Background The neuro-ophthalmological manifestations of Behcet’s disease (BD) are rare, and data regarding their characteristics and outcome are lacking.
Objective To report prevalence, main characteristics and outcome of neuro-ophthalmological manifestations in BD.
Patients and methods This is a retrospective monocentric study of 217 patients diagnosed with neuro-Behçet’s disease (NBD), of whom 29 (13.3%) patients presented with neuro-ophthalmological manifestations (55% of men and mean±SD age of 26±8 years). All patients underwent a detailed ophthalmological examination and were followed up in the internal medicine and the ophthalmology departments.
Results Neuro-ophthalmological manifestations were the first presentation of BD in 45% of patients and developed later in the course of the disease in 55% of patients. They are divided into parenchymal (PM) and non-parenchymal (NPM)-related manifestations in, respectively, 13 patients (45%) and 16 patients (55%). PM included papillitis in seven patients (53.8%), retrobulbar optic neuritis in four patients (30.8%) and third cranial nerve palsy in two patients (15.4%). NPM included papilloedema related to cerebral venous thrombosis in all 16 patients, of whom 6 patients (37.5%) had sixth cranial nerve palsy. At initial examination, 93.1% of patients had visual alterations, including mainly decreased visual acuity visual field defects and/or diplopia. All patients were treated with corticosteroids and 79% of patients received immunosuppressive agents. After treatment, the visual outcome improved or stabilised in 66.7% of patients while it worsened in 33.3. The mean±SD logarithm of the minimum angle of resolution visual acuity improved from 0.4±0.3 at diagnosis to 0.2±0.3 after therapy. 10.3% and 3.4% of patients were legally blind at diagnosis and after therapy, respectively.
Conclusion Neuro-ophthalmological manifestations of BD represented 13% of NBD. They could be potentially severe and disabling. Prompt treatment is the key factor in improving visual outcome.
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Behçet’s disease (BD) is an inflammatory, multisystem disease of unknown origin, characterised by recurrent oral aphthous ulcers, genital ulcers and intraocular inflammation.1 BD mainly affects young men, and has a peculiar geographical distribution in the ‘silk road’ countries, the ancient route between the Mediterranean, the Middle East and the Far East. Neurological involvement in BD was first reported in 1941 by Knapp. Its frequency is variable, ranging from 5.3% to more than 50% of patients.2 3 These lesions are typically described as ‘parenchymal’ and ‘extra-parenchymal’.4 Parenchymal neuro-Behçet’s disease (NBD) includes all neurological manifestations unrelated to vascular thrombosis. These parenchymal lesions are mainly located at the mesodiencephalic junction and the brainstem, with typical features consisting of small, scattered inflammatory lesions detected on MRI with contrast enhancement, and peripheral oedema.5 Patients are likely to present with acute symptoms such as headaches, and the main clinical signs include hemiparesis and brainstem involvement. Apart from these classical manifestations, parenchymal NBD also includes rare but severe presentations such as myelitis or pseudo-tumorous inflammatory lesions.6 7 Both parenchymal and non-parenchymal (ie, cerebral venous thrombosis (CVT)) forms can be simultaneously involved and have been classified in some studies as a mixed type.8 9
Neuro-ophthalmological manifestations of BD have been only reported in small case series.10–12 They include papilloedema (related to increased intracranial pressure), papillitis, retrobulbar optic neuritis and ocular motor nerve palsy. Optic nerve atrophy, which is an important complication of optic nerve involvement, was also described. However, the prevalence, the clinical characteristics and the outcome of these manifestations have been difficult to ascertain since reports specifically investigating neuro-ophthalmological manifestations of BD are lacking.
Therefore, the aim of the present study was to analyse the prevalence, main clinical characteristics and outcome of patients presenting with neuro-ophthalmological manifestations of BD.
