Acute neurological Behçet’s disease complicated by a syndrome of inappropriate secretion of antidiuretic hormone

Summary

We report a rare case of acute neurological Behçet’s disease (neuro-BD) diagnosed concurrently with systemic Behçet’s disease (BD), classified as definite BD, and complicated by syndrome of inappropriate antidiuretic hormone secretion (SIADH). A man in his 60s presented with fever, headache and mucocutaneous lesions including oral aphthae, folliculitis-like rashes, genital ulcers and hyponatraemia. He was diagnosed with BD based on mucocutaneous findings. Brain MRI showed no abnormalities, and cerebrospinal fluid analysis revealed aseptic meningitis, supporting the diagnosis of acute neuro-BD. Laboratory tests confirmed the diagnostic criteria for SIADH. Colchicine monotherapy led to a resolution of the patient’s mucocutaneous symptoms, neurological manifestations and hyponatraemia, without the need for corticosteroids or other immunosuppressants. This case suggests a possible association between acute neuro-BD and SIADH and underscores the importance of recognising concurrent neurological and endocrine manifestations in patients with newly diagnosed BD.

Background

Behçet’s disease (BD) is a chronic, multisystem inflammatory disorder characterised by recurrent oral and genital ulcers, uveitis and skin lesions.¹ Neurological involvement, referred to as neuro-Behçet’s disease (neuro-BD), occurs in approximately 10%–20% of patients and typically develops several years after the initial diagnosis.² Acute neuro-BD usually presents with meningoencephalitis and parenchymal brain lesions, which commonly involve the brainstem.³ Although delayed onset is more common, BD and neuro-BD are rarely diagnosed concurrently. In such cases, clinicians should assess both mucocutaneous features and neurological symptoms, including headaches, behavioural changes, psychiatric symptoms and focal deficits.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a well-known cause of hyponatraemia and is often the result of central nervous system (CNS) inflammation, malignancy or certain medications.⁴ Given the inflammatory nature of acute neuro-BD, affected patients may be at risk for developing SIADH. Although SIADH has been reported in association with BD patients receiving treatments such as cyclophosphamide,⁵ its occurrence in the absence of pharmacological triggers, and caused solely by CNS inflammation related to acute neuro-BD, remains unclear.

We report a rare case in which BD and acute neuro-BD were diagnosed concurrently, complicated by SIADH. This case highlights the importance of considering SIADH as a potential manifestation of acute neuro-BD, particularly in patients presenting with non-specific CNS symptoms and hyponatraemia.

Case presentation

An Asian man in his 60s presented to the emergency department with a 3 day history of fever, headache, general malaise, loss of appetite, persistent hiccups and arthralgia affecting the shoulders and ankles. He also reported oral aphthae.

His medical history included type 2 diabetes mellitus, for which he was not receiving treatment because he had limited awareness of his condition and did not maintain appropriate dietary or physical activity habits. His family history was unremarkable, with no relatives affected by BD. He occasionally consumed alcohol, did not smoke, had not travelled recently and had not been exposed to animals or unwell individuals. He worked in the metalworking industry and had not engaged in recent sexual activity.

On examination, he was alert but appeared fatigued. His vital signs were: a temperature of 38.1°C, blood pressure of 135/73 mm Hg, a heart rate of 119 beats per minute (regular), a respiratory rate of 19 breaths per minute and an oxygen saturation of 96% on room air. Physical examination revealed oral aphthae and folliculitis-like rashes on the face and trunk (figure 1A, B and C). Cardiopulmonary and abdominal examination findings were unremarkable. Manual muscle testing revealed no muscle weakness in the upper or lower extremities. There was no peripheral oedema, and his volume status was clinically assessed as euvolemic. He was admitted for further evaluation.

Figure 1. Physical examination revealed oral aphthae (A) and folliculitis-like rashes on the face (B) and trunk (C). On day 5, a painful scrotal ulcer (D) appeared.

Investigations

Initial laboratory tests revealed marked hyponatraemia (124 mmol/L), elevated creatine kinase (1349 U/L), aspartate aminotransferase (77 U/L), alanine aminotransferase (64 U/L), C-reactive protein concentration (CRP) (180 mg/L; reference, <3 mg/L) and erythrocyte sedimentation rate (70 mm/hour; reference, <15 mm/hour), with normal renal function. The patient also presented with hyperglycaemia (plasma glucose 14.2 mmol/L) and an elevated HbA1c level of 8.2%, indicating poor glycaemic control. Hepatitis B and C markers were negative.

