Behçet Disease and Cognitive Impairment: A Case Study of an Overlooked Symptom

Introduction

Behçet disease (BD) is a rare autoimmune disorder characterized by systemic vasculitis [1–3]. Its global prevalence is about 10.3 per 100 000 population. Asia has higher rates, ranging from 13.5 to 20 per 100 000 population [4,5].

The cause of BD remains incompletely understood. However, genetic factors, particularly the HLA-B*51 allele and non-HLA genes, as well as environmental influences, such as elevated levels of proinflammatory cytokines, are believed to play significant roles [4,5]. The HLA-B*51 allele contributes to T-cell activation and amplifies inflammation cascades [6], whereas non-HLA genes modulate innate immunity and autoinflammatory pathways. This systemic immune dysregulation renders the central nervous system vulnerable, even in the absence of direct structural lesions, through mechanisms such as cytokine-mediated neurotoxicity, microvascular ischemia, and impaired neurogenesis [7–9]. In BD, the elevation of proinflammatory cytokines induces endothelial dysfunction and reduces the production of brain-derived neurotrophic factor (BDNF), leading to neuronal cell death [9]. Endothelial dysfunction further contributes to impaired blood flow and vasculitis, which can lead to ischemia, particularly in vulnerable regions such as the hippocampus, an area critical for cognitive processing, and watershed areas like the parietal lobe, which also plays a role in cognition [10–12]. These microstructural changes often escape detection on routine MRI, which helps explain cognitive decline in BD patients without overt neurological signs [13].

Common BD manifestations include oral aphthous ulcers (97–99%), genital ulcers (approximately 80%), and erythema nodosum. In contrast, neurological involvement is relatively uncommon, occurring in only 5% to 15% of cases. This neurological involvement is referred to as Neuro-Behçet Syndrome (NBS). This neurological involvement is defined by clinical or radiological evidence of central nervous system (CNS) inflammation, including parenchymal lesions on MRI or symptoms, including motor deficits, seizures, or brainstem syndromes [3,14]. Although cognitive deficits in NBS have traditionally been attributed to neuroimaging-visible CNS lesions, emerging data indicate that such impairments can precede or occur independently of detectable lesions, reflecting a form of neuroimmune dysfunction beyond standard NBS definitions [15]. Previous studies have shown that BD patients without overt neurological symptoms may still exhibit cognitive deficits, including impairments in visuospatial abilities, language, attention, psychomotor speed, non-verbal reasoning, and executive functions [16]. Atik et al (2020) evaluated 75 BD patients using the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) and found that 38% demonstrated cognitive impairment despite no clinical neurological signs [17]. Similarly, a case-control study by Monastero et al (2004) involving 26 BD patients and 26 controls found that 46.1% of patients had cognitive deficits based on a comprehensive neurocognitive assessment battery, comprising the Digit Span Test, Token Test, Rey Complex Figure, and Trail-Making Tests A and B, despite the absence of overt neurological involvement. Interestingly, these impairments were more prevalent in patients with active disease, particularly those undergoing prednisone therapy [16]. Furthermore, Dutra et al (2013), in a case-control study conducted in Brazil, reported that 41.6% of BD patients experienced impairments in language and executive functions, independent of neurological manifestations. This was examined using a battery of neurocognitive assessments, including the Mini-Mental State Examination (MMSE), Wechsler Adult Intelligence Scale Revised (WAIS-R), Verbal Paired Associates (VPA), Rey-Osterrieth Complex Figure Test (ROCF), Clock-Drawing Test (CDT), Trail-Making Test (TMT), and the Boston Naming Test (BNT) [18].

Cognitive impairment in BD may arise as part of neurological involvement (ie, NBS), or occur independently in the absence of radiologically evident CNS lesions [14]. Moreover, corticosteroid use has also been linked to treatment-related cognitive decline [19]. Despite mounting evidence of neurocognitive dysfunction in BD, routine clinical screening remains rare, especially for patients without overt neurologic signs. The present case report is particularly significant because it presents cognitive impairment in a patient with BD without any clinical or radiological signs of neurological involvement, a scenario that remains under-recognized in current clinical practice. Unlike prior reports, this case underscores the diagnostic ambiguity in the early stages of cognitive dysfunction, the need for neuropsychological vigilance, and the management of cognitive dysfunction in BD. This case report aims to underscore the need for heightened clinical vigilance in patients with BD presenting with subtle cognitive changes, even in the absence of neurological or radiological findings. Through this case study, we highlight key diagnostic challenges and propose implications for routine cognitive screening in BD. Routine neuropsychological screening in patients with BD may enable earlier detection and timely intervention, thereby reducing the risk of progression to irreversible cognitive decline. This sets the stage for a broader discussion of the underlying mechanisms, diagnostic challenges, and management implications detailed in the subsequent sections.