Patients and methods
Medical records of 217 patients diagnosed with NBD between 1986 and 2015 were retrospectively reviewed. All patients fulfilled the international criteria for BD.1 The diagnosis of NBD was based on objective neurological symptoms not explained by any other known disease or therapy, associated with neuroimaging findings suggestive of BD-related CNS involvement and with cerebrospinal fluid (CSF) findings showing elevated CSF opening pressure (>25 mm Hg) or aseptic inflammation. Patients with neuro-ophthalmological manifestations of BD were included in the study (figure 1). They included papilloedema, papillitis, retrobulbar optic neuritis and ocular motor nerve palsy. Papillitis was distinguished from papilloedema by the unilateral involvement of the optic nerve, the important decrease in the visual acuity associated with altered colour vision, and the appearance of visual scotoma as well as the presence of an afferent pupillary defect of the involved eye with no features of raised intracranial pressure neither on neuroimaging nor on lumbar puncture. All patients were followed in the ophthalmology and internal medicine departments at the Pitié Salpêtrière University Hospital in Paris, France. The study was driven in accordance with the Declaration of Helsinki.
Data collection and outcome measurement
The following data were collected: age at diagnosis, gender, date of neuro-ophthalmological BD diagnosis, geographical origin and clinical manifestations of BD (mucocutaneous lesions, eyes, joint, NBD and vascular involvement). Data regarding the therapeutic modalities (drug, duration) were collected.
Ophthalmological assessment included visual acuity, slit-lamp examination, fundus examination, visual field and fluorescein angiography. A thorough medical examination was also performed to detect the presence of extraocular manifestations. human leukocyte antigen (HLA)-B51 antigen testing was available for all of our patients.
Stabilised or improved visual outcome was defined by either stabilisation or improvement of visual acuity in logarithm of the minimum angle of resolution (logMAR) by 0.2 log units, stabilisation or improvement of visual field scotomas, and disappearance of diplopia over a period of 6 months after appropriate management.
Worsening visual outcome was defined by worsening of visual acuity in logMAR by 0.2 log units, enlargement of the visual field defect or appearance of further new scotoma or persistence of diplopia, over a period of 6 months despite appropriate management.
Visual alterations were defined by the presence of either a decrease in visual acuity, visual field defects or diplopia, and were evaluated at baseline and following treatment with steroids and/or immunosuppressant (IS) medications over a period of 6 months.
Visual acuity and visual field were evaluated before and after treatment with steroids and/or immunosuppressive therapy.
Patients who were legally blind were defined by a visual acuity ≥+1.00 logMAR.
Characteristics of patients with neuro-ophthalmological manifestations of BD
Data are summarised in table 1.
The medical records of 217 patients with NBD have been reviewed. Twenty-nine patients (13.3%) presented with neuro-ophthalmological manifestations of BD and were included in the study. The mean (±SD) age at diagnosis was 26 years (±8), ranging from 8 to 47 years. Out of the 29 patients included, 16 (55.5%) were male. Fourteen patients (48%) originated from North Africa, 12 (41%) patients were Caucasians and 3 (10.3%) patients were from Sub-Saharan Africa. Systemic findings of BD included genital ulcers (62%), joint disease (45%) and vascular manifestations (14%). HLA-B51 testing was positive in 6 (20.7%) patients.
euro-ophthalmological manifestations were the first presentation of BD in 13 (45%) patients.
All patients complained of headache. Twenty-three patients (79%) had blurred vision and eight patients (27.5%) had diplopia. Twenty-three patients (79%) had decreased visual acuity, 23 patients (79%) had visual field defects and 8 patients (27.5%) had ocular motor nerve palsies (of whom 25% had third cranial nerve involvement and 75% had sixth cranial nerve involvement). Forty-three per cent of patients had an acute onset of visual symptoms within 48 hours, whereas 57% had a progressive onset over a week. Sixteen patients (55%) had neuro-ophthalmological manifestations related to the non-parenchymal form of NBD. All of these 16 patients had papilloedema secondary to raised intracranial pressure on fundus examination, and 6 of whom (37.5%) had associated sixth cranial nerve palsy. Parenchymal-related manifestations were present in 13 patients (45%) and included papillitis in 7 patients (53.8%), retrobulbar optic neuritis in 4 patients (30.8%) and third cranial palsy in 2 patients (15.4%).
Eight patients developed optic atrophy in the course of the disease. Fifty five per cent were male and 62% of patients were of North African origin. Long-standing papilloedema was the origin of this sequela in five patients (62.5%) while severe optic neuropathy was the origin in three patients (37.5%).