Endocrine evaluations revealed normal thyroid-stimulating hormone (1.11 mIU/L; reference, 0.50–5.00 mIU/L), free T4 (1.25 ng/dL; reference, 0.90–1.70 ng/dL) and serum cortisol (42 µg/dL; reference, >6 µg/dL). Serum osmolality was low (267 mOsm/kg; reference, <270 mOsm/kg) and urine osmolality was elevated (900 mOsm/kg, reference, >300 mOsm/kg), with an increased urinary sodium concentration (88 mmol/L; reference, >20 mmol/L), consistent with impaired water excretion. Despite hypo-osmolar hyponatraemia, antidiuretic hormone (ADH) was elevated (22.4 pg/mL). His ECG was normal, and both chest X-ray and CT of the head, chest and abdomen were unremarkable. These findings supported a diagnosis of SIADH.⁴

On day 3, his headache and vertigo worsened. Although there was no neck stiffness or cranial nerve involvement, CNS inflammation was suspected. Brain MRI revealed no significant abnormalities involving the hypothalamus or other brain regions (figure 2). Cerebrospinal fluid (CSF) analysis revealed mildly elevated opening pressure (17 cmH₂O), increased protein (0.97 g/L) and mild lymphocytic pleocytosis (11 cells/µL). CSF cultures and tests for bacterial and mycobacterial pathogens, as well as herpes simplex virus (HSV), varicella zoster virus (VZV) and cryptococcal antigen, were all negative. CSF cytology showed no malignant cells.

Figure 2. Brain MRI revealed no significant abnormalities involving the hypothalamus or other brain regions.

Further investigations were performed to evaluate underlying systemic diseases. Tests for sarcoidosis revealed normal lysozyme (5.1 µg/mL; reference 5–10) and angiotensin-converting enzyme levels (11.4 U/L; reference 7–25). Screening for haematological malignancy revealed soluble interleukin-2 receptor (sIL-2R) (704 U/mL; reference, 122–496 U/mL), with negative human T-cell leukaemia virus type 1 antibody.

On day 5, a painful scrotum ulcer appeared (figure 1D). In combination with oral aphthae and folliculitis-like rashes, these findings suggested a systemic form of BD. He did not exhibit hypersensitivity to a pinprick. Ophthalmological examination revealed no uveitis. HLA-B51 was positive.

Differential diagnosis

At the time of presentation, the combination of fever, headache, general malaise and hyponatraemia suggested CNS infection or a systemic inflammatory disorder. Viral meningoencephalitis, particularly caused by HSV or VZV, was suspected initially. However, CSF testing was negative for viral antigen and antibodies, effectively excluding these possibilities. Bacterial meningitis was also considered but ruled out based on the absence of neutrophilic predominance, mild lymphocytic pleocytosis and negative CSF cultures. Tuberculous meningitis was excluded because the results for acid-fast staining and tuberculosis DNA testing were negative.

Primary CNS malignancy was considered, given the neurological symptoms. However, brain MRI showed no abnormal findings, and CSF cytology did not reveal malignant cells. Although the sIL-2R level was mildly elevated, this finding alone was insufficient to support a diagnosis of CNS lymphoma.

Autoimmune diseases were evaluated but excluded due to the absence of characteristic systemic symptoms and negative screening autoantibody test results. Neurosarcoidosis was included in the differential diagnosis because MRI findings may be normal in the early stages,⁶ but subsequent laboratory data made this diagnosis unlikely. The mildly elevated sIL-2R level was regarded as a non-specific finding.

This patient was diagnosed with definite BD based on clinical features, including fever and fatigue, oral aphthae (two points), genital aphthosis (two points) and a folliculitis-like rash (one point). According to the International Criteria for Behçet’s Disease, he had a total score of five points (≥4 indicates definite disease).¹ In particular, genital aphthosis is considered to be a specific finding of BD, and these findings strongly suggest BD. After excluding infectious, neoplastic and autoimmune causes, a diagnosis of acute neuro-BD² was established, with CNS symptoms in the context of mucocutaneous findings.

Treatment

On day 1 of admission, an underlying inflammatory condition was suspected, although the exact aetiology remained unclear. Empirical antimicrobial therapy with cefepime was initiated after blood cultures were collected, targeting a potential bacterial infection despite the absence of a specific infectious focus.

On day 3, the patient’s headache and vertigo worsened, suggesting CNS inflammation or infection. Acyclovir was administered empirically but was discontinued after tests ruled out HSV and VZV encephalitis.

