often, but not always, show high signal abnormalities which enhance. The symptoms and signs respond well to corticosteroid treatment, although long-term immuno suppression is often necessary. The syndrome behaves in a way which is typical of the condition known as granulomatous optic neuropathy, but during a median follow-up of 8 (2–26) years in no case has evidence for systemic sarcoidosis been identified. We suggest that the disorder be named chronic relapsing inflammatory optic neuropathy (CRION).
Keywords: optic neuropathy; granuloma; sarcoidosis
Abbreviations: CRION = chronic relapsing inflammatory optic neuropathy
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Introduction |
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Subacute loss of vision accompanied by pain is most commonly due to some form of inflammatory optic neuropathy, the most common cause of which is demyelinating optic neuritis. In demyelinating optic neuritis, patients present with periorbital ache and pain elicited by eye movement, which usually begins insidiously and worsens, in synchrony with or preceding a reduction in vision, which deteriorates over days. The pain tends to diminish as the visual symptoms supervene; the visual loss reaches a variable nadir at around 5 days, then begins to improve. Substantial recovery of vision occurs within 6 weeks, and is followed by slower recovery over 12–18 months (Newman, 1998
). Demyelinating optic neuropathies also occur following viral infections, particularly in children, in whom the disorder is more commonly bilateral. Herpes viruses, hepatitis A, enteroviruses and exanthemata have all been associated with this complication, as have bacterial infections involving such organisms as streptococcus, meningococcus, Brucella, Pertussis, Salmonella typhi, Treponema pallidum, Borrelia and Mycobacterium tuberculosis. Post-vaccinial optic neuritis also occurs. Systemic vasculitis may cause optic neuropathy. In the majority of cases this is associated with an acute painless onset, resembling acute anterior ischaemic optic neuropathy, but in other cases there is subacute, progressive, painful optic neuropathy (Unsold, 1994). Optic neuropathy is also known in sarcoidosis, in which condition granulomatous masses are often seen to involve the anterior visual pathways but in some cases imaging is normal. Compressive or infiltrative lesions, such as metastatic carcinoma or lymphoreticular disease, meningioma and glioma, and fungal diseases may all present in similar ways. |
Methods |
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The diagnostic databases of the neuro-ophthalmology clinics of the National Hospital and the Medical Eye Unit of St Thomas’ Hospital were reviewed. The notes of all cases described as relapsing optic neuropathy or granulomatous optic neuropathy were inspected and the clinical course, natural history, response to treatment and investigation results were reviewed.
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Results |
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We report a series of 15 patients seen over the past 10 years at the neuro-ophthalmology departments of the National Hospital for Neurology and Neurosurgery and Moorfield’s Eye Hospital and the Medical Eye Unit of St Thomas’ Hospital, in which all patients shared a characteristic clinical syndrome of subacute optic neuropathy with prominent pain, in whom there was a clear and prompt response to treatment with systemic corticosteroids but with relapse upon steroid withdrawal. Although the syndrome behaves in a way which is typical of granulomatous optic neuropathy, in no case was there evidence for systemic sarcoidosis and no case showed evidence of a granulomatous mass on imaging.
Table 1 notes the clinical characteristics of the patients and the appearance of the discs in the presenting period. No patient showed evidence of uveitis. Most patients noted pain at the onset (Table 2) and all patients responded favourably to steroids. Relapse as steroids were withdrawn was common (Fig. 1) but varied in latency from days to several months. Table 3 summarizes the investigations carried out in each case. Blood investigations were normal throughout and CSF was acellular, with normal protein values. Oligoclonal bands were absent in nine cases, and in four cases matched serum and CSF bands were seen. Unmatched oligoclonal bands were not seen in any case. Mantoux responses, Kveim tests and gallium scans, when performed, were normal in each case. Table 4 notes the visual field abnormalities and imaging findings at presentation in each case. In 13 of 30 affected eyes the visual field was constricted. Five eyes had an altitudinal pattern of field loss and five had a central scotoma. MRI of the brain was normal in all but one case, in which a single white matter lesion was seen. However, optic nerve images were clearly abnormal in 19 out of 30 nerves examined.