Posterior uveitis was present in 13 patients (45%), and it was mainly associated with papillitis in six patients, with retrobulbar optic neuritis in two patients and with papilloedema in four patients.
The characteristics of patients with BD according to the neuro-ophthalmological findings are summarised in table 2.
Outcome of patients with neuro-ophthalmological manifestations of BD
Data are summarised in tables 3 and 4.
The median follow-up was 8 (range 1–28) years. Among the 27 patients with visual alterations (whether it was decreased visual acuity, visual field defects or diplopia), 18 patients (66.7%) showed a stabilised or improved visual outcome following treatment.
All 29 patients received treatment with corticosteroids and 23 of them received adjuvant immunosuppressive therapy. IS therapy included azathioprine in 12 patients, mycophenolate mofetil in 4 patients, interferon-α in 3 patients, cyclophosphamide in 4 patients and infliximab in 1 patient. Patients who presented with CVT were treated with anticoagulants and acetazolamide in addition. The mean logMAR visual acuity was 0.4±0.3 at diagnosis, and improved to 0.2±0.3 after 6 months of follow-up. Out of the 23 patients presenting with visual field defects, 9 (39%) patients showed worsening of visual field over a period of 6 months. Visual field defects ranged from scotomas in 13 patients (56.5%), enlargement of the blind spot in 11 patients (47.8%), concentric constriction of visual field isopters in 9 patients (39%) and a nasal step in 3 patients (10.3%). Eight patients presented with ocular motor nerve palsy, but only one patient had persistent third cranial nerve palsy after 6 months of follow-up.
Since the first description of neurological involvement of BD in 1941, only few cases and small series of neuro-ophthalmological manifestations of BD have been reported.10–12 In most of the reports, certain features of these manifestations like optic neuritis, papilloedema or ocular cranial nerve palsy have been discussed. Here we present a series of neuro-ophthalmological manifestations in BD aiming to provide information relative to the prevalence, clinical characteristics and outcome of these manifestations. Among a cohort of 217 patients with NBD, neuro-ophthalmological manifestations were present in 29 patients (13%). In a study conducted by Lamari et al 13 on 148 patients with BD, optic nerve involvement was noted in 37%. Conflicting results have been reported in other studies. In a retrospective study of 22 patients with NBD, conducted by Joseph and Scolding,14 only 9% of optic nerve involvement was found.
In our series, neuro-ophthalmological manifestations were the first presentation of BD in 13 patients (45%). In a series of 18 patients, Frigui et al 11 found that optic nerve involvement was the revealing sign of the disease in eight patients (44.4%). The onset of these manifestations was variable in our study. Forty-three per cent of patients reported an acute onset (ie, within 48 hours) of decreased visual acuity or diplopia, whereas 57% had a progressive onset (ie, over a week). The demographics of the patients in our series confirm the well-known geographical distribution of the disease, as well as the age and male predominance.
Optic nerve involvement was by far the most frequent manifestation. Its presentation can be divided into papilloedema, related to increased intracranial pressure, most commonly bilateral, which is the most common presentation; anterior optic neuropathy or papillitis, seen as an optic disc oedema on fundus exam; and posterior optic neuropathy or retrobulbar optic neuritis, characterised by a normal optic disc on fundus exam and optic disc atrophy, which is a serious complication or sequela of all untreated long-standing optic nerve involvement.
Papilloedema is a frequent result of non-parenchymal neurological involvement in the form of CVT. The diagnosis of CVT was documented in all patients by cerebral angiography and MRI showing partial or total lack of filling of at least one dural sinus and an elevated CSF opening pressure (>25 mm Hg) on lumbar puncture. In this study, papilloedema was present in 55% of patients who had neuro-ophthalmological manifestations related to BD, and in large series of CVT related to BD, papilloedema was present in 62.5%–89% of patients.4 15 These findings show that papilloedema is by far the most frequent neuro-ophthalmological manifestation of BD.
