When stroke is not stroke: cryptococcal meningitis presenting as progressive cerebral infarction in a patient with rheumatoid arthritis – a case report and literature review

When stroke is not stroke: cryptococcal meningitis presenting as progressive cerebral infarction in a patient with rheumatoid arthritis – a case report and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report When stroke is not stroke: cryptococcal meningitis presenting as progressive cerebral infarction in a patient with rheumatoid arthritis – a case report and literature review Yihui Qiu, Tengyun Ma, Lijuan Wang, Jiehao Zhao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9106010/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Cryptococcal meningitis (CM) is a prevalent fungal infection of the central nervous system, particularly in immunocompromised hosts. Cerebral infarction, a well-recognized yet underappreciated severe complication, occurs in approximately 13% of CM cases, with a notably higher incidence observed in non-HIV populations than in those with HIV infection. Due to its frequently nonspecific clinical features, diagnosis and treatment are often delayed. Herein, we report a case of CM in which multiple cerebral infarctions constituted the predominant clinical manifestation, aiming to enhance clinicians' recognition of this atypical presentation. Case presentation A 66-year-old male with a history of rheumatoid arthritis(RA) presented with dizziness and headache initially diagnosed as "cerebral infarction" at another hospital. Despite standard secondary stroke prevention, his condition progressively worsened to gait instability, bilateral limb weakness, and neuropsychiatric abnormalities. Brain magnetic resonance imaging revealed newly developed infarctions in the bilateral basal ganglia, temporo-occipital lobes, and pons with meningeal enhancement. Cerebrospinal fluid analysis detected Cryptococcus neoforman s by culture, next-generation sequencing, and positive cryptococcal antigen. The patient showed clinical improvement following antifungal therapy with amphotericin B, flucytosine, and fluconazole, though treatment was complicated by nephrotoxicity requiring regimen adjustment. Conclusion This case highlights that CM should be considered in immunocompromised patients presenting with cryptogenic multiple deep cerebral infarctions, particularly those involving the basal ganglia and posterior circulation with concomitant meningeal enhancement. Early cerebrospinal fluid examination is crucial for timely diagnosis and intervention. Cryptococcal meningitis Cerebral infarction Rheumatoid arthritis Opportunistic infection Magnetic resonance imaging Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Cryptococcal meningitis (CM) is the most common fungal infection of the central nervous system (CNS), caused predominantly by Cryptococcus neoformans or Cryptococcus gattii 1 . While CM typically affects immunocompromised individuals, including those with HIV infection, organ transplantation, or corticosteroid therapy, it can also occur in apparently immunocompetent hosts 2 . The clinical presentation of CM is often nonspecific, with headache, fever, and altered mental status being the most common manifestations 1 . Cerebral infarction is a well-recognized but underappreciated severe complication of CM, occurring in approximately 13% of patients 3 . Mishra et al. demonstrated that compared to patients without infarcts, those CM with infarcts had a 50% higher incidence of poor outcomes and double the mortality. Interestingly, the incidence of CM-associated infarction is higher in non-HIV populations compared to HIV-infected individuals (78% vs. 22% in one series) 3 . The non-specificity of clinical symptoms frequently poses a significant diagnostic challenge, consequently delaying therapeutic intervention and contributing to increased mortality. Herein, we report a case of CM presenting with progressive multiple cerebral infarctions in a patient with rheumatoid arthritis(RA) and suspected long-term use of corticosteroid-containing health supplements. This case highlights the diagnostic challenges when fungal infection mimics atherosclerotic stroke and underscores the importance of considering opportunistic infections in immunocompromised patients with cryptogenic cerebral infarction. Case Report Clinical Presentation A 66-year-old man was admitted to our hospital on December 4, 2024, with a 3-month history of dizziness and a 10-day history of worsening symptoms with left-sided limb weakness. In September 2024, the patient experienced sudden onset dizziness with rotational vertigo, accompanied by right frontal electric shock-like pain and nausea. Each episode lasted approximately 20 minutes and resolved spontaneously. Subsequently, he developed persistent head heaviness with intermittent right frontal drilling pain lasting several minutes. On October 21, 2024, he experienced another similar episode. Brain magnetic resonance imaging (MRI) at a primary hospital revealed multiple ischemic foci in the bilateral basal ganglia, temporal, and parietal lobes (Fig. 1 a-c). Magnetic resonance angiography (MRA) showed no abnormalities. He was started on secondary stroke prevention with clopidogrel and atorvastatin, along with neurotrophic therapy, but his dizziness and headache persisted. On November 6, 2024, he acutely developed gait instability with right-sided limb weakness. Diffusion weighted imaging (DWI) demonstrated an acute infarction involving the left posterior limb of the internal capsule. (Fig. 2a1-a3). Despite continued secondary prevention and rehabilitation, his right-sided weakness progressed. Follow-up DWI revealed enlargement of the left basal ganglia infarction with extension into the putamen and corona radiata, along with a new infarct in the insular lobe. (Fig. 2b1-b3). Accordingly, aspirin was added to his antiplatelet regimen. On November 27, 2024, family members noted new-onset left-sided limb weakness that rendered him unable to walk, accompanied by mutism, paranoia (believing cameras were watching him), and refusal to eat, though he still recognized family members. Consequently, he was referred to our hospital. Throughout his illness, the patient remained afebrile. He exhibited poor appetite, weight loss (exact amount unspecified), and normal bowel and bladder function. Medical History The patient had a long-standing history of RA. Family members reported that he had been taking self-prescribed "health supplements" (powder form) for pain relief, which were suspected to contain corticosteroids. He had no history of hypertension, diabetes mellitus, or hyperlipidemia, and denied smoking or alcohol consumption. His father had a history of cerebral infarction. Physical Examination On admission, vital signs revealed a temperature of 37.6°C. Neurological examination showed an alert but apathetic patient with impaired comprehension, judgment, calculation, and orientation. Pupils were equal and reactive to light without gaze palsy. Cranial nerve examination revealed