Severe neuro-behçet’s disease refractory: Radiologic improvement with tocilizumab

Abstract

Neuro-Behçet’s disease (NBD) is a rare and potentially severe manifestation of Behçet’s disease, frequently associated with poor neurological outcomes. Management relies on high-dose corticosteroids and immunosuppressive agents, yet a subset of patients develops rapidly progressive and treatment-refractory disease. We report the case of a 39-year-old man with Behçet’s disease who presented with progressive neurological deterioration. Brain magnetic resonance imaging (MRI) revealed multiple inflammatory lesions involving the brainstem and cerebral hemispheres, with subsequent radiological progression despite intensive immunosuppressive therapy. Tocilizumab, an interleukin-6 receptor antagonist, was introduced as salvage treatment in the context of rapid disease worsening. Follow-up MRI demonstrated a striking regression of inflammatory lesions. However, this radiological improvement was not accompanied by clinical recovery, and the patient ultimately died due to severe systemic complications. This case illustrates a marked dissociation between radiological response and clinical outcome in severe, refractory neuro-Behçet’s disease. While the imaging findings suggest a potential effect of IL-6 blockade on inflammatory brain lesions, they also underscore the limitations of radiological improvement as a surrogate marker of clinical benefit. This observation highlights the complexity of disease progression in NBD and the critical importance of early intervention and comprehensive systemic management.

Introduction

Neuro-Behçet's disease (NBD) encompasses some of the most severe presentations of Behçet’s disease (BD). Diagnosis and management of NBD can be challenging, as no specific diagnostic test exists. NBD must be differentiated from multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), stroke, cerebral venous sinus thrombosis, spinal cord disorders, presenile dementia, aseptic meningitis, and other common neurological conditions [1]. Neurological involvement occurs in approximately 5% to 18% of patients with BD [2,3]. Regarding treatment, most patients show a favorable response to glucocorticoids (GCs) and cyclophosphamide [4]. Furthermore, due to elevated IL-6 levels observed in Behçet’s patients with active inflammation, a potential therapeutic benefit can be hypothesized from inhibiting IL-6 signaling using tocilizumab, a monoclonal antibody targeting the IL-6 receptor [5,6].

This case reports a patient with NBD who showed progressive disease activity under standard immunosuppressive treatment and later exhibited significant radiological improvement after initiation of tocilizumab, an IL-6 receptor antagonist.

Case presentation

A 39-year-old man with a known history of Behçet’s disease presented to the emergency department of our university hospital with progressive left-sided hemiparesis, ataxia, psychomotor agitation, and visual hallucinations. Neurological examination revealed a left pyramidal syndrome with muscle strength graded at 3/5, along with static cerebellar signs. Physical examination showed recurrent oral aphthae and a genital ulcer. Brain MRI showed 2 contrast-enhancing brainstem lesions affecting both cerebral hemispheres: 1 involving the right basal ganglia and thalamus with extension into the midbrain and pons, and another located in the left temporal lobe. These lesions were hyperintense on FLAIR sequences and showed contrast enhancement (Fig. 1).

Fig. 1.

(A,B,C) Axial T2 FLAIR and (D,E,F) axial T1 postcontrast of Brain MRI revealed 2 hyperintense FLAIR lesions with contrast-enhancing, involving both cerebral hemispheres: 1 lesion located in the right basal ganglia and thalamus and extending to the midbrain and pons, and another lesion in the left temporal region.

Routine blood tests showed elevated ESR (45 mm/h; normal 1-25) and C-reactive protein (2.5 mg/dL). Extensive screening for autoimmune, neoplastic, and infectious etiologies—including ANA, ANCA, LAC, ACA, TPHA, HIV, Toxoplasma gondii, VZV, and HSV—was negative. Cerebrospinal fluid analysis revealed pleocytosis (100 cells/mm³: 67% neutrophils, 33% lymphocytes); cultures were negative. A brain biopsy, performed to exclude neoplasm or tumefactive lesions, revealed perivascular lymphocytic infiltration with gliosis. A postbiopsy noncontrast brain CT scan demonstrated small punctate hypodensities in the right frontoparietal region, consistent with the biopsy tract, without evidence of significant hemorrhagic complication (Fig. 2).

Fig. 2.

Noncontrast axial brain CT scan performed after stereotactic brain biopsy, showing small punctate hypodensities in the right frontoparietal region, corresponding to the biopsy tract and consistent with expected postprocedural changes.

Initial treatment comprised 10 days of intravenous methylprednisolone (1000 mg/day) and cyclophosphamide (200 mg/day), resulting in symptomatic improvement. Maintenance therapy included oral prednisolone (1 mg/kg/day, tapered by 5 mg after 1 month), azathioprine (150 mg/day), and monthly cyclophosphamide infusions (200 mg). One month later, the patient developed left hemiplegia and received another 5-day cycle of IV methylprednisolone and cyclophosphamide, followed by the same oral regimen.

Several months later, the patient experienced further neurological deterioration with behavioral changes (aggression and agitation), recurrent visual hallucinations, right-sided hemiplegia, and 3 generalized tonic–clonic seizures. Repeat MRI revealed marked enlargement of the pre-existing lesions, exhibiting mixed signal characteristics (isointense on T1-weighted images, hyperintense on FLAIR sequences, and hypointense foci on T2*-weighted images suggestive of hemorrhagic components), intense contrast enhancement, and extensive perilesional edema causing subfalcine herniation (Fig. 3). Shortly thereafter, the patient’s condition worsened (Glasgow Coma Scale score of 8/15 with bilateral mydriasis), requiring admission to the intensive care unit, endotracheal intubation, and sedation.

