CNS Involvement by CLL Mimicking Demyelinating Disease: A Five-Year Case Study

CNS Involvement by CLL Mimicking Demyelinating Disease: A Five-Year Case Study | 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 CNS Involvement by CLL Mimicking Demyelinating Disease: A Five-Year Case Study Weining Sun, Yaming Wang, Dawei Li, Dandan Wang, Zhilian Zhao, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8631569/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Central nervous system involvement by chronic lymphocyte leukemia (CNS-CLL) without Richter transformation is a rare and hard-to-diagnose condition. Nonspecific symptoms and the need for a brain biopsy complicate diagnosis. We report a 58-year-old male with Rai stage 0 CLL who had severe neurological signs. His initial MRI suggested autoimmune-related demyelinating disease. However, high-dose steroids and intravenous immunoglobulin (IVIG) did not help. His neurological status continued to worsen. A multidisciplinary team used advanced imaging (PET-CT showing a hypermetabolic lesion with SUVmax 8.2) and stereotactic brain biopsy. Immunoglobulin heavy chain (IGH) gene clonal rearrangement showed identical clones (IGHV3-64*01/02/07) in both cerebral tissue and bone marrow. This confirmed CNS-CLL. Treatment with ibrutinib stabilized the disease and led to partial cognitive recovery. The patient survived five years without progression. This case and a literature review show that CNS-CLL can have atypical imaging and occur even in early-stage disease. Under targeted therapy, this rare condition may have a better prognosis than previously reported. The report highlights the importance of molecular studies for diagnosis and recommends a multidisciplinary diagnostic approach. Central nervous system Chronic lymphocyte leukemia Multidisciplinary diagnosis Immunoglobulin heavy chain variable regionmutations Positron emission tomography-computed tomography Figures Figure 1 Figure 2 Figure 3 Figure 4 Highlights 1. CNS involvement can be seen in early-stage (Rai 0) CLL, independent of systemic disease status. 2. PET-CT and molecular clonality analysis (demonstrating an identical IGHV clone) are pivotal for confirming the diagnosis of CNS-CLL. 3.Sustained response to ibrutinib over five years suggests that CNS-CLL managed with targeted therapy may have a favorable prognosis. 1. Introduction Chronic lymphocytic leukemia (CLL) is a cancer of lymphoid hematopoietic tissue. It is marked by the accumulation of clonal, CD5+/CD23 + mature B lymphocytes in the blood, bone marrow, spleen, and lymph nodes[ 1 ]. The disease mainly involves the blood and bone marrow. Extramedullary manifestations (EM-CLL), such as skin or central nervous system (CNS) infiltration, are rare [ 2 , 3 ]. Diagnosing CNS-CLL is challenging. Its clinical presentation is nonspecific. Cerebrospinal fluid (CSF) cytology and flow cytometry are not sensitive. MRI features often overlap with infectious, inflammatory, or neoplastic conditions[ 4 ]. This overlap leads to misdiagnosis, delayed treatment, and poor outcomes. Here, we present a case of CNS-CLL that was initially misdiagnosed and treated as an autoimmune demyelinating disorder (a disease affecting the nerve covering). Furthermore, we integrate this case with a review of the current literature to summarize the epidemiological, clinical, diagnostic, and therapeutic overview of CNS-CLL. The primary aim of this report is to improve clinical awareness of this rare complication and to propose a multidisciplinary team (MDT) diagnostic approach, emphasizing the crucial role of molecular techniques for definitive diagnosis. 2. Case Presentation 2.1. Initial Misdiagnosis and Treatment A 58-year-old man was admitted to Neurology, Xuanwu Hospital, Capital Medical University, on June 8, 2021. He had a 47-day history of blurred vision in his right eye and increasing cognitive impairment. The patient had no major past medical or family history of similar neurological diseases. Initial labs showed leukocytosis at 18.94 × 10⁹/L (normal 3.5–9.5). There was an absolute lymphocytosis of 9.19 × 10⁹/L (1.1–3.2). Hemoglobin was 142 g/L. Platelets were 210 × 10⁹/L (100–300). Lactate dehydrogenase (LDH) measured 245 U/L (120–250). β2-microglobulin was 2.4 µg/ml (1.58–2.62). The neurology exam showed fluent speech but severe disorientation, poor arithmetic, recent memory loss, and weak comprehension. The MMSE score was 3 out of 30. Initial MRI scans from another hospital showed multiple abnormal signals in the left parietotemporo-occipital lobe and right temporal paraventricular region. This led to a diagnosis of autoimmune-related demyelinating disease. He received high-dose corticosteroids: Methylprednisolone 500 mg/day for 3 days, then 240 mg/d for 3 days, then 120 mg/d for 3 days. He also received intravenous immunoglobulin. These treatments proved ineffective. His lesions continued to expand on follow-up imaging. 