left nasolabial fold flattening, preserved gag reflex, and choking with swallowing. Motor examination demonstrated bilateral upper extremity weakness (grade 4/5), right lower extremity weakness (grade 3/5), and left lower extremity weakness (grade 2/5). Left Babinski sign was present. Nuchal rigidity was noted, while Kernig and Brudzinski signs were negative. The remainder of the examination was limited by poor cooperation. Laboratory Findings Laboratory investigations revealed: white blood cell count 10.3 × 10⁹/L (elevated), hemoglobin 87 g/L (decreased), platelet count 292 × 10⁹/L, neutrophil ratio 0.787 (elevated), D-dimer 2790 ng/mL (elevated), erythrocyte sedimentation rate 91 mm/h (elevated), interleukin-6 24.0 pg/mL (elevated), C-reactive protein 33.44 mg/L (elevated), and procalcitonin 0.050 ng/mL (elevated). Whole blood T-SPOT.TB was positive (antigen well spot count 12, exceeding the positive threshold of 11). Rheumatoid factor was markedly elevated at 672.8 IU/mL, and anti-cyclic citrullinated peptide antibody was > 500 U/mL (both elevated). Liver and renal function tests, cardiac enzymes, coagulation parameters, tumor markers, HIV, and syphilis serology were unremarkable. Cerebrospinal fluid (CSF) analysis showed: opening pressure 200 mmH₂O (elevated), white blood cell count 92 × 10⁶/L (elevated) with 65% lymphocytes, glucose 1.30 mmol/L (decreased; simultaneous blood glucose 6.29 mmol/L), chloride 112.7 mmol/L (simultaneous blood chloride 96.0 mmol/L), and protein 1970 mg/L (elevated). CSF PCR for Mycobacterium tuberculosis was negative, while cryptococcal antigen was positive, and both culture and next-generation sequencing confirmed Cryptococcus neoformans (sequence count 718, 99% confidence). Neuroimaging MRI of the brain demonstrated disease progression. DWI revealed new areas of restricted diffusion involving the right putamen, right corona radiata, right pons, and left temporal lobe. Additionally, the pre-existing infarct in the left basal ganglia and corona radiata had further enlarged, with extension into the genu of the internal capsule (Fig. 2c1-c3). With the right putamen as the region of interest, magnetic resonance spectroscopy (MRS) showed a decreased N-acetylaspartate (NAA) peak, an elevated lactate (Lac) peak with an inverted doublet, and a normal choline (Cho) peak, with NAA/Cr and Cho/Cr ratios of 1.28 and 1.03, respectively (Fig. 3 ). These findings were consistent with the progression of acute cerebral infarction. Contrast-enhanced T1-weighted imaging revealed meningeal enhancement(Fig. 4 a-d). MR angiography (MRA) and MR venography (MRV) were unremarkable (Fig. 4 e-f). Additional Investigations Chest computed tomography showed fibrotic lesions in the left upper lobe and mild bronchiectasis with chronic inflammation in both lower lobes. Wrist ultrasound revealed synovial thickening with bone erosion, consistent with RA. Diagnosis and Treatment The patient was diagnosed with: (1) CM with multiple cerebral infarctions; and (2) Rheumatoid arthritis. Antifungal therapy was initiated with amphotericin B (0.5 mg/kg/day), flucytosine (100 mg/kg/day), and fluconazole (400 mg/day). After three weeks of treatment, the patient developed elevated serum creatinine, prompting discontinuation of amphotericin B and adjustment of fluconazole to 600 mg/day. Follow-up CSF analysis on January 26, 2025, showed improvement: opening pressure 160 mmH₂O, white blood cell count 4 × 10⁶/L, glucose 3.04 mmol/L (decreased; simultaneous blood glucose 6.60 mmol/L), chloride 128.3 mmol/L (simultaneous blood chloride 104.1 mmol/L), and protein 892 mg/L (elevated). The patient's hospital course was complicated by gastrointestinal bleeding, pulmonary infection, and respiratory failure, requiring intensive care unit admission. Due to financial constraints, the family requested transfer to a local hospital for continued care. Discussion CM complicated by cerebral infarction is a severe complication in immunocompromised patients 3 . In this case, the patient initially presented without the classic acute symptoms of CM, subsequently manifesting with progressive stroke as the predominant clinical feature. This atypical presentation posed a diagnostic challenge and delayed the initiation of appropriate antifungal therapy. The pathogenesis of cerebral infarction in CM involves multiple interconnected mechanisms. First, the patient's underlying immune compromise represents the critical foundation upon which disseminated infection developed. Two interconnected factors contributed to this susceptibility: the autoimmune disease itself (the patient has a history of RA) and, more significantly, suspected long-term use of corticosteroid-containing health supplements. Corticosteroid use has been reported in 17.5% − 28% of HIV-negative patients with CM and represents a significant risk factor by impairing cell-mediated immunity 4 , 5 . Glucocorticoids suppress T lymphocyte proliferation, reduce pro-inflammatory cytokine production, and impair macrophage phagocytic activity, thereby creating favorable conditions for fungal dissemination to the central nervous system. Importantly, the patient's underlying RA may independently contribute to susceptibility. Williamson et al. note associations between cryptococcosis and various autoimmune diseases including systemic lupus erythematosus, dermatomyositis, and ankylosing spondylitis 1 , 6 . The markedly elevated rheumatoid factor (672.8 IU/mL) and anti-CCP antibodies (> 500 U/mL) confirm active autoimmune disease. The Th17/IL-17 axis is vital for immunity to fungi. Accumulating evidence suggests that patients with RA exhibit functional defects in Th17-mediated immunity, characterized by an impaired antigen-specific response to fungi. Thus, the inherent Th17 functional deficits in RA, combined with the immunosuppressive effects of therapeutic agents such as corticosteroids, may collectively create a permissive immunological environment that facilitates the proliferation of Cryptococcus neoformans 7 . Once this permissive immunological environment is established, Cryptococcus neoformans is able to disseminates from the basal cisterns through Virchow-Robin spaces to the basal ganglia, internal capsule, and brainstem, where perivascular accumulation causes inflammatory infiltration, endothelial injury, and small vessel occlusion 3 , 8 . Concurrently, direct fungal invasion of arterial walls and strangulation of vessels by basal exudates may induce vasculitis, vasospasm, and thrombosis, culminating in cerebral infarction 9 . Notably, non-HIV patients with CM have a higher risk of cerebral infarction compared to HIV-infected individuals 3 , 10 . This paradox may reflect an exaggerated host inflammatory response in immunocompetent patients, leading to more severe vasculitis and thrombosis. In our patient, markedly elevated D-dimer levels (2790 ng/mL) suggested a hypercoagulable state contributing to thrombus formation, consistent with the vascular inflammatory mechanism described by Mishra et al. 3 . The absence of traditional vascular risk