Fig. 3.

(A, B, C, D) Axial T2 FLAIR, (E, F, G) axial T1 postcontrast and (H) axial T2* of Brain MRI revealed enlargement of pre-existing lesions with contrast-enhancing and hemorrhagic foci.

Given the rapid progression and lack of response to conventional immunosuppressive therapy, tocilizumab was initiated as salvage treatment, administered intravenously at a dose of 8 mg/kg on 2 occasions 4 weeks apart, following careful assessment of the risk–benefit profile. Prior to IL-6 blockade, an additional course of intravenous methylprednisolone and cyclophosphamide had failed to induce any clinical improvement. After tocilizumab therapy, the patient’s neurological status remained unchanged; however, follow-up MRI demonstrated a marked and diffuse regression of the inflammatory lesions (Fig. 4). Despite this radiological improvement, the clinical course was complicated by the development of severe pressure ulcers, leading to sepsis and septic shock, which ultimately resulted in a fatal outcome.

Fig. 4.

(A,B,C) Axial T2 FLAIR and (D,E,F) axial T1 postcontrast of Brain MRI revealed a clear regression of pre-existing lesions after treatment.

Discussion

Behçet disease (BD) is a multisystemic inflammatory disorder of unknown etiology that can affect various organs, including the central nervous system (CNS) [7,8]. NBD is a potentially severe complication of BD, associated with high morbidity and, in some cases, long-term neurological disability [9].

Although the precise pathogenesis of NBD remains unclear, therapeutic strategies have historically relied on high-dose corticosteroids followed by tapering, often in combination with immunosuppressants like cyclophosphamide and azathioprine. These regimens have shown efficacy in nonrandomized, open-label studies [4]. However, a subset of patients remains refractory to these treatments, highlighting the need for alternative approaches [10].

According to the most recent European League Against Rheumatism (EULAR) recommendations, anti–tumor necrosis factor (anti-TNF) agents represent a recommended option for severe or refractory BD, including NBD [11]. Monoclonal anti-TNF antibodies are increasingly used as first-line biologics in severe neurological involvement. Nevertheless, resistance or suboptimal response to anti-TNF therapy has been reported, and evidence guiding treatment escalation remains limited [12]. Importantly, current guidelines do not provide clear recommendations regarding the optimal sequencing or timing of biologic therapies in fulminant NBD.

In the present case, anti-TNF therapy was not initiated following cyclophosphamide due to the patient’s rapidly progressive neurological deterioration and radiological worsening despite aggressive conventional immunosuppression. The marked enlargement of lesions, and rapid decline in consciousness prompted the treating team to escalate directly to a cytokine-targeted therapy with a potentially faster and more specific anti-inflammatory effect. This decision was supported by accumulating evidence implicating IL-6 as a key mediator in the pathogenesis of parenchymal NBD.

IL-6 has emerged as a key pro-inflammatory cytokine in the pathogenesis of NBD. Elevated IL-6 levels have been observed in both serum and cerebrospinal fluid (CSF) during active phases of the disease [5,13,14]. These findings underscore IL-6 as a potential therapeutic target, especially in refractory cases.

Tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has shown promise in this setting. While controlled trials are lacking, several case reports and small series have demonstrated clinical and radiological improvement following tocilizumab treatment in patients with refractory NBD [10,15].

Our case closely mirrors these reports. Notably, the patient experienced continued clinical deterioration and clear radiological progression while receiving high-dose corticosteroids, cyclophosphamide, and azathioprine. In contrast, a marked and relatively rapid regression of inflammatory lesions was observed on MRI only after the introduction of tocilizumab. Although cyclophosphamide and other immunosuppressive agents may also lead to radiological improvement, the temporal relationship between tocilizumab administration and the reversal of lesion progression strongly suggests that IL-6 blockade played a major role in controlling neuroinflammation in this case. Similar radiological responses following tocilizumab initiation have been reported in the literature, reinforcing the plausibility of this observation [10,15].

Despite this radiological improvement, the absence of clinical recovery underscores an important and well-recognized challenge in severe NBD: the dissociation between imaging findings and neurological outcome. Advanced disease stage at treatment initiation, irreversible parenchymal damage, and systemic complications—most notably severe infection in our patient—likely limited the potential for functional recovery. These findings emphasize that radiological response alone should be interpreted cautiously and cannot be equated with clinical efficacy.

Overall, this case contributes additional evidence supporting the biological and radiological efficacy of IL-6 blockade in refractory NBD, particularly in rapidly progressive forms unresponsive to standard therapies. At the same time, it highlights the critical importance of early therapeutic intervention, before irreversible neurological injury and life-threatening complications occur. Further prospective and controlled studies are urgently needed to better define the role, timing, and optimal positioning of tocilizumab and other non–TNF biologics in the treatment algorithm of severe NBD [12].

Conclusion

This case highlights the value of advanced neuroimaging in monitoring disease activity and therapeutic response in severe neuro-Behçet’s disease. In a rapidly progressive and treatment-refractory course, a marked and near-complete regression of inflammatory lesions was observed shortly after initiation of tocilizumab. Although this radiological response was not accompanied by clinical recovery, it supports the potential role of interleukin-6 blockade in controlling neuroinflammatory activity in selected cases. The dissociation between imaging and clinical outcomes underscores the importance of early intervention, careful patient selection, and cautious interpretation of radiological improvement. This case adds to the growing imaging-based evidence supporting further investigation of IL-6 inhibitors, particularly their earlier use in severe or rapidly worsening neuro-Behçet’s disease.

Patient consent

Written informed consent for the publication of this case report was obtained from the patient.