On day 8, colchicine was started following the diagnosis of systemic BD and acute neuro-BD. Oral aphthous lesions were treated with topical corticosteroid ointment. Genital ulcers and cutaneous lesions were managed with silver sulfadiazine cream. SIADH was managed conservatively with fluid restriction (<800 mL/day), careful daily monitoring of serum sodium and avoidance of the rapid correction of sodium levels. Hypertonic saline and vasopressin receptor antagonists were not required.

Outcome and follow-up

The patient’s fever resolved, and his appetite improved the day after he started taking colchicine. Over the following 2 weeks, his symptoms, including vertigo, general malaise, hiccups and mucocutaneous lesions, gradually improved. By day 16, serum sodium had normalised to 136 mmol/L, and ADH levels had decreased to 1.8 pg/mL. Myogenic enzyme levels also returned to normal.

Importantly, no systemic corticosteroids or other immunosuppressants were used during treatment. The patient was discharged after a 1 month hospitalisation, during which recovery from the acute phase was achieved, hyponatraemia was carefully monitored and managed, and rehabilitation was provided for the associated decline in physical function. Colchicine therapy was continued for approximately 4 years, with no recurrence of BD or neurological symptoms during that time. After his BD stabilised, biguanide therapy was initiated, and good glycaemic control has since been maintained.

Discussion

This case involved the simultaneous diagnosis of systemic BD and acute neuro-BD, which is a rare clinical scenario. It also demonstrated that acute neuro-BD can be complicated by SIADH. The resolution of mucocutaneous symptoms, neurological manifestations and hyponatraemia following colchicine monotherapy suggests a possible direct association between BD, neuro-BD and SIADH. In patients with BD who present with fever or headache accompanied by hyponatraemia, clinicians should consider acute neuro-BD as a potential underlying cause.

This case is notable for the simultaneous diagnosis of systemic BD and acute neuro-BD, supported by mucocutaneous lesions and CNS involvement. Typically, major organ involvement, such as CNS lesions, occurs around 4 years after the initial diagnosis of BD, and neurological manifestations at presentation are uncommon, occurring in fewer than 5% of patients.⁷ Only a minority of patients, approximately 10%, experience headaches that are directly related to neuro-BD.² Therefore, the initial recognition of neuro-BD in this case was inherently challenging. Acute neuro-BD most commonly presents as a self-limiting meningoencephalitis, with or without focal neurological deficits.³ In this patient, brain MRI revealed no specific abnormalities at the typical BD lesion sites, including the hypothalamic region.² Acute neuro-BD may present as aseptic meningitis without parenchymal brain lesions, and a normal brain MRI, particularly in the early phase of the disease, does not exclude the diagnosis.² This lack of radiological findings further complicated the diagnostic process. Although HLA-B51 testing was performed, it did not contribute to establishing the diagnosis. This aligns with international BD criteria, which do not require HLA-B51 and rely mainly on clinical features. This case highlights the importance of considering neuro-BD when patients with mucocutaneous findings present with non-specific neurological symptoms.

In the initial phase of the differential diagnosis, we prioritised infection as a cause of CNS inflammation because of the combination of fever of unclear origin, neurological symptoms and hyponatraemia; however, we did not identify any specific pathogen. We also considered other causes of CNS inflammation, including connective tissue diseases and malignancies, and included sarcoidosis and haematologic malignancy in the differential diagnosis. Therefore, as part of an initial broad evaluation, we measured autoimmune serological markers, serum ACE and sIL-2R as screening investigations. We performed these tests in a limited manner as part of an exclusion-based approach rather than based on strong clinical suspicion. We found no clinical, radiological or CSF findings to support these diagnoses, and these investigations did not meaningfully contribute to the final diagnosis. ACE has limited sensitivity for sarcoidosis,⁸ and although sIL-2R may be informative in the evaluation of malignant lymphoma, mild elevations are non-specific and may reflect inflammatory activity.⁹ In this case, the absence of genital ulcers at the early stage of symptom onset made the diagnosis of BD uncertain, leading to a broad differential diagnosis. This diagnostic process highlights the importance of avoiding indiscriminate testing and emphasises that clinicians should perform such investigations only when supported by appropriate clinical features and interpret them with caution.