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Representative cases
Case 3
This 31-year-old female developed bilateral visual loss in 1994, which progressed over 4 days to no light perception. She was admitted to hospital and a compressive lesion was ruled out. Visual evoked responses showed an asymmetrical delay on both sides. She was noted to have swollen optic discs. She was treated with steroids and the vision improved to 6/6 bilaterally within 1 week. Three weeks later, however, her vision deteriorated again in the left eye, to 6/18. Treatment with oral steroids failed to improve vision but following intravenous methylprednisolone her acuity improved to 6/5 on the right and 6/9 on the left. The disc swelling resolved. With steroid reduction, vision in the left eye declined again, with recurrent disc swelling. Vision improved on each occasion that the steroid dose rose to >20 mg per day, and deteriorated below this dose. A further relapse occurred in late 1996, and her vision again improved on 60 mg oral prednisolone; since then a very gradual reduction in dose has been successful without further relapse on 2.5 mg prednisolone on alternate days. She has remained well for 36 months with acuity 6/5 bilaterally, normal colour vision and full fields.
Case 7
This 26-year-old female presented in 1975 with a subacute deterioration in visual acuity on the left over 5 days, accompanied by pain on eye movement. Several days later she developed an altitudinal field defect in the right eye. On examination at that time right visual acuity was 6/9 with 8/12 colour plates, and there was a lower altitudinal field defect; left visual acuity was 6/24 with 1/12 colour plates, and there was an upper altitudinal field defect. Both discs were swollen, the left greater than the right, with haemorrhages and exudates. She was treated with oral corticosteroids and her vision improved; vision deteriorated on steroid reduction but stabilized with reinstitution of therapy. This pattern has repeated itself since then such that she has been unable to reduce the steroid below 10 mg per day. Her current right visual acuity is 6/6 with 6/12 colour plates, with a marked inferior field defect and left visual acuity perception of hand movements.
Case 14
This female presented in 1991 at the age of 40 years with pain in the left eye exacerbated by eye movement, followed 2 days later by subacute visual loss which fluctuated but deteriorated to no perception of light over the course of 1 week. No treatment was prescribed, but the vision improved slightly over the course of the next 2 weeks, then stabilized. She then received treatment with oral corticosteroids and the vision improved. However, as steroids were withdrawn she developed recurrence of the eye pain and her vision deteriorated, so that she was treated over several months with continuous steroids in varying doses. At that time her vision was normal on the right, 6/18 on the left with reduced colour vision and a relative afferent pupillary defect. The left disc was considered to be pale but not swollen, and the right was normal. An ophthalmic assessment at Moorfield’s Eye Hospital was normal. MRI of the brain and optic nerves was also normal. The left central visual field showed paracentral defects. She continued on steroids and vision continued to fluctuate. In 1994 she was reassessed. MRI scan of the orbits revealed an enlarged left optic nerve with high signal intensity in the posterior portion of the nerve, which enhanced, and no other lesion was seen. CSF was normal. In the following year she developed a painless reduction in vision on the right eye to 6/9 and underwent further investigations; MRI scan of the orbits and CSF examination were normal. Her vision continued to fluctuate thereafter and she remained under the care of her general practitioner. In April 2000 she developed pain in the right eye with a progressive reduction in vision. She was readmitted to the National Hospital, where she was found to have left visual acuity 6/18 and right visual acuity 6/36. Colour vision was impaired on both sides. MRI scan of the orbits again showed no abnormality. She was treated with intravenous then oral corticosteroids and her vision improved to 6/9 and 6/18 respectively over the course of 4 weeks. Azathioprine was added, and as steroids were reduced she developed two further episodes of eye pain which responded to increases in steroid dosage. Current visual acuities are 6/18 and 6/6 respectively, with normal colour vision on the right and 8/17 on the left. The fields show very marked peripheral constriction on both sides.