Case Report

A 59-year-old woman first developed persistent oral aphthous ulcers 7 years before the current admission. Over the following years, she also experienced unexplained lethargy, intermittent fever, a coin-shaped itchy skin lesion on her lower extremity, and significant weight loss. The skin lesion was erythematous, coin-shaped, and itchy. Initially, she consulted a dermatologist and was diagnosed with pemphigus vulgaris. She was treated with a corticosteroid cream, which led to lesion healing; however, the site eventually developed into a black scar within 1 year. She denied any history of cardiovascular disease, diabetes mellitus, stroke, dyslipidemia, or other systemic illnesses. Her family history was notable for maternal cardiovascular disease, paternal renal disease, a cousin with breast cancer, and a brother with rectal cancer. She denied alcohol consumption and smoking. She was of Javanese ethnicity and had a bachelor’s degree. She worked full-time managing a local orphanage, which limited her physical activity (Table 1).

Regarding the oral aphthous ulcers, she initially presented to a primary healthcare facility and was diagnosed with stomatitis. Despite treatment with mouthwash and topical corticosteroids, her oral ulcers progressively worsened over several days, significantly impairing her appetite and resulting in a weight loss of 15 kg. Four years later, she was referred to the Internal Medicine Department at RSUP Dr. Sardjito. At that time, she also reported blurred vision, joint pain, and a history of skin lesions. An autoimmune process was suspected. ANA testing by indirect immunofluorescence (ANA-IF) was positive, supporting this suspicion. HLA typing was not performed due to resource limitations.

The patient underwent a skin biopsy. Histopathological examination revealed an inflammatory infiltrate, epidermal orthokeratosis, mild spongiosis, and an empty subepidermal cleft. There was no evidence of intraepidermal cleft, vasculitis, vasculopathy, panniculitis, eosinophilic infiltration, or malignancy (Figure 1). Immunohistochemistry showed weak linear deposition of immunoglobulin G (IgG) along the basement membrane, strong granular deposition of immunoglobulin M (IgM) in the perivascular subepidermal region, and weak granular deposition of immunoglobulin A (IgA) and complement split product (C3c) in the same area. These findings suggested an inflammatory process consistent with BD. She was initially treated with oral methylprednisolone 16 mg/day, with tapering based on the clinical response. Immunosuppressive therapy included azathioprine 50 mg twice daily, mycophenolic acid 360 mg twice daily, and cyclosporine 25 mg twice daily, which was continued for over 12 months with regular follow-up. Following this regimen, her oral aphthous lesions improved significantly, with marked healing.

Six months after her Behçet disease (BD) diagnosis, she presented with a chronic productive cough and chest fullness. Initial evaluation at a private hospital raised a suspicion of lung cancer, but chest computed tomography (CT) instead revealed an incidental anterior mediastinal mass suspected to be a thymoma. She was referred to the Pulmonology Department at RSUP Dr. Sardjito. Chest radiography showed a well-defined, rounded isodense lesion in the anterior right mediastinum, suggestive of a thymoma (Figure 2). A biopsy confirmed stage 2 thymoma. Although surgery, chemotherapy, and radiotherapy were advised, she declined all treatments due to concerns about exacerbating weight loss.

One year later, the patient reported having frequent palpitations and chest pain. Electrocardiography (ECG) revealed arrhythmia, prompting further evaluation. She also experienced heat intolerance, excessive sweating, and increased fatigue. Suspecting a systemic disorder, the internist ordered thyroid function tests, which showed suppressed thyroid-stimulating hormone (TSH) at 0.13 μIU/mL and elevated free thyroxine 4 (FT4) at 1.51 ng/dL, confirming hyperthyroidism. She was started on thiamazole 5 mg daily. After 2 months of therapy, thyroid function normalized (TSH 0.33 μIU/mL, and FT4 1.29 ng/dL), and her symptoms improved, including arrhythmia, heat intolerance, sweating, and fatigue.

Another year later, she developed persistent headache and memory difficulties, such as frequently forgetting prayer times and misciting verses. She was referred to the Memory Clinic at RSUP Dr. Sardjito and diagnosed with mild cognitive impairment. Physical examination and vital signs were unremarkable. Cognitive testing using the Montreal Cognitive Assessment-Indonesia Version (MoCA-INA) yielded a score of 27/30, with deficits in memory and attention. Further evaluation included Forward Digit Span (FDS) (6 digits), Backward Digit Span (BDS) (4 digits), Trail-Making Test A (47 seconds), and Trail-Making Test B (80 seconds). Baseline cognitive function was retrospectively assessed using the Informant Questionnaire on Cognitive Decline in the Elderly-Short version (S-IQCODE) and the Indonesian version of the AD-8 (INA-AD8), with scores of 3 and 0, respectively, both indicating no prior cognitive impairment (Table 2).