Although drug-induced SIADH has been reported in patients with BD receiving medications such as cyclophosphamide,⁵ the association between acute neuro-BD and SIADH remains poorly understood. Neuro-BD is characterised by CNS inflammation,² which may contribute to dysregulated ADH secretion. Several studies have shown that interleukin-6 (IL-6), a proinflammatory cytokine frequently elevated in neuroinflammatory disorders, is associated with increased ADH release.¹⁰ In BD, aberrant monocyte activation leads to spontaneous IL-6 production,¹¹ and elevated IL-6 levels have been detected in the CSF of patients with acute neuro-BD.² These findings suggested that IL-6–mediated inflammation might contribute to SIADH in this setting. Although IL-6 levels were not measured in the serum or CSF in the present case, the markedly elevated serum CRP concentration may reflect an underlying IL-6–mediated inflammatory response.¹¹ Although SIADH is associated with various conditions, including CNS inflammation, pulmonary disease, malignancy and certain medications,⁴ the present findings do not allow a direct causal link between SIADH and acute neuro-BD to be established. The temporal association observed in this case may reflect a non-specific response to CNS inflammation rather than a disease-specific mechanism.

The present case also illustrates the potential complications of hyponatraemia caused by SIADH in the setting of acute neuro-BD. Previous reports have reported that persistent hiccups may serve as an important clinical clue to severe hyponatraemia caused by SIADH secondary to CNS inflammation, including meningitis.¹² In addition, we measured CK as part of the initial evaluation of fever, arthralgia and general fatigue, which may be related to inflammatory or metabolic muscle damage, and this revealed rhabdomyolysis, a recognised but often overlooked complication of severe hyponatraemia that is not routinely investigated.¹³ These manifestations are known, yet often underappreciated, clinical implications of profound hyponatraemia. Clinicians should be aware that apparently unrelated symptoms, such as hiccups or rhabdomyolysis, may reflect underlying electrolyte disturbances, particularly in the context of neuroinflammatory conditions.

Corticosteroids are considered the mainstay of treatment for acute neuro-BD, and most patients respond favourably.³ However, spontaneous resolution has been reported in cases presenting solely with meningoencephalitis-like symptoms.³ In the present case, colchicine monotherapy improved mucocutaneous and neurological symptoms, as well as hyponatraemia. Colchicine exerts anti-inflammatory effects by inhibiting neutrophil migration and activation, and by suppressing cytokine production, including IL-1β and IL-6.¹⁴ Although colchicine is widely used for the treatment of mucocutaneous manifestations in BD,¹⁵ systematic reviews have shown that colchicine is ineffective for acute neuro-BD and that immunosuppressive agents are generally required for adequate disease control.¹⁶ In fact, in reported cases, colchicine has been used as an adjunct to corticosteroids or other immunosuppressive therapies, rather than as a monotherapy.¹⁷ Although spontaneous recovery cannot be excluded in this case, our findings suggest that colchicine may be a useful treatment option for acute neuro-BD and related complications such as SIADH, particularly when corticosteroid therapy is undesirable or contraindicated.

Conclusion

We described a rare case of BD and acute neuro-BD diagnosed concurrently, in which the SIADH complicated the neuro-BD. This case demonstrates that SIADH may occur as a complication of acute neuro-BD, highlighting the importance of clinician awareness of this potential association. Colchicine monotherapy led to rapid improvement in mucocutaneous symptoms, neurological manifestations and hyponatraemia, suggesting that colchicine may be a practical therapeutic option in the early phase of neuro-BD. In patients with BD who present with non-specific CNS symptoms such as fever and headache in combination with hyponatraemia, clinicians should maintain a high suspicion for acute neuro-BD in patients with BD complicated by SIADH.

Patient’s perspective.

At first, I developed painful mouth ulcers and pain in my ankles. Soon after, I had a fever and lost my appetite. I became weak and dizzy and started feeling confused without understanding what was happening to me. Feeling overwhelmed, I called an ambulance. When the headache and dizziness were at their worst, I had the strange sensation of floating in the sky and looking down at myself. It was frightening and surreal.

After receiving a diagnosis and starting treatment, my condition gradually improved. I was able to eat again, and the sores in my mouth and on my scrotum started to heal. The pain became more manageable. I now hope to return home and regain my strength. Once I recover, I feel a responsibility to return to work.

There were times when the pain was so intense that I could not sleep. Now the pain is gone, I can have a normal daily life again. I had never heard of Behçet’s disease before this experience. I hope that my case can contribute to medical knowledge and help support other patients in similar situations.

Learning points.

• Behçet’s disease (BD) and acute neurological Behçet’s disease (neuro-BD) may occur simultaneously at initial presentation. Clinicians should consider acute neuro-BD when neurological symptoms are present at the first consultation, even in newly diagnosed BD.

• Acute neuro-BD can be associated with the syndrome of inappropriate antidiuretic hormone secretion. Hyponatraemia in patients with BD should prompt evaluation for central nervous system inflammation.

• Non-specific symptoms such as hiccups or rhabdomyolysis may indicate severe hyponatraemia. Early recognition of these features may help avoid misdiagnosis and enable timely, appropriate management.