Neuro-Behçet, pseudotumor cerebri and ocular signs: a rare association.

INTRODUCTION: The central nervous system involvement in Behçet's disease occurs in 5-30% of cases. The diagnosis of pseudotumor cerebri is even rarer (only 22 cases reported worldwide).
PURPOSE: To emphasize the importance of differential diagnosis in a case of pseudotumor cerebri in the context of ocular inflammation.
METHODS: V.A.V.R., a 31 year old female, was diagnosed with pan-uveitis on the left eye associated with recurrent bipolar aphthosis. During the etiological investigation, there was an onset of a left hemiparesis and facial palsy.
RESULTS: The central nervous system (CNS) neuroradiological investigation revealed a space-occupying lesion within the right hemisphere with intense signal enhancement with gadolinium. It globally reached the nucleo-basal structures and induced deviation of the middle structures (including homolateral ventricle). Cytochemical analysis of cerebrospinal fluid (CSF) was negative for atypical cells. The ophthalmological features regressed with the corticosteroid and immunosuppressive therapy instituted. The final diagnosis was of pseudotumor cerebri in the context of Behçet's disease.
CONCLUSION: In Behçet's disease, a cerebral space-occupying lesion should lead to a diagnosis of pseudotumor cerebri. The correct diagnosis will determine an appropriate therapy and may prevent an inappropriate neurosurgical approach. The cortico and immunotherapy allowed a substantial regression of the lesion.

Introduction

Behcet’s disease is a multisystemic vasculitis of unknown cause characterized by the triad of genital ulceration, oral ulceration and uveitis and has a relapsing-remitting course [1], [2], [3], [4], [5], [6], [7].

Ocular involvement occurs in 80% of cases [8], generally after oral ulceration; clinically, it presents itself as an intraocular inflammation [3], [9], at the anterior and posterior segment in various combinations: conjunctival hyperemia, photophobia, hypopion, posterior synechiae, vitreous opacification and retinal lesions, namely macular edema [9]. Decreased visual acuity can result from glaucoma, cataracts, optic neuritis, vitreous hemorrhage or retinal vascular occlusion and may progress rapidly to blindness [8], [10], [11]. Bilateral involvement occurs in 75% of the cases [9].

Systemically, central nervous system involvement is seen in 5–30% [2], [12], [13], [14] of the cases, and pseudotumoral form is even rarer – only 22 cases reported so far [2], [3], [4], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. This neurological variety is the most serious, associated with high mortality rates [5], [11], [14]. The initial symptom is, in most cases, a severe headache [31].

There’s no pathognomic laboratorial test and therefore the diagnosis is based on clinical evidence [3]. The symptoms are divided in minor and major and, according to a combination of these, the disease may be complete, incomplete or possible. The pathergy test is an auxiliary data, although its low sensitivity [4], [32]. The disease is strongly associated with HLA B-51 [8], [33], [34].

Treatment aims to suppress the inflammation and must be administered as early as possible [35]. Therefore, the frequency and intensity of relapses may be minimized, avoiding further eye injuries. Despite treatment, the natural progression of the disease is by attacks and remissions [35].

Materials and methods

A 31 year-old woman, with an unconfirmed history of erythema nodosum, is diagnosed with a pan-uveitis, associated with bipolar recurrent ulceration. During the etiological investigation, she presented a facial paresis and left hemiparesis. The patient underwent further examination, namely neuro-imaging (Computed Tomography – TC-scan; Magnetic Ressonance Imaging – MRI-scan; diffusion-weighted MRI) and ophthalmologic exams (Optical Coherence Tomography – OCT, fluorescein angiography and automatic static perimetry). Systemic (cyclophosphamide, cyclosporine and prednisone) and topical (dexamethasone and cyclopentolate) therapies were implemented.

Results

On the first examination the patient presented with decreased visual acuity (0.3 in Snellen’s chart) in the left eye associated with an exuberant anterior chamber reaction, posterior synechiae, dense vitritis and macular star; in the right eye, despite a preserved visual acuity, the funduscopy revealed a whitish lesion on peripheral retina, at 12 h, suggestive of chorioretinitis focus, surrounded by satellite lesions and superficial small hemorrhages. The intraocular pressure was within normal limits (Figure 1 (Fig. 1)).

Figure 1

Fundus photographs before treatment. A: right eye, showing no changes. B: left eye, with macular star and vitritis. C: right eye, middle periphery: chorioretinitis focus surrounded with satellite small lesions and superificial round hemorrhages.

The patient was further investigated, both systemically and ophthalmologically.

Systemically:

HLA typing: B51 positive;

Pathergy test: positive;

Sarcoidosis: serum and urine calcium levels and angiotensin converting enzyme within normal range;

Bartonellosis: Bartonella henselae serology turned negative (IgM and IgG);

Lyme disease: Borrelia burgdorferi serology also turned negative for both IgM and IgG;

HIV 1 and 2: negative serology (confirmed by Western-blot);

Syphilis: negative TPHA and non-reactive VDRL.

Ophthalmologically:

Ocular ultrasonography: vitreous opacities on the left eye;

Fluorescein angiography: lack of vasculitis signs bilaterally; vitritis and macular star on the left eye (Figure 2 (Fig. 2));

Figure 2

Fluoresceinic angiograms (both eyes) showing the evolution through time. A: at diagnosis, revealing opacities (vitritis) on left eye. B: first month after treatment. C: fourth month.