factors and normal MRA further supported an infectious rather than atherosclerotic etiology. Tuberculous meningitis (TBM) also frequently occurs in immunocompromised patients. Its clinical manifestations and routine CSF profiles are similar to those of CM, and it is also commonly complicated by cerebral infarction 11 . Infarction in TBM results from basal exudates causing strangulation of perforating arteries, predominantly affecting the thalamus, anterior limb of internal capsule, and cerebral lobes 10 , 12 . CM-associated infarcts show a predilection for deep nuclear structures and posterior circulation territories. In a comparative study by Kumar et al. 10 , 54.5% of CM patients developed cerebral infarctions, with caudate head (41.7% vs. 9.4%, p = 0.01) and cerebellar (33.3% vs. 9.4%, p = 0.05) involvement significantly more common in CM than in TBM. Basal ganglia (41.7%) and corona radiata (66.7%) were also frequently involved. Lan et al. 9 reported infarctions in 32% of CM patients, predominantly in the basal ganglia and internal capsule. Our patient's neuroimaging findings align with these patterns, showing acute infarctions in the bilateral basal ganglia, corona radiata, and pons—the latter representing posterior circulation involvement characteristic of CM. The initial symptom of vertigo may have reflected brainstem/cerebellar ischemia, though early imaging did not capture these lesions. In this patient, the clinical presentation of weight loss with recurrent afternoon fevers, along with a positive T-SPOT.TB result, initially raised suspicion for TBM co-infection. However, TBM was ultimately ruled out by two key findings: an infarction pattern involving the pons and basal ganglia without thalamic involvement, and negative CSF results for M. tuberculosis by PCR, culture, and next-generation sequencing. It is particularly noteworthy that T-SPOT.TB, an interferon-gamma(IFN-γ) release assay (IGRA), is an important tool for detecting tuberculosis infection 13 ; however, false-positive results may occur in the setting of cryptococcal infection. The underlying mechanism may involve the activation of T lymphocytes by Cryptococcus neoformans, leading to increased IFN-γ release 14 , 15 . This finding suggests that positive T-SPOT.TB results in the context of cryptococcal infection should be interpreted with caution and must be evaluated in conjunction with direct pathogen evidence. Current ECMM/ISHAM global guidelines for the management of cryptococcosis outline a standard three-phase regimen. Induction therapy consists of at least 2 weeks of high-dose amphotericin B (0.7–1.0 mg/kg/day) combined with flucytosine (100 mg/kg/day) for rapid CSF sterilization. This is followed by an 8-week consolidation phase with high-dose fluconazole (400–800 mg/day) monotherapy, and subsequently, low-dose fluconazole (200 mg/day) maintenance therapy to prevent relapse until immune reconstitution is achieved with ART 16 . In a cohort study from China, the triple regimen of amphotericin B + flucytosine + fluconazole resulted in a superior 2-week CSF sterilization rate relative to amphotericin B + flucytosine alone (75.9% vs. 69.2%). Notably, within the amphotericin B + flucytosine ± fluconazole regimen, a lower amphotericin B dose (0.4–0.5 mg/kg/day) not only reduced the frequency of adverse effects but also yielded clinical efficacy comparable to that of the conventional 0.6–0.7 mg/kg/day dose 17 . Accordingly, our patient received induction therapy with amphotericin B (0.5 mg/kg/day), flucytosine (100 mg/kg/day), and fluconazole (400 mg/day). When renal dysfunction was identified on monitoring, a timely switch to high-dose fluconazole (600 mg/day) was implemented, achieving a balance between treatment efficacy and safety. Clinical Implications This case offers several important lessons for clinicians: In immunocompromised patients presenting with cryptogenic multiple deep cerebral infarctions, particularly involving the basal ganglia and posterior circulation with concomitant meningeal enhancement, CM should be included in the differential diagnosis. The absence of traditional vascular risk factors and normal MRA does not exclude stroke—infectious vasculopathies should be considered. Positive T-SPOT.TB in suspected CM patients may represent false-positive results from fungal-induced IFN-γ release and requires confirmation with CSF direct pathogen detection. Early CSF examination including cryptococcal antigen, culture, and next-generation sequencing is essential for timely diagnosis and treatment initiation. Close monitoring for amphotericin B-associated nephrotoxicity is mandatory, with prompt regimen adjustment when indicated. Conclusion CM with cerebral infarction is a severe complication in immunocompromised patients that can mimic atherosclerotic stroke. The characteristic infarction pattern involves the basal ganglia, corona radiata, and posterior circulation territories. Clinicians should maintain a high index of suspicion for opportunistic fungal infections in patients with cryptogenic cerebral infarctions, particularly those with risk factors for immunosuppression. Early diagnosis through CSF analysis and prompt initiation of antifungal therapy are essential for improving outcomes in this devastating condition. Declarations Ethics approval and consent to participate Not applicable. Clinical trial number Not applicable. Consent for publication Written informed consent was obtained from the legal guardians for the anonymized information to be published in this article. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that there is no conflict of interest. Funding This study was supported by the National Natural Science Foundation of China (No. 82371249), the Science and Technology Planning Project of Guangzhou (No.202201000005). Author contributions Yi-Hui Qiu: Clinical data acquisition, analysis, and interpretation; manuscript drafting and revision. Teng-Yun Ma: Clinical data acquisition; patient follow-up and outcome assessment; literature review. Li-Juan Wang: Critical manuscript revision; study coordination; funding acquisition. Jie-Hao Zhao: Conceptualization, study design, data acquisition, analysis, and interpretation; manuscript drafting and revision; study supervision; final approval. Acknowledgments We thanked the patient and his family for their support and approval for publishing the case. References Williamson PR, Jarvis JN, Panackal AA, et al. Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy. NAT REV NEUROL. 2016;13:13–24. Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. CLIN INFECT DIS. 1995;21:28–34. Mishra A, Arvind V, Muliyil D, et al. Cerebrovascular injury in cryptococcal meningitis. INT J STROKE. 2017;13:57–65. Qu J, Zhou T, Zhong C, Deng R, Lü X. Comparison of clinical features and prognostic factors in HIV-negative adults with cryptococcal meningitis and tuberculous meningitis: a retrospective study. BMC Infect Dis. 2017;17:51. Pappas P, Perfect J, Cloud G, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. ClIN INFECT DIS. 2001;33:690–6. Bernard C, Maucort-Boulch D, Varron L, et al. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases. QJM-INT J MED. 2013;106:523–39. Bishu S, Su E, Wilkerson E et al. Rheumatoid arthritis patients exhibit impaired Candida albicans-specific Th17 responses. ARTHRITIS RES THER 2014;16. Shimoda Y, Ohtomo S, Arai H, Ohtoh T, Tominaga T. Subarachnoid small vein occlusion due to inflammatory fibrosis—a possible mechanism for cerebellar infarction in cryptococcal meningoencephalitis: a case report. BMC Neurol. 2017;17:157. Lan S, Chang W, Lu C, Lui C, Chang H. Cerebral infarction in chronic meningitis: a comparison of tuberculous meningitis and cryptococcal meningitis. QJM-INT J MED. 2001;94:247–57. Kumar M, Dhar N, Tiwari A, Siddiqui M. Comparison of patterns of infarction in TB and cryptococcal meningitis. T ROY SOC TROP MED H. 2021;115:1160–1167. Kalita J, Misra U, Nair P. Predictors of Stroke and Its Significance in the Outcome of Tuberculous Meningitis. J STROKE CEREBROVASC. 2009;18:251–8. Tai M, Viswanathan S, Rahmat K, et al. Cerebral infarction pattern in tuberculous meningitis. Sci Rep. 2016;6:38802. Borkowska D, Zwolska Z, Michałowska-Mitczuk D, et al. Interferon-gamma assays T-SPOT.TB for the diagnosis of latent tuberculosis infection. Pneumonol Alergol Pol. 2011;79:264–71. Miyahara A, Umeki A, Sato K, et al. Innate phase production of IFN-γ by memory and effector T cells expressing early activation marker CD69 during infection with Cryptococcus deneoformans in the lungs. INFECT IMMUN. 2024;92:1–20. Boulware D, Bonham S, Meya D, et al. Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory Syndrome. J Infect Dis. 2010;202:962–70. Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024;24:e495–512. Xu L, Tao R, Wu J, et al. Short-Course Rather Than Low-Dose Amphotericin B May Exert Potential Influence on Mortality in Cryptococcal Meningitis Patients Treated With Amphotericin B Plus Flucytosine Alone or in Combination With Fluconazole. Front Microbiol. 2019;10:2082. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 26 Apr, 2026 Reviewers agreed at journal 26 Apr, 2026 Reviewers invited by journal 01 Apr, 2026 Editor assigned by journal 01 Apr, 2026 Editor invited by journal 24 Mar, 2026 Submission checks completed at journal 24 Mar, 2026 First submitted to journal 24 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9106010","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":617755924,"identity":"9c47c52e-7eda-4114-841d-cf8d253d9150","order_by":0,"name":"Yihui Qiu","email":"","orcid":"","institution":"Guangdong Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yihui","middleName":"","lastName":"Qiu","suffix":""},{"id":617755925,"identity":"b2f38f5f-08db-48b5-a4a1-31d9717c1146","order_by":1,"name":"Tengyun Ma","email":"","orcid":"","institution":"Guangdong Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tengyun","middleName":"","lastName":"Ma","suffix":""},{"id":617755927,"identity":"d40eefb1-cfa2-4537-a7ec-4f2ba265acaf","order_by":2,"name":"Lijuan Wang","email":"","orcid":"","institution":"Guangdong Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lijuan","middleName":"","lastName":"Wang","suffix":""},{"id":617755929,"identity":"56c8c6d5-2738-49b4-a707-f8f2a1467251","order_by":3,"name":"Jiehao Zhao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYBACxmYGNjDDAMh+kFBRQ5oWZoMHZ44RZRFcC5vkwxZmwuqZ25mPPfhRwWBvzn74WEViAxsDf3t3AgGHsaUb9pxhYLbsSUu7kbhDhkHizNkNBLTwmEnwtjGwGRzIMbuReIaNwUAil5AW/m+Sf9sYeAzOvzErSGxjJkYLD5s00BYJgxs5ZgxEamEzk5Y5w2BgcONZskTCmWM8BP1i2H/4meQbYIgZnE8++PFHRY0cf3svAS0NYOo/XIAHr3IQkCeoYhSMglEwCkYBAGKPQpyfhxJoAAAAAElFTkSuQmCC","orcid":"","institution":"Guangdong Provincial People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jiehao","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2026-03-12 14:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9106010/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9106010/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106404366,"identity":"0b58e5c0-e23d-4943-a464-a48fa0ea1aa8","added_by":"auto","created_at":"2026-04-08 09:15:53","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":156035,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCranial MRI scanning of the patient.\u003c/strong\u003e (a-c) High t2-FLAIr signal in the bilateral basal ganglia, temporal, and parietal lobes by transection plane scan. Abbreviations: \u003cem\u003eMRI, \u003c/em\u003emagnetic resonance imaging; \u003cem\u003eFLAIR, \u003c/em\u003efluid-attenuated inversion-recovery sequence.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9106010/v1/59e82432b0c1a717063e102f.jpeg"},{"id":106310041,"identity":"86337c9e-ad95-4979-a3da-71f997eb20d1","added_by":"auto","created_at":"2026-04-07 10:21:53","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":228651,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerial DWI findings.\u003c/strong\u003e (a1-a3) Initial DWI shows restricted diffusion in the left posterior limb of the internal capsule, indicating acute infarction. (b1-b3) Follow-up DWI demonstrates enlargement of the left basal ganglia infarct with extension into the putamen and corona radiata, along with a new infarct in the insular lobe. (c1-c3) Subsequent DWI reveals additional areas of restricted diffusion in the right putamen, right corona radiata, right pons, and left temporal lobe; the prior left basal ganglia infarct has further enlarged, now involving the genu of the internal capsule.\u003c/p\u003e\n\u003cp\u003eAbbreviations: \u003cem\u003eDWI, \u003c/em\u003ediffusion-weighted imaging.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9106010/v1/2e5123446f4edbb61bb6fb14.jpeg"},{"id":106310044,"identity":"91fb949f-8778-4d81-aba4-e09ee043ac1a","added_by":"auto","created_at":"2026-04-07 10:21:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":237947,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMRS scanning of the patient. \u003c/strong\u003eMRS with the right putamen as the region of interest demonstrates a decreased NAA peak, an elevated Lac doublet, with NAA/Cr = 1.28 and Cho/Cr = 1.03, confirming acute infarction.\u003c/p\u003e\n\u003cp\u003eAbbreviations: \u003cem\u003eMRS, \u003c/em\u003eMagnetic resonance spectroscopy; \u003cem\u003eNAA, \u003c/em\u003eN-acetylaspartate; \u003cem\u003eLac, \u003c/em\u003elactate; \u003cem\u003eCho,\u003c/em\u003echoline; \u003cem\u003eCr, \u003c/em\u003ecreatine.\u003c/p\u003e","description":"","filename":"Onlinefig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-9106010/v1/097b565c53341cea96f816ee.png"},{"id":106403448,"identity":"f7602b1e-01d9-4826-802c-ab36730e21f6","added_by":"auto","created_at":"2026-04-08 09:14:17","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":247103,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eContrast-enhanced imaging and MRA/MRV.\u003c/strong\u003e Contrast-enhanced T1-weighted imaging(a-d) demonstrates meningeal enhancement. MRA(e) and MRV(f) were unremarkable.\u003c/p\u003e\n\u003cp\u003eAbbreviations: \u003cem\u003eMRA,\u003c/em\u003e magnetic resonance angiography; \u003cem\u003eMRV,\u003c/em\u003e magnetic resonance venography.