Given the complexity of her clinical conditions, hyperthyroidism, unresected thymoma, and BD, a volumetric brain MRI was performed to explore the causes of cognitive impairment. The MRI showed normal sulcal and gyral patterns, but revealed bilateral parietal atrophy with T1-weighted hypointensity and T2-weighted hyperintensity in the posteroinferior gyri of the temporal and left occipital lobes (Figure 3). Quantitative volumetric analysis revealed a whole-brain volume of 1061 cc and total intracranial volume of 1312 cc, yielding a brain-to-intracranial volume ratio of 80%, which is within normal limits. The hippocampal volumes were 4.09 cc (right) and 4.04 cc (left), totaling 8.13 cc. Qualitative assessments showed a Global Cortical Atrophy (GCA) score of 1, a Medial Temporal Atrophy (MTA) score of 1, a Parietal Atrophy (Koedam score) of 2, and White-Matter Hyperintensity (Fazekas grade 1) (Table 3). These findings do not indicate significant neurodegenerative atrophy such as that seen in Alzheimer dementia. There was no evidence of space-occupying lesions, infarction in strategic cognitive areas, meningeal enhancement, or abnormalities in the bilateral temporal lobes and limbic system.

To manage her cognitive deficits, she was prescribed donepezil 5 mg once daily and folic acid 1 mg 3 times daily, and underwent cognitive stimulation therapy, while continuing immunosuppressive and anti-inflammatory treatments. At 1-year follow-up, cognitive assessments showed improvement, with a normal MoCA-INA score of 30/30. Neuropsychological tests revealed that FDS increased to 7 digits, BDS to 6 digits, and Trail-Making Test A and B remained within normal limits (47 and 80 seconds, respectively). Functional assessments indicated preserved independence, with Activities of Daily Living (ADL) and Instrumental ADL (IADL) scores of 0, and a Barthel Index (BI) score of 100 (Table 2). Given her stable cognitive gains and limited imaging resources, follow-up volumetric MRI was not performed.

Discussion

DIAGNOSTIC CHALLENGES OF BEHçET DISEASE:

Diagnosing Behçet disease poses significant challenges due to its rarity and non-specific clinical manifestations [3,20]. BD patients present with a wide range of clinical symptoms that often overlap with other autoimmune diseases [21]. Moreover, no laboratory assay is pathognomonic for BD; the diagnosis relies exclusively on clinical criteria [22]. BD is frequently misdiagnosed as systemic lupus erythematosus (SLE), leading to a delay in appropriate treatment [23]. In this case, the patient came to the clinic with the concern of persistent oral aphthous, which has a broad differential diagnosis, and was treated only as stomatitis. She was later referred after several years due to persistent oral aphthous despite taking medicine. This delay in referral resulted in a delayed diagnosis and initiation of appropriate treatment, which may have further intensified the symptoms and contributed to the development of other complications, such as cognitive impairment [1].

Based on the International Criteria for Behçet’s Disease (2014), the diagnostic approach for Behçet disease (BD) includes recurrent ocular lesions, recurrent genital aphthous, recurrent oral aphthous, recurrent skin lesions, neurological manifestations, vascular manifestations, and a positive pathergy test. The first 3 criteria – ocular lesions, genital aphthous, and oral aphthous – each carry a score of 2, while the other criteria are assigned a score of 1. A cumulative score of 4 or more confirms BD, 3 points indicates probable disease, and fewer than 3 points excludes it [24]. Initially, our patient presented with recurrent oral aphthous, skin lesions, and ocular symptoms, corresponding to a diagnostic score of 4, thereby establishing a definitive diagnosis of BD. Additionally, the presence of arthralgia – reported in 30% to 70% of BD cases – and blurred vision – occurring in 34.8% to 90% – further supports the diagnosis [25,26].

HISTOPATHOLOGICAL AND IMMUNOLOGICAL SUPPORT FOR BD DIAGNOSIS:

A skin biopsy of a papulopustular lesion can support a BD diagnosis. Typical histopathological features include intraepidermal pustules, spongiosis, basal keratinocyte vacuolization, dermal edema, and lymphocytic or neutrophilic infiltrates in the dermis and perivascular areas [27]. In our patient, these features were observed (Figure 1), along with supportive immunohistochemical (IHC) findings. Additionally, histopathology revealed inflammatory cell infiltration, which may consist of neutrophils or lymphocytes, and IHC revealed immune complex deposits (IgG, IgM, IgA, and C3c), consistent with BD-related immune activity [26,28].

A positive ANA test was also noted in this patient. While not specific to BD, ANA positivity may reflect an underlying autoimmune process, as observed in other conditions like SLE or Sjögren syndrome. However, in this context, it adds further immunological support [29]. Neurological symptoms, including cognitive impairment, were present and aligned with known neuro-Behçet manifestations, further strengthening the diagnosis.