2.2. CLL Diagnosis and Staging Persistent lymphocytosis triggered a hematology consult. Bone marrow cytology showed more mature lymphocytes, accounting for 31% of nucleated cells. Flow cytometric immunophenotyping revealed a monoclonal B-cell population. Immunophenotype was positive for CD19, CD20, CD23 (partial), CD5 (dim), CD22, CD79b, CD200, and kappa light chain restriction. Cells were negative for CD10, CD43, and lambda light chains. These findings matched CLL (Fig. 1 ). Immunofixation electrophoresis confirmed monoclonal IgG-kappa paraprotein. FISH analysis of bone marrow showed no high-risk cytogenetic features: no 17p or 11q deletions or trisomy 12. Targeted next-generation sequencing (NGS) was performed as part of the routine diagnostic evaluation. This analysis identified variants in APC (c.2507C > G, VAF: 5.05%; c.2510C > G, VAF: 5.09%), ARID1B (c.974_985delGAGGAGGAGGAG, VAF: 29.66%), BCL10 (c.403A > T, VAF: 1.13%), FBXO11 (c.161_169dupAGCAGCAGC, VAF: 30.03%), KMT2A (c.9452delC, VAF: 4.65%), MYD88 (c.649G > T, VAF: 5.86%), and SAMHD1 (c.895G > T, VAF: 7.53%). No pathogenic TP53 mutations appeared. Staging included a whole-body CT, showing no abnormalities. Blood tests revealed hepatitis B virus carrier status with a viral load of 1.17×10⁴ copies/mL (Table 1 ). IGHV gene analysis revealed clonal IGHV3-64*01, IGHV3-64*02, and IGHV3-64*07 (Table 2 ). The patient was diagnosed with Rai stage 0 CLL and hepatitis B carrier. Early CLL stage led to low suspicion for CNS involvement. Initial management was limited to entecavir antiviral therapy. No CLL-specific treatment was started then. Table 1 Summary of Diagnostic and Laboratory Findings Test / Assessment Results Peripheral blood flow cytometry Monoclonal B-cells (24.7% of total cells): CD19+, CD20+, CD5 (partial+), CD10–, Kappa+, Lambda– (See Fig. 1 A) Bone marrow smear Hypercellular marrow with 31% mature lymphocytes; 23% lymphocytes in peripheral blood; no lineage suppression noted Bone marrow biopsy Diffuse infiltration by small B-cells expressing: CD20, CD79a; scattered Kappa/Lambda positivity; CyclinD1– Bone marrow flow pattern Monoclonal B-cell population consistent with CLL (See Fig. 1 B) FISH No TP53, CEP12, or ATM mutations; IGH/CCND1 fusion–; D13S319 deletion– NGS Mutations detected: • APC (c.2507C > G, VAF 5.05%; c.2510C > G, VAF 5.09%) • ARID1B (c.974_985del, VAF 29.66%) • BCL10 (c.403A > T, VAF 1.13%) • FBXO11 (c.161_169dup, VAF 30.03%) • KMT2A (c.9452delC, VAF 4.65%) • MYD88 (c.649G > T, VAF 5.86%) • SAMHD1 (c.895G > T, VAF 7.53%) • TP53 mutation not detected Lumbar puncture Normal intracranial pressure CSF analysis Scattered lymphocytes and monocytes; no monoclonal B-cells detected; flow cytometry: 0% B-cells, IGHV rearrangement–, NGS– MRS Left paraventricular lesion: NAA/Cr 1.2, Cho/Cr 1.9; right paraventricular region: NAA/Cr 1.7, Cho/Cr 1.1; suggests neoplastic process MRI Multiple paraventricular demyelinating lesions with mild ring enhancement; some non-neoplastic features, possibly influenced by prior steroid therapy (See Fig. 2 ) PET-CT Multiple hypermetabolic CNS lesions (SUVmax 8.2); bilateral temporal hypodense shadows (SUVmax 7.6); focal hypometabolism in left basal ganglia and thalamus; mild mediastinal lymph node uptake (SUVmax 2.09); spleen normal (SUVmax 2.61) (See Fig. 3 ) Brain biopsy Dense perivascular lymphocytic infiltration, myelin loss, reactive gliosis, vascular hyperplasia; IHC: CD20+, CD79a+, CD23+/–, CD5–, CD38+, Kappa+/–, Lambda–, LFB+ (See Fig. 4 ) Table 2 IGH Gene Clonal Rearrangement Analysis Sample IGHV Gene Usage IGHV mutation rate (%) Bone marrow IGHV3-64*01/*02/*07 >9.17 Brain biopsy IGHV3-64*01/*02/*07 >9.17 2.3. Re-evaluation and Multidisciplinary Diagnosis Due to worsening clinical