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9106010/v1/d35b2c8dd1f79378374e83e9.jpeg"},{"id":106405576,"identity":"60ebb097-5275-4306-9418-69e448b90739","added_by":"auto","created_at":"2026-04-08 09:27:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1529767,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9106010/v1/647ce039-a197-44f3-8d91-6d4c09ee2f63.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"When stroke is not stroke: cryptococcal meningitis presenting as progressive cerebral infarction in a patient with rheumatoid arthritis – a case report and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCryptococcal meningitis (CM) is the most common fungal infection of the central nervous system (CNS), caused predominantly by Cryptococcus neoformans or Cryptococcus gattii\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. While CM typically affects immunocompromised individuals, including those with HIV infection, organ transplantation, or corticosteroid therapy, it can also occur in apparently immunocompetent hosts\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The clinical presentation of CM is often nonspecific, with headache, fever, and altered mental status being the most common manifestations\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCerebral infarction is a well-recognized but underappreciated severe complication of CM, occurring in approximately 13% of patients\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Mishra et al. demonstrated that compared to patients without infarcts, those CM with infarcts had a 50% higher incidence of poor outcomes and double the mortality. Interestingly, the incidence of CM-associated infarction is higher in non-HIV populations compared to HIV-infected individuals (78% vs. 22% in one series)\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe non-specificity of clinical symptoms frequently poses a significant diagnostic challenge, consequently delaying therapeutic intervention and contributing to increased mortality. Herein, we report a case of CM presenting with progressive multiple cerebral infarctions in a patient with rheumatoid arthritis(RA) and suspected long-term use of corticosteroid-containing health supplements. This case highlights the diagnostic challenges when fungal infection mimics atherosclerotic stroke and underscores the importance of considering opportunistic infections in immunocompromised patients with cryptogenic cerebral infarction.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical Presentation\u003c/h2\u003e \u003cp\u003eA 66-year-old man was admitted to our hospital on December 4, 2024, with a 3-month history of dizziness and a 10-day history of worsening symptoms with left-sided limb weakness.\u003c/p\u003e \u003cp\u003eIn September 2024, the patient experienced sudden onset dizziness with rotational vertigo, accompanied by right frontal electric shock-like pain and nausea. Each episode lasted approximately 20 minutes and resolved spontaneously. Subsequently, he developed persistent head heaviness with intermittent right frontal drilling pain lasting several minutes. On October 21, 2024, he experienced another similar episode. Brain magnetic resonance imaging (MRI) at a primary hospital revealed multiple ischemic foci in the bilateral basal ganglia, temporal, and parietal lobes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea-c). Magnetic resonance angiography (MRA) showed no abnormalities. He was started on secondary stroke prevention with clopidogrel and atorvastatin, along with neurotrophic therapy, but his dizziness and headache persisted.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOn November 6, 2024, he acutely developed gait instability with right-sided limb weakness. Diffusion weighted imaging (DWI) demonstrated an acute infarction involving the left posterior limb of the internal capsule. (Fig.\u0026nbsp;2a1-a3). Despite continued secondary prevention and rehabilitation, his right-sided weakness progressed. Follow-up DWI revealed enlargement of the left basal ganglia infarction with extension into the putamen and corona radiata, along with a new infarct in the insular lobe. (Fig.\u0026nbsp;2b1-b3). Accordingly, aspirin was added to his antiplatelet regimen.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOn November 27, 2024, family members noted new-onset left-sided limb weakness that rendered him unable to walk, accompanied by mutism, paranoia (believing cameras were watching him), and refusal to eat, though he still recognized family members. Consequently, he was referred to our hospital. Throughout his illness, the patient remained afebrile. He exhibited poor appetite, weight loss (exact amount unspecified), and normal bowel and bladder function.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMedical History\u003c/h3\u003e\n\u003cp\u003eThe patient had a long-standing history of RA. Family members reported that he had been taking self-prescribed \"health supplements\" (powder form) for pain relief, which were suspected to contain corticosteroids. He had no history of hypertension, diabetes mellitus, or hyperlipidemia, and denied smoking or alcohol consumption. His father had a history of cerebral infarction.\u003c/p\u003e\n\u003ch3\u003ePhysical Examination\u003c/h3\u003e\n\u003cp\u003eOn admission, vital signs revealed a temperature of 37.6\u0026deg;C. Neurological examination showed an alert but apathetic patient with impaired comprehension, judgment, calculation, and orientation. Pupils were equal and reactive to light without gaze palsy. Cranial nerve examination revealed left nasolabial fold flattening, preserved gag reflex, and choking with swallowing. Motor examination demonstrated bilateral upper extremity weakness (grade 4/5), right lower extremity weakness (grade 3/5), and left lower extremity weakness (grade 2/5). Left Babinski sign was present. Nuchal rigidity was noted, while Kernig and Brudzinski signs were negative. The remainder of the examination was limited by poor cooperation.\u003c/p\u003e\n\u003ch3\u003eLaboratory Findings\u003c/h3\u003e\n\u003cp\u003eLaboratory investigations revealed: white blood cell count 10.3 \u0026times; 10⁹/L (elevated), hemoglobin 87 g/L (decreased), platelet count 292 \u0026times; 10⁹/L, neutrophil ratio 0.787 (elevated), D-dimer 2790 ng/mL (elevated), erythrocyte sedimentation rate 91 mm/h (elevated), interleukin-6 24.0 pg/mL (elevated), C-reactive protein 33.44 mg/L (elevated), and procalcitonin 0.050 ng/mL (elevated). Whole blood T-SPOT.TB was positive (antigen well spot count 12, exceeding the positive threshold of 11). Rheumatoid factor was markedly elevated at 672.8 IU/mL, and anti-cyclic citrullinated peptide antibody was \u0026gt;\u0026thinsp;500 U/mL (both elevated). Liver and renal function tests, cardiac enzymes, coagulation parameters, tumor markers, HIV, and syphilis serology were unremarkable.