Optic neuropathies result from an inflammatory or ischaemic process associated with the parenchymal form of the disease, presenting with a decreased visual acuity and visual field scotoma. Anterior involvement is more frequent than the posterior form in most series of the literature.11 13 In our series, 11 patients (38%) presented with optic neuritis, of whom 64% had anterior optic neuritis or papillitis and 36% had posterior optic neuritis. Posterior uveitis was associated mainly with optic neuritis and the parenchymal form of the disease, presenting in 85.7% of patients with papillitis and 50% of patients with retrobulbar optic neuritis.
An important complication of optic nerve involvement in NBD is optic atrophy. This irreversible sequela presents the end stage of optic nerve disease. It can result from a long-standing untreated papilloedema due to raised intracranial pressure, or of a severe optic neuropathy. In our series, eight patients (30%) developed optic atrophy on follow-up. It was slightly more common in men (55%) and was frequently found in patients of North African origin (62%). Five patients (62.5%) developed optic atrophy as a sequela of papilloedema and three patients (37.5%) had optic atrophy as a complication of severe optic neuropathy. This complication was reported in 15.3%–45% of patients in a series of NBD.13 16
Ocular motor nerve palsy is another neuro-ophthalmological manifestation of BD. Presenting usually with diplopia, it can either be isolated or in association with optic nerve involvement. There are only few case reports and studies in the literature that describe these manifestations in BD.17 Benamour et al 18 reported that the most frequent ocular motor nerve palsy was sixth cranial nerve palsy, with 24.4% of patients having external ophthalmoplegia. Sixth cranial nerve palsy results from an increased intracranial pressure secondary to CVT. In the same study, third cranial nerve palsy was present in only 6.7% of patients with ocular motor nerve involvement and was associated with the parenchymal form of NBD. In our study, eight patients (27.5%) presented with ocular motor nerve palsy. Seventy-five per cent had sixth cranial nerve and 25% had third cranial nerve palsy. All cases of sixth cranial nerve palsy were associated with papilloedema as a result of raised intracranial pressure secondary to CVT, whereas third cranial nerve palsy was exclusively associated with the parenchymal form of NBD.
In the present study, all patients with neuro-ophthalmological manifestations of BD received high-dose corticosteroids and 79% had an IS including mainly azathioprine. Patients who presented with CVT were also treated with anticoagulants and acetazolamide. Overall prognosis of neuro-ophthalmological manifestations was satisfactory as 66.7% of patients showed improvement or stabilisation of visual outcome. One-third of patients worsened and had definitive visual sequelae. Only one patient became legally blind.
This study presents certain limitations. Even though it was conducted in a tertiary referral centre for systemic and ocular inflammatory diseases, only 29 patients were found to have neuro-ophthalmological manifestations related to BD. Furthermore, BD is generally known to affect mainly young men, usually with a ratio of 3:1, but in this study neuro-ophthalmological manifestations were only slightly more common in men (55%). Moreover, there were no patients of a Middle Eastern or Asian origin even though BD traditionally had a geographical distribution that extends from the Middle Eastern region to the Far East. Finally, the cut-off period of follow-up in order to evaluate the visual outcome of these manifestations was defined in this study by 6 months, which is a relatively short period for a chronic relapsing and remitting inflammatory disease such as BD.
In conclusion, although neuro-ophthalmological manifestations of BD are quite rare, they could be potentially severe and disabling. The differential diagnosis of these manifestations often requires a multidisciplinary expertise (ophthalmologists, neurologists and internists). Clinicians should be aware of these manifestations in order to establish an early diagnosis of NBD. This is particularly important in cases of BD with inaugural neuro-ophthalmological manifestations. Early adequate treatment is a key factor to improve the outcome of these patients.
Contributors AA, BB, VT and DS: contributed to the conception of this study and designing it, as well as acquiring and analysing the data, writing the paper, revising it critically and approving its final version. CC, ACD, FD, BW, RD, PLH and PC: contributed to the conception and the design of this study, acquiring and analysing the data, as well as revising it critically and approving its final version. AA, BB, CC, ACD, FD, BW, RD, PLH, PC, VT and DS agree to be accountable for all aspects of the work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Ethics approval The study was approved by the institutional review board of Pitié Salpêtrière University Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no additional unpublished data from this study.