symptoms, a lumbar puncture was performed. CSF pressure was normal. Tests for demyelination, infection, and autoimmunity were negative. CSF flow cytometry showed 0% B cells and anIGH rearrangement. IL-8 and IL-6 were higher in the CSF. IL-10 was higher in the blood. MRI in August 2021 showed ongoing, persistent paraventricular lesions with mild ring enhancement. Previous images showed new 'soft' foci, sometimes linked to non-neoplastic inflammation. Recent high-dose steroids may have altered these changes, as treatment can affect the evolution of imaging findings. The effects of both the inflammatory and neoplastic processes were considered (Fig. 2 ). Magnetic resonance spectroscopy (MRS) revealed metabolic changes suggestive of a tumor. The NAA/Cr ratio was1.2 on the lesion side and 1.7 on the contralateral side, indicating neuronal loss. The Cho/Cr ratio was 1.9 versus 1.1 contralaterally, and increased cell membrane production was seen in aggressive tumors. A whole-body 18F-FDG PET-CT subsequently revealed a key finding: hypermetabolic left occipital white matter with an SUVmax of 8.2. This result strongly suggested malignancy and outweighed the inconclusive MRI findings (Fig. 3 ). Given the difference between the clinical course and the initial diagnosis, and guided by the hypermetabolic PET-CT findings, an MDT discussion was held. A decision was made to proceed with a stereotactic biopsy of the left paraventricular lesion. Histopathology of the brain tissue showed a dense perivascular lymphocytic infiltrate. Immunohistochemistry was atypical for CLL (CD20+, CD79a+, but CD5-) (Fig. 4 ). To definitively establish clonality and origin, IGH gene clonal rearrangement analysis was on both the brain biopsy and bone marrow specimens. This analysis showed an identical clonal sequence (IGHV3-64*01/02/07) in both tissues, with a 90.83% degree of homology. This finding confirmed that the CNS infiltrate was clonally identical to the systemic CLL and established the definitive diagnosis of CNS-CLL[ 5 ] (Table 2 ). 2.4. Treatment and Outcome The patient was started on oral ibrutinib (560 mg/day) in combination with antiviral therapy. Over a five-year follow-up, his disease remained stable. While his visual and hearing deficits persisted (suggesting irreversible structural damage). Follow-up MRI showed a reduction in lesion size. His MMSE score increased to 16/30 (Fig. 2 ). 3. Discussion CNS-CLL is identified in a significant proportion of autopsy studies of CLL patients, with reported prevalence rates ranging from 7% to 71% [ 6 , 7 ]. However, the incidence of clinically significant CNS involvement is markedly lower, estimated at only 0.8% to 2%[ 8 ]. This pronounced discrepancy shows that although seeding of the CNS by CLL cells may be a common event, it rarely culminates in symptomatic disease, which directly accounts for the low rate of clinical diagnosis. The diagnostic challenge is additionally complicated by the limitations of CSF analysis. Although sensitive, detection of CLL cells in the CSF is not pathognomonic for CNS-CLL, as contamination from peripheral blood during lumbar puncture can yield false-positive results. Conversely, as demonstrated in our case, the absence of CLL cells in the CSF does not exclude the diagnosis, yielding false-negative results. Therefore, A definitive diagnosis of CNS-CLL requires integration of clinical presentation, neuroimaging, and histopathological evidence, rather than relying on CSF analysis alone.The differentiation of CNS-CLL from other neurological disorders in CLL patients is clinically challenging due to the highly nonspecific nature of the symptoms, which overlap with a wide spectrum of conditions, including infections, metabolic disorders, autoimmune diseases, treatment-related complications, and other malignancies. Crucially, the detection of clonal B cells in the CSF does not definitively establish CNS-CLL as the symptomatic cause, necessitating a broad diagnostic evaluation. This is exemplified by a study of 172 CLL patients with neurological symptoms, in which only 33% had CNS-CLL, while 67% had alternative diagnoses such as opportunistic infections or other cancers[ 9 ] Therefore, neurological decline in CLL mandates a systematic investigation of all potential etiologies rather than presumptive attribution to leukemic involvement. The diagnosis of CNS-CLL requires a high index of suspicion and an MDT approach, as no single investigation is definitive. Neuroimaging plays a pivotal role in the initial evaluation. On MRI, CNS-CLL often presents with diverse features, including demyelinating and ring-enhancing lesions, which typically appear isointense on T1-weighted images (T1WI) and hypointense on T2-weighted images (T2WI).