\u003c/p\u003e \u003cp\u003eCerebrospinal fluid (CSF) analysis showed: opening pressure 200 mmH₂O (elevated), white blood cell count 92 \u0026times; 10⁶/L (elevated) with 65% lymphocytes, glucose 1.30 mmol/L (decreased; simultaneous blood glucose 6.29 mmol/L), chloride 112.7 mmol/L (simultaneous blood chloride 96.0 mmol/L), and protein 1970 mg/L (elevated). CSF PCR for Mycobacterium tuberculosis was negative, while cryptococcal antigen was positive, and both culture and next-generation sequencing confirmed Cryptococcus neoformans (sequence count 718, 99% confidence).\u003c/p\u003e\n\u003ch3\u003eNeuroimaging\u003c/h3\u003e\n\u003cp\u003eMRI of the brain demonstrated disease progression. DWI revealed new areas of restricted diffusion involving the right putamen, right corona radiata, right pons, and left temporal lobe. Additionally, the pre-existing infarct in the left basal ganglia and corona radiata had further enlarged, with extension into the genu of the internal capsule (Fig.\u0026nbsp;2c1-c3). With the right putamen as the region of interest, magnetic resonance spectroscopy (MRS) showed a decreased N-acetylaspartate (NAA) peak, an elevated lactate (Lac) peak with an inverted doublet, and a normal choline (Cho) peak, with NAA/Cr and Cho/Cr ratios of 1.28 and 1.03, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These findings were consistent with the progression of acute cerebral infarction. Contrast-enhanced T1-weighted imaging revealed meningeal enhancement(Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea-d). MR angiography (MRA) and MR venography (MRV) were unremarkable (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ee-f).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAdditional Investigations\u003c/h2\u003e \u003cp\u003eChest computed tomography showed fibrotic lesions in the left upper lobe and mild bronchiectasis with chronic inflammation in both lower lobes. Wrist ultrasound revealed synovial thickening with bone erosion, consistent with RA.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnosis and Treatment\u003c/h3\u003e\n\u003cp\u003eThe patient was diagnosed with: (1) CM with multiple cerebral infarctions; and (2) Rheumatoid arthritis.\u003c/p\u003e \u003cp\u003eAntifungal therapy was initiated with amphotericin B (0.5 mg/kg/day), flucytosine (100 mg/kg/day), and fluconazole (400 mg/day). After three weeks of treatment, the patient developed elevated serum creatinine, prompting discontinuation of amphotericin B and adjustment of fluconazole to 600 mg/day. Follow-up CSF analysis on January 26, 2025, showed improvement: opening pressure 160 mmH₂O, white blood cell count 4 \u0026times; 10⁶/L, glucose 3.04 mmol/L (decreased; simultaneous blood glucose 6.60 mmol/L), chloride 128.3 mmol/L (simultaneous blood chloride 104.1 mmol/L), and protein 892 mg/L (elevated).\u003c/p\u003e \u003cp\u003eThe patient's hospital course was complicated by gastrointestinal bleeding, pulmonary infection, and respiratory failure, requiring intensive care unit admission. Due to financial constraints, the family requested transfer to a local hospital for continued care.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCM complicated by cerebral infarction is a severe complication in immunocompromised patients\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. In this case, the patient initially presented without the classic acute symptoms of CM, subsequently manifesting with progressive stroke as the predominant clinical feature. This atypical presentation posed a diagnostic challenge and delayed the initiation of appropriate antifungal therapy.\u003c/p\u003e \u003cp\u003eThe pathogenesis of cerebral infarction in CM involves multiple interconnected mechanisms. First, the patient's underlying immune compromise represents the critical foundation upon which disseminated infection developed. Two interconnected factors contributed to this susceptibility: the autoimmune disease itself (the patient has a history of RA) and, more significantly, suspected long-term use of corticosteroid-containing health supplements. Corticosteroid use has been reported in 17.5% \u0026minus;\u0026thinsp;28% of HIV-negative patients with CM and represents a significant risk factor by impairing cell-mediated immunity\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Glucocorticoids suppress T lymphocyte proliferation, reduce pro-inflammatory cytokine production, and impair macrophage phagocytic activity, thereby creating favorable conditions for fungal dissemination to the central nervous system. Importantly, the patient's underlying RA may independently contribute to susceptibility. Williamson et al. note associations between cryptococcosis and various autoimmune diseases including systemic lupus erythematosus, dermatomyositis, and ankylosing spondylitis \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The markedly elevated rheumatoid factor (672.8 IU/mL) and anti-CCP antibodies (\u0026gt;\u0026thinsp;500 U/mL) confirm active autoimmune disease. The Th17/IL-17 axis is vital for immunity to fungi. Accumulating evidence suggests that patients with RA exhibit functional defects in Th17-mediated immunity, characterized by an impaired antigen-specific response to fungi. Thus, the inherent Th17 functional deficits in RA, combined with the immunosuppressive effects of therapeutic agents such as corticosteroids, may collectively create a permissive immunological environment that facilitates the proliferation of Cryptococcus neoformans\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOnce this permissive immunological environment is established, Cryptococcus neoformans is able to disseminates from the basal cisterns through Virchow-Robin spaces to the basal ganglia, internal capsule, and brainstem, where perivascular accumulation causes inflammatory infiltration, endothelial injury, and small vessel occlusion\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Concurrently, direct fungal invasion of arterial walls and strangulation of vessels by basal exudates may induce vasculitis, vasospasm, and thrombosis, culminating in cerebral infarction\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Notably, non-HIV patients with CM have a higher risk of cerebral infarction compared to HIV-infected individuals\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. This paradox may reflect an exaggerated host inflammatory response in immunocompetent patients, leading to more severe vasculitis and thrombosis. In our patient, markedly elevated D-dimer levels (2790 ng/mL) suggested a hypercoagulable state contributing to thrombus formation, consistent with the vascular inflammatory mechanism described by Mishra et al.\u003csup\u003e3\u003c/sup\u003e. The absence of traditional vascular risk factors and normal MRA further supported an infectious rather than atherosclerotic etiology.