COGNITIVE IMPAIRMENT IN BD: PATHOPHYSIOLOGY AND MECHANISMS:

BD is a complex autoimmune disease characterized by systemic vasculitis, which can affect multi-system organs, including the central nervous system and vascular system [2,3,7,25,30]. Neurologic manifestations typically present as brainstem syndrome, movement disorders, and myelopathic syndrome [14]. Our patient experienced isolated cognitive impairment without any evident neurological symptoms.

Cognitive impairment in BD is believed to result from a combination of cerebral vascular inflammation and corticosteroid treatment [16]. Vascular inflammation, driven by neutrophil activation, proinflammatory cytokine release, and T-cell dysregulation, leads to endothelial dysfunction and tissue hypoxia [7,8]. Certain brain regions, including the hippocampus and parietal lobes, are particularly vulnerable to ischemia due to their high metabolic demands and location within watershed zones [11,12,31].

Elevated levels of cytokines such as IL-6, IL-1β, and TNF-α disrupt the blood–brain barrier (BBB), facilitating immune cell infiltration into the CNS. This process activates microglia, induces oxidative stress, and triggers synaptic degradation and neuronal apoptosis, all of which contribute to chronic neuroinflammation and cerebral atrophy [1,32–35]. The MRI confirmed bilateral parietal lobe atrophy, regions known to play a role in memory, spatial processing, and attentional control [11].

In addition, inflammation-induced endothelial dysfunction reduces the levels of BDNF, impairing neurogenesis, synaptic plasticity, and neuronal survival [9]. Chronic hypoperfusion and impaired neuroplasticity further exacerbate cortical atrophy and cognitive decline [10].

Genetic factors may also contribute to the neurological involvement in BD. Padula et al (2020) identified ERAP1 (rs17482078) and IL23R (rs17375018) polymorphisms linked to an increased risk of CNS manifestations in BD [32]. In particular, ERAP1 downregulation intensifies neutrophil infiltration and inflammatory cascades within the CNS [36]. In our patient, such mechanisms may have caused the observed bilateral parietal atrophy and resultant cognitive impairment. The parietal lobe’s vulnerability to hypoxic injury due to its watershed location may further explain its selective involvement in this case [10–12]. Therefore, we propose that the patient’s cognitive dysfunction is a consequence of immune-mediated cerebral vasculitis and chronic neuroinflammation, possibly exacerbated by genetic susceptibility, leading to localized neuronal loss and atrophy in functionally critical brain regions.

CONTRIBUTION OF CORTICOSTEROID THERAPY TO COGNITIVE DECLINE:

Long-term corticosteroid use, the main anti-inflammation treatment for BD, may contribute to cognitive impairment [37–39]. Ghaleb et al (2024) demonstrated that the long-term use of steroids is associated with the occurrence of cognitive impairment in patients with BD (r=0.44; p=0.01) [19]. Studies suggest that long-term corticosteroid use can cause irreversible neuronal damage, particularly in the hippocampus, which has a high density of glucocorticoid receptors [40]. Corticosteroids decrease dendritic branching, resulting in hippocampal atrophy. A study on BD showed a significant correlation between corticosteroid use and cognitive dysfunction (r=0.44; p=0.01) [19,40,41]. The correlation between the treatment duration and cognitive impairment remains unclear. The study suggests that 6 months of prednisolone at doses ≥10 mg/day leads to hippocampal shrinkage, amygdala atrophy, and reduced neuronal vitality (F=5.28; df=1.52; p=0.26). The relationship between the corticosteroid dose and cognitive impairment appears to follow an inverted U-shaped curve, indicating a dose-dependent effect. A study suggests 20 mg/day of hydrocortisone is a threshold, and a higher dose results in cognitive impairment [37]. Prolonged corticosteroid intake likely contributed to our patient’s cognitive decline. She had been receiving methylprednisolone at an average dose of 16 mg/day and tapering off for 2 years, a duration and dose consistent with levels shown to cause hippocampal and white-matter changes in prior studies. Although MRI findings indicate that the hippocampal volume is within normal limits compared to the population with normal cognitive function, the emergence of Fazekas grade 1 suggests the presence of cerebral small-vessel disease. Long-term corticosteroids use has been associated with the development of cerebral small-vessel disease. Excessive steroid levels can lead to reduced cerebral blood flow, decreased neuronal activity, and endothelial damage due to impaired nitric oxide release, which subsequently manifest as white-matter hyperintensities [42].