[ 10 ] These imaging characteristics, when considered alongside clinical and CSF findings, help distinguish CNS-CLL from other CNS disorders. 18F-FDG PET-CT scans are highly sensitive for detecting aggressive lymphomas. Most hematological malignancies exhibit increased glycolytic activity, enabling detection with 18F-FDG-PET imaging. PET-CT was instrumental in our case. The high SUVmax (8.2) within a CNS lesion was a critical red flag, strongly suggesting a neoplastic process over inflammation and providing a precise target for biopsy. [ 11 ] [ 12 ] Brain biopsy remains the diagnostic cornerstone. However, as seen in our case, the immunohistochemical profile can be atypical (e.g., CD5 negativity). To further determine the clonality and origin of the lymphocytic infiltrate, IGH gene clonal rearrangement analysis was performed as a diagnostic adjunct, demonstrating identical clonal sequences in the brain tissue and bone marrow, confirming that the intracerebral lesions resulted from CNS involvement by systemic CLL. As CLL arises from the unconstrained expansion of a single transformed B cell and is characterized by the presence of clonal rearrangements of immunoglobulin (IG). In B cell lymphoma, gene fragments are rearranged, and random nucleotide insertions and deletions occur, thereby generating unique sequences for each B lymphocyte.[ 13 ] [ 14 ] There is no standard of therapy for CNS-CLL; evidence is derived from case reports and small series. The advent of novel agents has improved prospects. Bruton's tyrosine kinase (BTK) inhibitors, such as ibrutinib, form a cornerstone of this modern therapeutic approach due to their favorable central nervous system penetration and potent inhibition of B-cell receptor (BCR) and NF-κB signaling. Ibrutinib has demonstrated efficacy in CNS-CLL across various IGHV mutational subgroups [ 15 ]. Current treatments for CNS-CLL that have been shown to be effective include Ibrutinib[ 16 ], Venetoclax[ 17 ], Venetoclax with Ibrutinib[ 18 ], Ibrutinib with rituximab and methotrexate [ 19 ], Venetoclax with high-dose methotrexate and rituximab[ 20 ]. Regimens such as venetoclax-obinutuzumab-ibrutinib, venetoclax-rituximab, and venetoclax-obinutuzumab have shown comparable patient survival outcomes, with all demonstrating superior efficacy compared to chemotherapy alone.[ 21 ] 4. Conclusion This case highlights the diagnostic challenges associated with CNS-CLL. It reinforces several critical lessons. CNS-CLL can occur in patients with low-grade or previously undiagnosed systemic CLL. A negative CSF flow cytometry result cannot rule out the diagnosis.18F-FDG PET-CT is a valuable tool for identifying suspicious lesions and guiding biopsy. Molecular confirmation of clonal identity between CNS and systemic disease is the gold standard for diagnosis, especially when pathology is atypical. BTK inhibitors like ibrutinib are effective treatment options that aim for disease control and functional preservation, albeit with the understanding that some deficits may be permanent. A high index of suspicion and a structured, multidisciplinary algorithm incorporating advanced imaging and molecular techniques are essential for the timely and accurate diagnosis of this rare but serious complication. Abbreviations CLL : Chronic lymphocytic leukemia CNS-CLL : Central nervous system involvement by chronic lymphocytic leukemia EM-CLL : Extramedullary manifestations of chronic lymphocytic leukemia FISH : Fluorescence in situ hybridization MDT : Multidisciplinary collaborative treatment mode MRI : Magnetic Resonance Imaging PET : Positron emission tomography NGS : Next-generation sequencing Declarations Acknowledgements We would like to thank TOPEDIT for their assistance with language editing and proofreading of this manuscript. We are grateful to the patient and the families for their contributions to this work. Authors’ contributions Y.X.G,W.L.S conceptualized and developed