\u003c/p\u003e \u003cp\u003eTuberculous meningitis (TBM) also frequently occurs in immunocompromised patients. Its clinical manifestations and routine CSF profiles are similar to those of CM, and it is also commonly complicated by cerebral infarction\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Infarction in TBM results from basal exudates causing strangulation of perforating arteries, predominantly affecting the thalamus, anterior limb of internal capsule, and cerebral lobes\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. CM-associated infarcts show a predilection for deep nuclear structures and posterior circulation territories. In a comparative study by Kumar et al.\u003csup\u003e10\u003c/sup\u003e, 54.5% of CM patients developed cerebral infarctions, with caudate head (41.7% vs. 9.4%, p\u0026thinsp;=\u0026thinsp;0.01) and cerebellar (33.3% vs. 9.4%, p\u0026thinsp;=\u0026thinsp;0.05) involvement significantly more common in CM than in TBM. Basal ganglia (41.7%) and corona radiata (66.7%) were also frequently involved. Lan et al. \u003csup\u003e9\u003c/sup\u003ereported infarctions in 32% of CM patients, predominantly in the basal ganglia and internal capsule. Our patient's neuroimaging findings align with these patterns, showing acute infarctions in the bilateral basal ganglia, corona radiata, and pons\u0026mdash;the latter representing posterior circulation involvement characteristic of CM. The initial symptom of vertigo may have reflected brainstem/cerebellar ischemia, though early imaging did not capture these lesions.\u003c/p\u003e \u003cp\u003eIn this patient, the clinical presentation of weight loss with recurrent afternoon fevers, along with a positive T-SPOT.TB result, initially raised suspicion for TBM co-infection. However, TBM was ultimately ruled out by two key findings: an infarction pattern involving the pons and basal ganglia without thalamic involvement, and negative CSF results for M. tuberculosis by PCR, culture, and next-generation sequencing. It is particularly noteworthy that T-SPOT.TB, an interferon-gamma(IFN-γ) release assay (IGRA), is an important tool for detecting tuberculosis infection\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e; however, false-positive results may occur in the setting of cryptococcal infection. The underlying mechanism may involve the activation of T lymphocytes by Cryptococcus neoformans, leading to increased IFN-γ release\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. This finding suggests that positive T-SPOT.TB results in the context of cryptococcal infection should be interpreted with caution and must be evaluated in conjunction with direct pathogen evidence.\u003c/p\u003e \u003cp\u003eCurrent ECMM/ISHAM global guidelines for the management of cryptococcosis outline a standard three-phase regimen. Induction therapy consists of at least 2 weeks of high-dose amphotericin B (0.7\u0026ndash;1.0 mg/kg/day) combined with flucytosine (100 mg/kg/day) for rapid CSF sterilization. This is followed by an 8-week consolidation phase with high-dose fluconazole (400\u0026ndash;800 mg/day) monotherapy, and subsequently, low-dose fluconazole (200 mg/day) maintenance therapy to prevent relapse until immune reconstitution is achieved with ART\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In a cohort study from China, the triple regimen of amphotericin B\u0026thinsp;+\u0026thinsp;flucytosine\u0026thinsp;+\u0026thinsp;fluconazole resulted in a superior 2-week CSF sterilization rate relative to amphotericin B\u0026thinsp;+\u0026thinsp;flucytosine alone (75.9% vs. 69.2%). Notably, within the amphotericin B\u0026thinsp;+\u0026thinsp;flucytosine\u0026thinsp;\u0026plusmn;\u0026thinsp;fluconazole regimen, a lower amphotericin B dose (0.4\u0026ndash;0.5 mg/kg/day) not only reduced the frequency of adverse effects but also yielded clinical efficacy comparable to that of the conventional 0.6\u0026ndash;0.7 mg/kg/day dose \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Accordingly, our patient received induction therapy with amphotericin B (0.5 mg/kg/day), flucytosine (100 mg/kg/day), and fluconazole (400 mg/day). When renal dysfunction was identified on monitoring, a timely switch to high-dose fluconazole (600 mg/day) was implemented, achieving a balance between treatment efficacy and safety.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eClinical Implications\u003c/h2\u003e \u003cp\u003eThis case offers several important lessons for clinicians:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIn immunocompromised patients presenting with cryptogenic multiple deep cerebral infarctions, particularly involving the basal ganglia and posterior circulation with concomitant meningeal enhancement, CM should be included in the differential diagnosis.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe absence of traditional vascular risk factors and normal MRA does not exclude stroke\u0026mdash;infectious vasculopathies should be considered.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePositive T-SPOT.TB in suspected CM patients may represent false-positive results from fungal-induced IFN-γ release and requires confirmation with CSF direct pathogen detection.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEarly CSF examination including cryptococcal antigen, culture, and next-generation sequencing is essential for timely diagnosis and treatment initiation.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eClose monitoring for amphotericin B-associated nephrotoxicity is mandatory, with prompt regimen adjustment when indicated.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCM with cerebral infarction is a severe complication in immunocompromised patients that can mimic atherosclerotic stroke. The characteristic infarction pattern involves the basal ganglia, corona radiata, and posterior circulation territories. Clinicians should maintain a high index of suspicion for opportunistic fungal infections in patients with cryptogenic cerebral infarctions, particularly those with risk factors for immunosuppression. Early diagnosis through CSF analysis and prompt initiation of antifungal therapy are essential for improving outcomes in this devastating condition.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the\u0026nbsp;legal guardians for the anonymized information to be published in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China (No. 82371249), the Science and Technology Planning Project of Guangzhou (No.202201000005).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYi-Hui Qiu:\u0026nbsp;\u003c/strong\u003eClinical data acquisition, analysis, and interpretation; manuscript drafting and revision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTeng-Yun Ma:\u0026nbsp;\u003c/strong\u003eClinical data acquisition; patient follow-up and outcome assessment; literature review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLi-Juan Wang:\u0026nbsp;\u003c/strong\u003eCritical manuscript revision; study coordination; funding acquisition.\u003cbr\u003e\u003cstrong\u003eJie-Hao Zhao:\u0026nbsp;\u003c/strong\u003eConceptualization, study design, data acquisition, analysis, and interpretation; manuscript drafting and revision; study supervision; final approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thanked the patient and his family for their support and approval for publishing the case.