Automated static perimetry: severe and diffuse visual field defect rapidly progressive, more evident in the left eye (Figure 3 (Fig. 3));

Figure 3

Automated static perimetry (Octopus 101®) serial exams in A, right eye and B, left eye

OCT: subtle macular edema on the left eye, with a central retinal thickness of 240 micra (Figure 4 (Fig. 4));

Figure 4

Optical Coherence Tomography (OCT) Stratus Zeiss® findings. A: right eye. B: left eye, macular edema, more pronounced on nasal quadrants.

Visually Evoked Potencial (VEP) pattern: assymetric evoked cortical potentials, (P100 wave with an increased delay and reduced amplitude – abnormal conduction on the pre-chiasmatic optic tract);

Electroretinogram (ERG) full field: bilateral, but assymetric, global retinal response dysfunction, under escotopic and photopic conditions; b-wave OD = 223 mV, OE=51.9 MV; flicker response OD = 59.8 mV, OE = 10.1 mV.

The sudden installation of a facial paresis and left hemiparesis justified the neuroradiological study. The cranial CT revealed a hypodensity at the nucleo-capsular with radiated crown and sublenticular extension, which conditioned molding of the body and the frontal horn of the right lateral ventricle (Figure 5 (Fig. 5)).

Figure 5

Cranial CT: space occupying lesion on the right hemisphere deforming the ipsilateral ventricle

Cranial MRI revealed a large and deep right hemispheric lesion centered at the lenticulo-capsular region that involved the thalamus, the caudate nucleus, the external capsule, subthalamic areas, the right cerebral peduncle and the midbrain, also extending to the radiate crown. It produced a mass effect that deformed the ipsilateral ventricle and deflected the midline structures, disproportionately to its size. After gadolinium administration there was an enhancement of the signal in the center of the lesion; water restriction was also detected in the center of the lesion (FLAIR) (Figure 6 (Fig. 6)). The Angio-MRI was normal.

Figure 6

Cranial MRI. A: before gadolinium. B: after gadolinium: central enhancement is evident. C: FLAIR: periventricular high-signal intensity lesion (coronal and sagital sections). D: Diffusion Weighted (DW): hydric restriction at the center of the lesion. E: Apparent Diffusion Coefficient (ADC): weaker signal.

The cerebrospinal fluid (CSF) had a high cellular (mainly lymphocytes) and protein content, which suggested an inflammatory process; the protein content also suggests a mild permeability of the blood-brain barrier. Its pressure was within normal limits.

Endovenous therapy was instituted with prednisolone (1.5 mg/kg/day) and cyclosporine A (150 mg 12–12 h) [36], justified by the severity of the clinic, and, at the 32nd day, cyclosporine was replaced for cyclophosphamide (1 cycle/month, 3 months, 500 mg/m2). Control MRI (17th day of therapy) revealed a residual parenchymal lesion, which induced less mass effect.

The ophthalmological signs partially remitted, despite a deterioration of the visual field and persistence of a mild macular edema in the left eye.

Discussion

A patient with intraocular inflammation presents a broad differential diagnosis.

In this case, the initial ophthalmologic features (neuroretinitis, vitritis, anterior uveitis and whitish retinal lesion on the left eye) associated with the oral-genital ulcers oriented the diagnosis towards Behçet’s disease [1], [3]; however, arising neurological symptoms suggested a concomitant ischemic stroke, without apparent connection with the ocular symptoms.

Once the vascular theory was ruled out by neuroradiological exams, other hypotheses were considered on the differential diagnosis of a cerebral mass lesion: neoplastic or inflammatory (infectious or not) [37], [38]. Brain perfusion MRI is a very sensitive exam [39]; the diffusion weighted image and ADC map allows a better characterization of the lesion [40], and therefore a more accurate diagnose.

Upon neurorradiologic findings and considering the eye inflammation, oral and genital ulceration, HLA B51 positiive [8], [33], [34] and positive pathergy test [4], [32] the most likely diagnose was Behçet’s disease, pseudotumor cerebri variant.

The correct diagnosis is extremely important because it can avoid unnecessary neurosurgical approachs [41].

The most appropriate medical treatment consists of corticosteroids associated with immunosuppression, in different combinations [7], [13], [35], [37], [42], [43]. The immunosuppression was initially achieved by cyclosporine, but because of the severity of the symptoms in this case and the eventual neurotoxicity of the drug [36], [38], [44], [45], it was replaced by cyclophosphamide [5], [6], [12], [46]. The patient went under remarkable neurological improvement, according the neurologic exam (improvement of limbs’ strength) and neuroimaging (reducing the effect of a local mass effect and no enhancement after gadolinium).

Ophthalmologically, the best corrected visual acuity oscillated over time in both eyes. There was a good initial response to cyclosporine and cyclophosphamide, with a significant improvement in visual acuity (from counting fingers to 0.3) and remarkable regression of the tumor lesion. However, through time, we might admit worsening of the visual acuity and perimetry.

Currently, biological therapy with infliximab (interferon alpha) is being considered [6], [8], [12], [42], [43], [47].

Conclusions

In Behçet’s disease, a cerebral space-occupying lesion should orient diagnosis towards pseudotumor cerebri [37], [40].

The correct diagnosis and a proper and timely treatment can prevent inappropriate neurosurgical approach [41].

The steroid and immunosuppressive therapy allow a significant regression of the lesion [7], [13], [35], [37], [42], [43].

Notes

Competing interests

The authors declare that they have no competing interests.