the study.W.N.S. collected materials and wrote the article. Y.M.W. performed the stereotactic biopsy surgery; D.W.L.managed the neurology treatment ;D.D.W.conducted the pathological examination;Z.L.Z performed the cranial MRI examination;T.B.S. conducted the PET-CT examination；Y.X.G managed the hematology treatment and revised the article. Funding Undergraduate Scientific Research Training Program of Capital Medical University (XSKY2024) Availability of data and materials All data generated or analysed during this case report is available. The next-generation sequencing (NGS) results generated by this case have been deposited in an open database. For further information, you can inquire with the corresponding author . Ethics approval and consent to participate Not applicable. Based on international ethical standards and Chinese laws and regulations, case reports are not classified as clinical studies and, consequently, do not necessitate ethical review. Written informed consent has been provided by the patient.Written informed consent has been obtained from the patient to publish this case report. Consent for publication The patient has granted written informed consent for the publication of this case report and any associated photos. Competing interests The authors declare that they have no competing interests. Author details Weining Sun, Yixian Guo, Wanling Sun: Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China Yaming Wang: Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China Dawei Li: Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China Dandan Wang: Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China Zhilian Zhao: Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China Tianbin Song: Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China References Eichhorst, B., et al., Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2021. 32(1): p. 23-33. Cramer, P., et al., Extramedullary manifestations of chronic lymphocytic leukaemia are not unusual. Leuk Res, 2014. 38(3): p. 284-5. Albakr, A., et al., Central Nervous System Lymphoma in a Patient with Chronic Lymphocytic Leukemia: A Case Report and Literature Review. Cureus, 2018. 10(11): p. e3660. Timmers, N., et al., Central nervous system localisation of chronic lymphocytic leukaemia, description of two very distinct cases and a review of the literature. Ann Hematol, 2018. 97(9): p. 1627-1632. Agathangelidis, A., et al., Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: the 2022 update of the recommendations by ERIC, the European Research Initiative on CLL. Leukemia, 2022. 36(8): p. 1961-1968. Barcos, M., et al., An autopsy study of 1206 acute and chronic leukemias (1958 to 1982). Cancer, 1987. 60(4): p. 827-837. Bojsen-Møller, M. and J.L. Nielsen, CNS involvement in leukaemia. An autopsy study of 100 consecutive patients. Acta Pathol Microbiol Immunol Scand A, 1983. 91(4): p. 209-16. Hanse, M.C.J., et al., Incidence of central nervous system involvement in chronic lymphocytic leukemia and outcome to treatment. Journal of Neurology, 2008. 255(6): p. 828-830. Strati, P., et al., Prevalence and characteristics of central nervous system involvement by chronic lymphocytic leukemia. Haematologica, 2016. 101(4): p. 458-65. Guo, R., et al., Primary central nervous system small lymphocytic lymphoma in the bilateral ventricles: two case reports. BMC Neurol, 2019. 19(1): p. 200. Zirakchian Zadeh, M., Clinical Application of (18)F-FDG-PET Quantification in Hematological Malignancies: Emphasizing Multiple Myeloma, Lymphoma and Chronic Lymphocytic Leukemia. Clin Lymphoma Myeloma Leuk, 2023. 23(11): p. 800-814. Dewaide, R. and K. Saevels, Treatment strategy in chronic lymphocytic leukemia with symptomatic central nervous system involvement: A case report. Clin Case Rep, 2023. 11(11): p. e7965. Dudley, D.D., et al., Mechanism and control of V(D)J recombination versus class switch recombination: similarities and differences. Adv Immunol, 2005. 86: p. 43-112. Scheijen, B., et al., Next-generation sequencing of immunoglobulin gene rearrangements for clonality assessment: a technical feasibility study by EuroClonality-NGS. Leukemia, 2019. 33(9): p. 2227-2240. Mousinho, F., et al., Treatment Sequencing in a Chronic Lymphocytic Leukemia Patient with Central Nervous System Involvement. Case Rep Hematol, 2018. 