Case 15
This female presented at the age of 37 years with the subacute onset of right supraorbital pain radiating to the temporal region, then pain on eye movement. This worsened progressively; she noticed a change in her vision in that eye about 10 days later. Over the next 4 days the pain persisted and the visual acuity deteriorated to no perception of light. A diagnosis of optic neuritis was made and she did not receive treatment. A minor spontaneous improvement in her vision occurred thereafter, but then she developed supraorbital pain on the left side with diminishing visual acuity. She was admitted to hospital, where she was found to have maximum acuity of perception of light bilaterally. She was referred to our care. The neuro-ophthalmic findings at that time were acuities counting fingers bilaterally; the discs were both pale and the left was swollen (Fig. 2). The retinal pigment epithelium was normal, with no evidence of retinal vasculitis. A fluorescein angiogram showed leakage from the left optic disc but no vascular or retinal pigment epithelial or choroidal abnormality (Fig. 3). Visual evoked potentials showed absence of the central field responses bilaterally, with markedly prolonged whole-field responses. MRI scan of the orbits revealed high signal within the left optic nerve (Fig. 4). The results of the remaining investigations are summarized in Tables 1 and 4. Treatment was instituted with prednisolone 100 mg per day. This resulted in an improvement in visual acuity over the next 4 months. Azathioprine was not tolerated, so methotrexate 10 mg weekly was added. Gradually the dose of steroids was tapered, and she withdrew successfully from this after 18 months of treatment. Two months later she also stopped methotrexate, and has remained well on no treatment for 18 months.
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Discussion |
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This series of patients presented with a clinical syndrome of unilateral or bilateral optic neuropathy characterized by pain followed by subacute visual loss, in keeping with an inflammatory cause. In the majority of cases pain was severe and persistent, arising before or coincidental with visual loss. The degree of visual loss was more severe than is the case in demyelinating optic neuritis in general. Involvement of both optic nerves was common, usually sequentially, although the latency was in some cases several years.
Treatment with corticosteroids induced abrupt and prompt relief of pain and, at times, complete restoration of normal visual acuity and colour vision even months after the onset of the symptoms (Cases 2, 6, 12 and 14). Following steroid withdrawal, patients tended to relapse, necessitating long-term immunosuppression, which appears to arrest progression of the disease in the majority of cases. However in two cases (8 and 10) abrupt steroid withdrawal led to irreversible visual loss.
The clinical characteristics differed from demyelinating optic neuropathy with respect to the severity of the pain, its persistence after onset of the visual loss, and the relapsing and steroid-dependent nature of the disease. In general the nadir acuity was lower than that seen in demyelinating optic neuritis; 65% had an acuity in the worse affected eye of 20/200 or lower, whereas in the Optic Neuritis Treatment Trial (ONTT) 35% had acuity of 20/200 or lower (Optic Neuritis Study Group, 1991). In four cases it was no perception of light (28%), whereas in the ONTT there were 14 cases (3.1%). The absence of intrathecal immunoglobulin synthesis is also against a demyelinating cause. Patients who underwent visual evoked potential examinations in general showed a prolongation in latency with relative preservation of amplitude, or conduction block, in keeping with an inflammatory lesion, and the pattern electroretinogram showed only a reduction in amplitude of the N95 peak, in keeping with a pure optic nerve disorder. It is also notable that there was an absence of systemic acute-phase response. Further investigation has shown that in no case was there evidence for systemic sarcoidosis. Optic neuropathy in this disease, which is by definition a multisystem disorder, arose in some 5% of cases in one published series (Obenauf et al., 1978), although in the Baltimore series of 649 patients only one case had optic neuropathy (Stern et al., 1985) and the Australian series (Chen and McLeod, 1989) had no cases in 285 patients with systemic sarcoidosis. Optic neuropathy has been shown to be caused by compression due to an intracerebral mass lesion, to hydrocephalus and to complications of posterior uveitis, but in the majority optic neuropathy occurs due to involvement of the nerve itself. In general the clinical syndrome closely resembled that of other inflammatory optic neuropathies, including that associated with sarcoidosis, since the condition developed subacutely, over days, with blurred vision and the appearance of a central scotoma. In one case spontaneous improvement occurred (Galetta et al., 1989) and recovery of function was observed to be appreciable, in association with systemic corticosteroids in the majority of cases. It is known that some patients may undergo worsening in acuity after steroid withdrawal (Beardsley et al., 1984; Graham et al., 1986).