Research on alternative treatment for corticosteroid-related cognitive effects is limited. French guidelines suggest the early use of immunosuppressants to minimize long-term corticosteroid adverse effects [43]. A case report indicated that methotrexate and infliximab can improve glucocorticoid-refractory cognitive dysfunction [44]. Infliximab targets TNF-α, a key proinflammatory cytokine in parenchymal neuro-BD [45]. This aligns with the International Society for BD recommendations. In acute parenchymal involvement, treatment includes high-dose glucocorticoids and immunosuppressants like azathioprine, followed by gradual glucocorticoid tapering [2,46]. In cases of chronic neurological involvement, where the corticosteroid and azathioprine are ineffective, low doses of methotrexate and infliximab can be prescribed [2,33]. Additionally, previous studies demonstrated the benefits of other anti-inflammatory therapies beyond corticosteroids in the management of uveitis in patients with BD. The treatment selection should be individualized, considering systemic involvement and potential complications. Therefore, further research is needed to explore non-steroidal therapies as alternative treatment options to address the underlying vasculitis and inflammation in patients with BD [25]. It is hoped that such therapies may serve as effective alternatives to improve cognitive function, with an individualized approach based on the patient’s systemic condition and risk of complications.

COMORBID CONDITIONS AND POTENTIAL OVERLAP:

Thymoma frequently coexists with autoimmune disorders, but its association with Behçet’s disease (BD) remains controversial. Thymoma is a malignant tumor often associated with autoimmune disease and paraneoplastic syndrome (PNS). The thymus is a crucial organ for T-cell maturation and preventing autoimmunity, and in thymoma, the disruption of positive and negative selection of T-cells results in autoimmune-mediated disease [47,48]. T-cells are divided into 2 main types: CD4+ and CD8+ T-cells. These T-cell subsets are further differentiated into Th1, Th2, and Th17 cells. The presence of thymoma is associated with an increased differentiation toward Th1 and Th17 cells, along with a decreased population of regulatory T-cells. This imbalance contributes to the development of autoimmune disorders (ie, autoreactive T-cells). Damage to epithelial cells in the thymic medulla also leads to a decreased expression of the autoimmune regulatory (AIRE) protein, which plays a critical role in regulating the negative selection of self-reactive T-cells [49–52]. As a result, these autoreactive T-cells can enter the peripheral circulation, potentially contributing to the pathogenesis of autoimmune disorders, such as myasthenia gravis (MG), which is the most common paraneoplastic syndrome associated with thymoma (30–44%), SLE (1.5%), and BD (<1%) [47,53]. In contrast, a case report describing a patient with concurrent BD, thymoma, and IgA nephropathy found no change in BD disease activity following thymectomy. This observation suggests that BD and thymoma may have developed independently, despite both being associated with an immune-related pathophysiology [54].

This patient had a history of hyperthyroidism, which raises additional immunologic considerations. A previous case study reported the association between thymoma and hyperthyroidism in Grave’s disease, in which thyroid-stimulating hormone receptor (TSHR) is also expressed in the thymus at approximately 20% of the expression level in the thyroid. The presence of an antibody against TSHR in Grave’s disease may interact with TSHR in the thymus and abnormally stimulate thymocytes [55]. The second hypothesis suggests that the thyroid hormones, both T3 and T4, play a role in inducing thymic epithelial cell proliferation [56]. A few studies have reported the co-existence of hyperthyroidism and BD. A case report suggested that autoantibodies in BD share pathogenic mechanisms with other autoimmune diseases, but there is little information supporting a definitive explanation about the association of these 2 conditions [57]. Although rare, the triad of thymoma, hyperthyroidism, and BD in our patient likely reflects convergent autoimmune pathogenesis.

DIAGNOSTIC EVALUATION OF COGNITIVE IMPAIRMENT IN BD:

In our patient, no overt neurological symptoms were observed, and cognitive impairment is often overlooked in patients with BD without obvious neurological involvement, highlighting the importance of comprehensive evaluation even when classic neurologic features are absent. Cognitive impairment in BD typically affects memory, followed by visuospatial or frontal executive functioning, and attention [17,19]. Ghaleb et al (2024) reported that patients with BD who were included in the study had significant cognitive impairments in memory, visuospatial awareness, attention, and frontal executive functions [19]. The study suggests that BD patients with no neurological involvement have milder cognitive impairment than those with neurological manifestations [39]. However, untreated cognitive impairment can progress to dementia [44]. Our patient reported short-term memory issues, but had an abnormal cognitive assessment, leading to a diagnosis of mild cognitive impairment.

The distinguishing feature of cognitive impairment in patients with Alzheimer disease (AD) is its typical onset after the age of 65 years. When it occurs before this age, it is classified as early-onset dementia, which accounts for approximately 5% to 6% of all cases [58]. The earliest cognitive symptom in AD is usually impaired recent memory, while long-term memory remains relatively preserved initially. This is followed by impairments in other cognitive domains. In contrast, cognitive impairment in vascular dementia (VaD) typically emerges following a stroke and is characterized predominantly by executive dysfunction, slowed thinking, and visuospatial disturbances, although the exact presentation depends on the location of the vascular lesions. Memory impairment generally appears at a later stage [59]. The presence of comorbidities such as thymoma and hyperthyroidism may also contribute to cognitive dysfunction. In thymoma, cognitive impairment can occur acutely through the mechanism of autoimmune encephalitis. In such cases, cognitive disturbances are often accompanied by additional neurological manifestations, including seizures, psychiatric symptoms, language disturbances, autonomic dysfunction, sleep disturbances, and altered levels of consciousness [60]. Meanwhile, in hyperthyroidism, cognitive impairment tends to involve executive function, attention, concentration, and verbal memory. Importantly, these cognitive symptoms are generally transient and improve with appropriate treatment of the hyperthyroid state [61]. The clinical features observed in our patient were more consistent with cognitive impairment secondary to BD than those caused by alternative etiologies or comorbid conditions.