2018: p. 7817918. Martín-Moro, F., et al., Intracranial hemorrhage as presentation of chronic lymphocytic leukemia successfully treated with ibrutinib. Annals of Hematology, 2021. 101(1): p. 213-215. Reda, G., et al., Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica, 2019. 104(5): p. e222-e223. Soumerai, J.D., et al., Venetoclax activity in a patient with central nervous system involvement by chronic lymphocytic leukaemia. The Lancet Haematology, 2022. 9(10). Wang, W., et al., Richter’s syndrome in central nervous system with MYD88L265P and CD79b mutation responded well to ibrutinib containing chemotherapy: a case report and review of the literature. Annals of Hematology, 2022. 101(8): p. 1869-1872. Beziat, G., et al., Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report. Clin Case Rep, 2020. 8(2): p. 269-273. Eichhorst, B., et al., First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med, 2023. 388(19): p. 1739-1754. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 11 Mar, 2026 Editor assigned by journal 09 Mar, 2026 Editor invited by journal 17 Feb, 2026 Submission checks completed at journal 14 Feb, 2026 First submitted to journal 14 Feb, 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8631569","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":604522698,"identity":"7c16b5f4-af68-4f06-aee4-8ec44240a803","order_by":0,"name":"Weining Sun","email":"","orcid":"","institution":"Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Weining","middleName":"","lastName":"Sun","suffix":""},{"id":604522699,"identity":"e14bdaf1-98fc-4e90-a928-12cc68dfb6b8","order_by":1,"name":"Yaming Wang","email":"","orcid":"","institution":"Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yaming","middleName":"","lastName":"Wang","suffix":""},{"id":604522700,"identity":"db926ed8-a306-4210-8164-c021f5550157","order_by":2,"name":"Dawei Li","email":"","orcid":"","institution":"Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dawei","middleName":"","lastName":"Li","suffix":""},{"id":604522701,"identity":"ca14f8f8-e00f-46c8-be8e-8306e870f2a6","order_by":3,"name":"Dandan Wang","email":"","orcid":"","institution":"Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dandan","middleName":"","lastName":"Wang","suffix":""},{"id":604522702,"identity":"e3d8f7c1-41e4-45a9-9df9-59132a4100c6","order_by":4,"name":"Zhilian Zhao","email":"","orcid":"","institution":"Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhilian","middleName":"","lastName":"Zhao","suffix":""},{"id":604522703,"identity":"7bfc40c6-3364-438b-8005-a082e1df1a09","order_by":5,"name":"Tianbin Song","email":"","orcid":"","institution":"Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tianbin","middleName":"","lastName":"Song","suffix":""},{"id":604522704,"identity":"d56316c7-8237-4df8-b631-5fbc5817f170","order_by":6,"name":"Wanling Sun","email":"","orcid":"","institution":"Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wanling","middleName":"","lastName":"Sun","suffix":""},{"id":604522706,"identity":"b5478759-c5b4-433e-b86a-c7e3729a6922","order_by":7,"name":"Yixian Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYLCCBAYJBgb2BgZmErXwHCBFCxhIJBCpRT4i+ZjEwzYLeXPJN2bSBRV1eQzsvY9f4NNieCMtTSLhjIThztlpadIzzhwuZuA5bmaBV8uMHDOJhAoJxg23k4/d5m07kNggkcZmQFiLgYT9hpsH24Ba6ghrkZeA2JK44QYzyBZmkBbmB/i0GPA8S7YA+iV5w5m09N88QL+w8Rxjw6eDQb49+eDNn211thuOnzE25gGGGD97G/MHvLYcYGCRQBZIAFrBJoFLOdgWYDJBMTMBiPHbMgpGwSgYBSMOAADErkftxtIewAAAAABJRU5ErkJggg==","orcid":"","institution":"Xuanwu Hospital, Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yixian","middleName":"","lastName":"Guo","suffix":""}],"badges":[],"createdAt":"2026-01-18 13:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8631569/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8631569/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104689920,"identity":"118080de-e107-4843-99ee-d06654f8a119","added_by":"auto","created_at":"2026-03-16 06:03:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":633276,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Flow cytometry analysis of peripheral blood at initial chronic lymphocytic leukemia (CLL) diagnosis demonstrates a monoclonal B-cell population (24.7% of total cells) expressing CD19, CD20, and CD5 (partial), with kappa light chain restriction, and negative for CD10. (B) Flow cytometry analysis of bone marrow confirms a monoclonal B-cell population positive for CD19, CD20, CD23 (partial), CD5 (dim), CD22, CD79b, CD200, and kappa light chain restriction, and negative for CD10, CD43, and lambda light chains.