The pathology of granulomatous optic neuropathy is known from cases in which nerve biopsies have been carried out owing to concern that marked nerve swelling is due to neoplastic infiltration; in these cases there is an infiltration of the nerve by lymphocytes and plasma cells, and epithelioid and giant cells with granuloma formation (Frisen et al., 1977; Gudeman et al., 1982; Graham et al., 1986, Ing et al., 1997). This is most marked, according to Frisen and colleagues, within the dura and the interfascicular septa, and granulomata within the nerve itself tend to be more common around vessels. Diffuse loss of myelin is seen and some axonal degeneration is evidenced by the formation of axon terminal swelling. There is little gliosis. The mechanism of visual loss is likely to be primarily inflammation within the nerve, since there is in general rapid resolution of the majority of symptoms with corticosteroids, and even more rapid recurrence following steroid withdrawal. The presence of demyelination and axon loss will also contribute, particularly to the persistent visual deficit following treatment.
Frisen and colleagues reported two cases in which the discovery of granulomatous optic neuropathy by biopsy was followed by a search elsewhere for evidence of systemic sarcoidosis (Frisen et al., 1977). In neither case was this found, with patients followed up for 1 and 7 years respectively. A similar case without follow-up has been published more recently (Ing et al., 1997). Statton and colleagues reported a case in which granulomatous optic neuropathy arose, to be followed not until 3 years later by systemic symptoms of sarcoidosis (Statton et al., 1964) and Castagna reported a similar case in whom symptoms of the systemic disease arose 6 months after the optic neuropathy (Castagna et al., 1994). The question therefore arises of whether the present series also comprises patients with a localized form of granulomatous disease which may, in time, present as systemic sarcoidosis. This may be so, and it could be argued that in several cases the follow-up has not been sufficiently long to rule this out, but in 10 cases follow-up has been longer than 5 years (median 10, range 6–26 years) without symptoms elsewhere. Whether the pathology of this form of relapsing inflammatory optic neuropathy is different from that of optic neuropathy due to sarcoidosis is as yet unknown.
In our series, the clinical syndrome of chronic relapsing inflammatory optic neuropathy (CRION) has clinical features similar to those considered to be due to neurosarcoidosis, except that there is no evidence for lesion dissemination even after a median of 8 (2–26) years of follow-up. It may be that in some cases granulomatous disease involves many organs and tissues, whilst in others the disease remains localized, possibly because of differences in immune activation and responsiveness.
It is important to recognize such cases since many were themselves initially diagnosed as demyelinating optic neuritis, and for this reason steroid treatment was withheld in view of the fact that it has been shown repeatedly (Beck, 1995; Kapoor et al., 1998) that steroids do not influence the outcome of optic neuritis. CRION requires careful consideration and differentiation from demyelinating optic neuritis since the treatment is entirely different and the outcome without treatment is likely to be very poor. Furthermore, the standard treatment regimen used in relapse of multiple sclerosis (for example, 3 g methylprednisolone intravenously) is not adequate for this condition; prolonged medium-dose treatment is necessary and reduction in the dose should be gradual, with careful monitoring by the patient and the clinician for evidence of relapse.
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