Diagnosing cognitive impairment in patients with BD also poses a significant challenge because it more commonly coincides with overt neurological involvement, such as brainstem syndrome, movement disorders, and myelopathic syndrome [17]. A comprehensive examination should cover a range of cognitive domains, including attention, memory, visuospatial, language, reasoning, and psychomotor speed. Recommended instruments include MOCA-INA, FDS, BDS, TMT-A, and TMT-B [19]. MoCA-INA is used to evaluate global cognitive function in patients with BD or another systemic inflammatory disease, like SLE. It encompasses several cognitive domains, including visuospatial abilities, memory, attention, abstract thinking, language, naming, and executive function. A MoCA-INA score of 26 or above indicates normal cognition [62–65]. The FDS and BDS tests were used to assess short-term verbal memory. FDS is considered normal if the patient can repeat 5 to 7 digits, while BDS is deemed normal if the patient can repeat at least 4 digits [66]. The TMT-A evaluates verbal fluency, attention, and memory, with a normal result defined as completion in less than 90 seconds. In contrast, the TMT-B assesses executive function, and a normal result is defined as completion in under 4 minutes [67]. Based on the assessments, our patient demonstrated impairment in the memory domain on the MoCA-INA, and the BDS score was found to be at the lower threshold of the normal range. These findings further support the likelihood that her cognitive dysfunction was attributable to BD, rather than to comorbid conditions or other etiologies.

Neuroimaging, such as brain MRI, can help detect neurological involvement in BD, including cognitive impairment [68]. Typical MRI findings in neurological involvement of Behçet disease include parenchymal lesions that appear hypointense on T1-weighted images and hyperintense on T2-weighted images, commonly affecting the upper brainstem and diencephalic areas, which are essential for memory formation [13,16]. In patients with cognitive decline but no overt neurologic signs, functional imaging has demonstrated right temporo-parieto-occipital hypoperfusion [16]. Key structures in the temporal region, including the hippocampus and limbic system, parietal lobe, precuneus, posterior cingulate gyrus, and parieto-occipital sulcus, play crucial roles in cognitive function, particularly in memory [11]. Our patient’s MRI showed parietal atrophy, T1W hypointensity, and T2W hyperintensity in the temporal and occipital lobes, along with a Fazekas score of 1, suggesting a vascular condition due to systemic vasculitis that occurred in BD [2,3]. Moreover, MRI scans also excluded other possible etiologies, such as tumors, infarcts, or degenerative processes. In cases of brain tumors, cognitive impairment typically manifests according to the tumor site. In vascular dementia, infarctions in strategic regions of the brain, such as the caudate nuclei, medial frontal lobe, inferomedial temporal lobe, left angular gyrus, left capsular genu, and thalamus, are responsible for cognitive decline [69,70].

In Alzheimer disease, global and hippocampal atrophy, which are pathological hallmarks of the condition, contribute significantly to cognitive deterioration. These features are typically reflected by elevated scores on the MTA, Koedam, Fazekas, and GCA scales. Quantitative volumetry in our patient revealed a total brain volume within normal limits when compared to a population with normal cognitive function. A study conducted by Vinke et al (2019) reported that the average hippocampal volume in elderly individuals with normal cognitive function was 6.3 cc, with an average intracranial volume of 1229.4 cc [71]. In addition, the qualitative analysis showed low MTA, Koedam, and GCA scores, making Alzheimer-type neurodegeneration unlikely in this case [11,72]. In contrast, a higher Fazekas score is more indicative of the cognitive impairment caused by vascular dementia. The Fazekas score of 1, indicating mild periventricular white-matter hyperintensities, raises the possibility of cerebral small-vessel disease [73]. This may reflect a multifactorial etiology, potentially related to BD-associated vasculitis, age-related microvascular changes, or corticosteroid use [7,30,74,75]. This pattern was most consistent with a vascular or inflammatory basis for the cognitive symptoms, rather than primary neurodegeneration.