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8631569/v1/bf712688e88f4921dd2e5268.png"},{"id":104689922,"identity":"b9590f12-70e3-47af-b7a0-efa688d99a63","added_by":"auto","created_at":"2026-03-16 06:03:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":409553,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMagnetic resonance imaging (MRI) of multifocal central nervous system lesions before and after ibrutinib treatment.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline (August 2021)\u003c/strong\u003e: Axial T2-FLAIR (a-c) and T1-weighted post-contrast (j-l) images demonstrate multiple flaky, patchy abnormal signal intensities involving the bilateral occipitotemporal lobes, paraventricular regions, and centrum semiovale. A focal well-defined lesion in the left paraventricular region shows long T1 and T2 signals (isointense on T1WI, hyperintense on T2WI). \u003cstrong\u003ePost-treatment (September 2023)\u003c/strong\u003e: Follow-up axial T2-FLAIR (d-f) and T1-weighted post-contrast (m-o) images show significant reduction in the size of the corresponding lesions, with no change in the extent of involved areas and no new lesions. \u003cstrong\u003ePost-treatment (September 2025)\u003c/strong\u003e:Follow-up axial T2-FLAIR (g-i) and T1-weighted post-contrast (p-r) images show no significant changes in the location and size of the lesions.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8631569/v1/6d2333282c3dd906aec3cd8d.png"},{"id":104689919,"identity":"72ce4076-0109-4003-a822-1ebf91565151","added_by":"auto","created_at":"2026-03-16 06:03:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":856786,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMultimodal imaging characteristics of central nervous system involvement.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI\u003c/strong\u003e: A representative lesion (left paraventricular region) appears isointense on T1-weighted imaging (T1WI, red arrow) and hyperintense on T2-FLAIR (yellow arrow).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePET-CT:\u003c/strong\u003eMultiple slightly hypodense lesions with significantly increased glucose metabolism (SUVmax 8.2, blue arrow) are observed in the bilateral centrum semiovale, paraventricular regions, and left occipital white matter. Additional patchy hypodense shadows in the bilateral temporal lobes show no definite metabolic hyperactivity (SUVmax 7.6, green arrow).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8631569/v1/4bae2541db7d938a7a8e63e5.png"},{"id":104689921,"identity":"eca7de1f-e3ec-4c0b-b01a-d239b5acf42a","added_by":"auto","created_at":"2026-03-16 06:03:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1121446,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHistopathological and immunohistochemical findings of the brain biopsy.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHistology (High magnification):\u003c/strong\u003e Shows extensive lymphocytic infiltration forming perivascular sleeves, accompanied by significant myelin loss, reactive phagocytosis, and vascular hyperplasia. The infiltrating lymphocytes are small and monomorphic.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmunohistochemistry\u003c/strong\u003e: The infiltrate is composed predominantly of B-cells expressing CD20, CD79a, and CD38, with kappa light chain restriction (CD20+, CD79a+, CD23+/-, CD5-, CD38+, Lambda-, Kappa+/-). Staining for Luxol Fast Blue (LFB, myelin) is positive, and Hematoxylin and Eosin (H\u0026amp;E) staining is negative for specific inclusions.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8631569/v1/b3db579a8557b73ced5828d3.png"},{"id":104689951,"identity":"1788fbc0-3887-4ae6-8f93-e671621f46ad","added_by":"auto","created_at":"2026-03-16 06:03:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4151697,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8631569/v1/ecc372da-3003-4bb1-8b2b-4e2340aae8a6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"CNS Involvement by CLL Mimicking Demyelinating Disease: A Five-Year Case Study","fulltext":[{"header":"Highlights","content":"\u003cp\u003e1. CNS involvement can be seen in early-stage (Rai 0) CLL, independent of systemic disease status.