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWilliamson PR, Jarvis JN, Panackal AA, et al. Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy. NAT REV NEUROL. 2016;13:13\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpeed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. CLIN INFECT DIS. 1995;21:28\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMishra A, Arvind V, Muliyil D, et al. Cerebrovascular injury in cryptococcal meningitis. INT J STROKE. 2017;13:57\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQu J, Zhou T, Zhong C, Deng R, L\u0026uuml; X. Comparison of clinical features and prognostic factors in HIV-negative adults with cryptococcal meningitis and tuberculous meningitis: a retrospective study. BMC Infect Dis. 2017;17:51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePappas P, Perfect J, Cloud G, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. ClIN INFECT DIS. 2001;33:690\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernard C, Maucort-Boulch D, Varron L, et al. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases. QJM-INT J MED. 2013;106:523\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBishu S, Su E, Wilkerson E et al. Rheumatoid arthritis patients exhibit impaired Candida albicans-specific Th17 responses. ARTHRITIS RES THER 2014;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShimoda Y, Ohtomo S, Arai H, Ohtoh T, Tominaga T. Subarachnoid small vein occlusion due to inflammatory fibrosis\u0026mdash;a possible mechanism for cerebellar infarction in cryptococcal meningoencephalitis: a case report. BMC Neurol. 2017;17:157.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLan S, Chang W, Lu C, Lui C, Chang H. Cerebral infarction in chronic meningitis: a comparison of tuberculous meningitis and cryptococcal meningitis. QJM-INT J MED. 2001;94:247\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumar M, Dhar N, Tiwari A, Siddiqui M. Comparison of patterns of infarction in TB and cryptococcal meningitis. T ROY SOC TROP MED H. 2021;115:1160\u0026ndash;1167.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKalita J, Misra U, Nair P. Predictors of Stroke and Its Significance in the Outcome of Tuberculous Meningitis. J STROKE CEREBROVASC. 2009;18:251\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTai M, Viswanathan S, Rahmat K, et al. Cerebral infarction pattern in tuberculous meningitis. Sci Rep. 2016;6:38802.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorkowska D, Zwolska Z, Michałowska-Mitczuk D, et al. Interferon-gamma assays T-SPOT.TB for the diagnosis of latent tuberculosis infection. Pneumonol Alergol Pol. 2011;79:264\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyahara A, Umeki A, Sato K, et al. Innate phase production of IFN-γ by memory and effector T cells expressing early activation marker CD69 during infection with Cryptococcus deneoformans in the lungs. INFECT IMMUN. 2024;92:1\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoulware D, Bonham S, Meya D, et al. Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory Syndrome. J Infect Dis. 2010;202:962\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024;24:e495\u0026ndash;512.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu L, Tao R, Wu J, et al. Short-Course Rather Than Low-Dose Amphotericin B May Exert Potential Influence on Mortality in Cryptococcal Meningitis Patients Treated With Amphotericin B Plus Flucytosine Alone or in Combination With Fluconazole. Front Microbiol. 2019;10:2082.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cryptococcal meningitis, Cerebral infarction, Rheumatoid arthritis, Opportunistic infection, Magnetic resonance imaging","lastPublishedDoi":"10.21203/rs.3.rs-9106010/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9106010/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCryptococcal meningitis (CM) is a prevalent fungal infection of the central nervous system, particularly in immunocompromised hosts. Cerebral infarction, a well-recognized yet underappreciated severe complication, occurs in approximately 13% of CM cases, with a notably higher incidence observed in non-HIV populations than in those with HIV infection. Due to its frequently nonspecific clinical features, diagnosis and treatment are often delayed. Herein, we report a case of CM in which multiple cerebral infarctions constituted the predominant clinical manifestation, aiming to enhance clinicians' recognition of this atypical presentation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 66-year-old male with a history of rheumatoid arthritis(RA) presented with dizziness and headache initially diagnosed as \"cerebral infarction\" at another hospital. Despite standard secondary stroke prevention, his condition progressively worsened to gait instability, bilateral limb weakness, and neuropsychiatric abnormalities. Brain magnetic resonance imaging revealed newly developed infarctions in the bilateral basal ganglia, temporo-occipital lobes, and pons with meningeal enhancement. Cerebrospinal fluid analysis detected Cryptococcus neoforman\u003cem\u003es\u003c/em\u003e by culture, next-generation sequencing, and positive cryptococcal antigen. The patient showed clinical improvement following antifungal therapy with amphotericin B, flucytosine, and fluconazole, though treatment was complicated by nephrotoxicity requiring regimen adjustment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case highlights that CM should be considered in immunocompromised patients presenting with cryptogenic multiple deep cerebral infarctions, particularly those involving the basal ganglia and posterior circulation with concomitant meningeal enhancement. Early cerebrospinal fluid examination is crucial for timely diagnosis and intervention.\u003c/p\u003e","manuscriptTitle":"When stroke is not stroke: cryptococcal meningitis presenting as progressive cerebral infarction in a patient with rheumatoid arthritis – a case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-07 10:21:48","doi":"10.21203/rs.3.rs-9106010/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-27T01:45:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238061118376869398106209918557640368681","date":"2026-04-26T20:40:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-01T11:21:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-01T10:54:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-24T07:28:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-24T06:38:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-03-24T06:18:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a17c662d-5575-4861-86ca-89c7d83c6990","owner":[],"postedDate":"April 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T10:21:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-07 10:21:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9106010","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9106010","identity":"rs-9106010","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}