The presence of comorbidities in our patient – thymoma and hyperthyroidism – may also have contributed to her cognitive dysfunction. In cases of thymoma, cognitive impairment can result from paraneoplastic encephalitis. This condition is typically characterized on MRI by bilateral temporal lobe or limbic system hyperintensities [76]. However, in our patient, the temporal lobes appeared normal, with no evidence of limbic system hyperintensities. In hyperthyroidism, cognitive impairment is usually associated with thyrotoxicosis; however, the imaging did not reveal limbic system involvement typical of paraneoplastic encephalitis, nor were there features suggesting thyrotoxic encephalopathy, which often presents with normal MRI findings but abnormal in the connectivity of the posterior lobe of the cerebellum (PLC) and medial frontal gyrus (MeFG), which can only be detected by functional MRI (fMRI) [77]. While our patient’s cognitive profile and imaging findings were consistent with BD-associated cognitive dysfunction, particularly given the evidence of parietal atrophy and temporal lobe signal changes, the diagnosis remained inferential. Alternative or coexisting etiologies, including early vascular dementia, autoimmune processes related to thymoma, or reversible causes such as hyperthyroidism, were considered and appeared less likely based on the absence of supportive clinical or radiological findings. Nonetheless, the possibility of multifactorial contributors, particularly small-vessel disease or subclinical autoimmune effects, cannot be definitively excluded. Therefore, ongoing evaluation and a cautious interpretation of the diagnostic workup are warranted.

THERAPEUTIC CONSIDERATIONS AND MANAGEMENT:

Cognitive enhancers and neuroprotective agents may offer therapeutic benefit for cognitive impairment in BD. Donepezil, a cholinesterase inhibitor, increases synaptic acetylcholine levels and promotes cholinergic transmission, which is important for synaptic plasticity and memory consolidation, which are processes potentially disrupted by neuroinflammatory damage in BD [78,79]. Folic acid, an essential cofactor in methylation reactions and neurotransmitter synthesis, also lowers proinflammatory cytokines such as TNF-α and supports neurogenesis [80]. While no studies have evaluated donepezil or folic acid in BD, their observed benefits in other autoimmune diseases, such as multiple sclerosis, which similarly features CNS inflammation and cognitive impairment, suggest a potentially translatable effect, although this remains speculative and requires cautious interpretation [81,82].

Use of donepezil is well established in Alzheimer disease, with dosing typically starting at 5 mg daily and titrated to 10 mg, depending on the clinical response. Folic acid is also safe and has shown cognitive benefit in neurodegenerative diseases [78,83]. These treatments were selected over alternatives such as memantine or psychostimulants because of their good tolerability, minimal psychiatric adverse effects, and potential immunomodulatory properties [84,85]. Considering our patient’s autoimmune background and the absence of disease-specific guidelines for cognitive impairment in BD, the treatment selection was guided by mechanistic plausibility, safety, and indirect evidence from related conditions.

PROGNOSIS, FUNCTIONAL RECOVERY, AND SOCIOECONOMIC IMPLICATIONS:

BD represents not only a clinical challenge but also a substantial socioeconomic burden. A previous study estimated the annual total cost per patient to be approximately USD $3226±3488, with the highest costs observed in cases involving neurological complications (USD $5005±2707). Direct costs comprised 68% of the total expenditure, with medications accounting for the majority (79%). Indirect costs, such as loss of productivity and income, were reported by 42% of patients [64,86]. Cognitive impairment in BD is typically associated with overt neurological involvement, such as parenchymal or vascular neuro-Behçet disease manifestations. Our case is particularly notable for the presence of cognitive impairment in the absence of overt neurological symptoms, an uncommon and under-recognized presentation of neurological involvement in BD, and such cases remain sparsely reported in the literature. While most patients with neuro-Behçet disease present with brainstem syndromes, myelopathic features, or movement disorders, isolated cognitive dysfunction is rare and is easily overlooked in clinical practice [14].

Previous studies have shown that cognitive dysfunction in patients with NBS improves following rehabilitation therapy. In a study by Park et al (2018), participants received twice-daily physical, occupational, cognitive, and dysphagia rehabilitation along with corticosteroid therapy over 23 months. Significant improvement appeared across a neuropsychological battery – including the Mini-Mental State Examination (MMSE), Seoul Verbal Learning Test-Elderly version (SVLTE), Rey-Osterrieth Complex Figure Test (ROCF), Controlled Oral Word Association Test (COWAT), and Korean-Color Word Stroop Test (K-CWST) – supporting the value of early detection and prompt intervention for cognitive dysfunction in BD [87].

This underscores the need for heightened clinical vigilance for subtle cognitive symptoms in patients with BD, even in the absence of classical neuro-Behçet disease features. The absence of classic neurological signs in our patient underscores the possibility that cognitive decline can be an early or subclinical manifestation of CNS involvement in BD. This highlights a critical need for increased vigilance in assessing neuropsychological symptoms in patients with BD, even in the absence of overt neurological findings. Routine cognitive screening, even in the absence of overt neurological symptoms, is warranted. Our findings suggest that such atypical presentations may reflect localized inflammatory processes or hypoperfusion targeting metabolically vulnerable brain regions like the parietal lobes. This atypical presentation underscores the broader clinical spectrum of BD-related CNS involvement and suggests that cognitive impairment can precede, or occur independently from, other neurological signs. Therefore, comprehensive neuropsychological evaluation and advanced imaging should be considered in patients with BD presenting with subtle cognitive problems, as this could facilitate earlier diagnosis of neuro-Behçet disease and better-informed treatment strategies. Early detection of cognitive deficits and timely therapeutic intervention may help mitigate cognitive decline, improve quality of life, and potentially reverse symptoms, as seen in our patient, and ultimately reduce the broader socioeconomic impact on patients and healthcare systems.

LIMITATIONS AND FUTURE DIRECTIONS:

This study has several limitations. Cognitive evaluation was conducted using standardized tools – MoCA-Ina, TMT-A, TMT-B, FDS, and BDS – administered only at baseline and 1 year after therapy. These tools are widely accepted for assessing global cognition, executive function, and working memory [62,63]. The lack of intermediate assessments restricts the ability to monitor the trajectory of cognitive changes. Additionally, pre- and post-treatment neuroimaging, such as volumetric brain MRI, was not performed due to logistical and resource constraints, limiting our ability to link clinical improvement with potential structural brain changes.

Despite these limitations, follow-up assessments after 1 year demonstrated normal cognitive and functional outcomes. The patient achieved a MoCA-Ina score of 30/30, with TMT-A (47 seconds) and TMT-B (80 seconds) results within normal limits, reflecting preserved attention, executive function, and processing speed. Her working memory was also intact, as indicated by an FDS of 7 digits and a BDS of 6 digits [62,63]. In terms of daily functioning, she remained fully independent, with ADL and IADL scores of 0 and a BI of 100 [88,89]. Notably, these results were within normal limits at both baseline and follow-up, suggesting stability or improvement in cognitive function over the treatment period.

This case also presents the rare co-occurrence of BD, thymoma, and a history of hyperthyroidism. Although autoimmune processes may underlie all 3 conditions, the specific mechanisms linking them remain speculative. The literature suggests potential immune dysregulation in thymoma (eg, altered T-cell selection and AIRE expression) and Graves’ disease, but direct evidence connecting these processes to BD-related cognitive impairment is lacking. Thus, while we acknowledge the potential relevance of these comorbidities, their role in our patient’s cognitive decline cannot be confirmed and should be interpreted with caution.

To the best of our knowledge, there are no clinical trials or established guidelines supporting the use of donepezil or folic acid specifically for cognitive impairment in BD. However, the recognized benefits of these agents in other neuroinflammatory and neurodegenerative conditions, combined with the sustained cognitive improvement observed in our patient and the exclusion of alternative etiologies, suggest a potential therapeutic role for donepezil or folic acid. This warrants further investigation and provides a rationale for cautious extrapolation. This case report does not aim to establish efficacy but seeks to contribute to the limited body of literature on neurocognitive involvement in BD and to suggest possible avenues for treatment. Given that this is a single case and the pathophysiology of BD differs, the therapeutic efficacy should be interpreted with caution. Well-designed randomized controlled trials with larger sample sizes and longer follow-up periods are needed to evaluate the efficacy and safety of donepezil and folic acid in managing cognitive impairment associated with BD. Moreover, the presence of multiple comorbid conditions in this patient, such as thymoma and hyperthyroidism, alongside BD and its long-term treatment, highlights the need for further investigation into the potential causes and pathogenesis of cognitive impairment in BD. Such research would be instrumental in guiding appropriate and targeted therapeutic strategies.

Conclusions

Cognitive dysfunction in Behçet disease may manifest without overt neurologic signs, posing a diagnostic challenge. If left untreated, it can progress to dementia and result in a substantial socioeconomic burden due to long-term medication costs and loss of productivity. This case highlights the importance of early neuropsychological screening in patients with BD presenting with subtle cognitive changes. Our patient presented with mild cognitive impairment and parietal atrophy on MRI, in the context of comorbid thymoma and hyperthyroidism, associations that are rarely reported in BD. Initial misattribution of her oral ulcers to stomatitis delayed definitive diagnosis, underscoring the need for heightened clinical vigilance for atypical presentations. Neuropsychological screening tools such as the MoCA may be valuable in detecting early cognitive involvement. Although a combination of immunosuppressive therapy and cognitive enhancer yielded marked improvement, the long-term efficacy remains uncertain without extended follow-up. This case raises important questions regarding the role of inflammation, long-term corticosteroid use, and comorbid conditions in the pathogenesis of cognitive dysfunction in BD. While causal inferences are limited by the nature of a single case, early identification and individualized management strategies may help mitigate progression and improve quality of life. Further studies are needed to elucidate the prevalence, mechanisms, and optimal interventions for cognitive impairment in BD.