\u003c/p\u003e\u003cp\u003e2. PET-CT and molecular clonality analysis (demonstrating an identical IGHV clone) are pivotal for confirming the diagnosis of CNS-CLL.\u003c/p\u003e\u003cp\u003e3.Sustained response to ibrutinib over five years suggests that CNS-CLL managed with targeted therapy may have a favorable prognosis.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eChronic lymphocytic leukemia (CLL) is a cancer of lymphoid hematopoietic tissue. It is marked by the accumulation of clonal, CD5+/CD23\u0026thinsp;+\u0026thinsp;mature B lymphocytes in the blood, bone marrow, spleen, and lymph nodes[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The disease mainly involves the blood and bone marrow. Extramedullary manifestations (EM-CLL), such as skin or central nervous system (CNS) infiltration, are rare [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Diagnosing CNS-CLL is challenging. Its clinical presentation is nonspecific. Cerebrospinal fluid (CSF) cytology and flow cytometry are not sensitive. MRI features often overlap with infectious, inflammatory, or neoplastic conditions[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This overlap leads to misdiagnosis, delayed treatment, and poor outcomes. Here, we present a case of CNS-CLL that was initially misdiagnosed and treated as an autoimmune demyelinating disorder (a disease affecting the nerve covering). Furthermore, we integrate this case with a review of the current literature to summarize the epidemiological, clinical, diagnostic, and therapeutic overview of CNS-CLL. The primary aim of this report is to improve clinical awareness of this rare complication and to propose a multidisciplinary team (MDT) diagnostic approach, emphasizing the crucial role of molecular techniques for definitive diagnosis.\u003c/p\u003e"},{"header":"2. Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Initial Misdiagnosis and Treatment\u003c/h2\u003e \u003cp\u003eA 58-year-old man was admitted to Neurology, Xuanwu Hospital, Capital Medical University, on June 8, 2021. He had a 47-day history of blurred vision in his right eye and increasing cognitive impairment. The patient had no major past medical or family history of similar neurological diseases. Initial labs showed leukocytosis at 18.94 \u0026times; 10⁹/L (normal 3.5\u0026ndash;9.5). There was an absolute lymphocytosis of 9.19 \u0026times; 10⁹/L (1.1\u0026ndash;3.2). Hemoglobin was 142 g/L. Platelets were 210 \u0026times; 10⁹/L (100\u0026ndash;300). Lactate dehydrogenase (LDH) measured 245 U/L (120\u0026ndash;250). β2-microglobulin was 2.4 \u0026micro;g/ml (1.58\u0026ndash;2.62). The neurology exam showed fluent speech but severe disorientation, poor arithmetic, recent memory loss, and weak comprehension. The MMSE score was 3 out of 30. Initial MRI scans from another hospital showed multiple abnormal signals in the left parietotemporo-occipital lobe and right temporal paraventricular region. This led to a diagnosis of autoimmune-related demyelinating disease. He received high-dose corticosteroids: Methylprednisolone 500 mg/day for 3 days, then 240 mg/d for 3 days, then 120 mg/d for 3 days. He also received intravenous immunoglobulin. These treatments proved ineffective. His lesions continued to expand on follow-up imaging.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. CLL Diagnosis and Staging\u003c/h2\u003e \u003cp\u003ePersistent lymphocytosis triggered a hematology consult. Bone marrow cytology showed more mature lymphocytes, accounting for 31% of nucleated cells. Flow cytometric immunophenotyping revealed a monoclonal B-cell population. Immunophenotype was positive for CD19, CD20, CD23 (partial), CD5 (dim), CD22, CD79b, CD200, and kappa light chain restriction. Cells were negative for CD10, CD43, and lambda light chains. These findings matched CLL (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Immunofixation electrophoresis confirmed monoclonal IgG-kappa paraprotein. FISH analysis of bone marrow showed no high-risk cytogenetic features: no 17p or 11q deletions or trisomy 12. Targeted next-generation sequencing (NGS) was performed as part of the routine diagnostic evaluation. This analysis identified variants in APC (c.2507C\u0026thinsp;\u0026gt;\u0026thinsp;G, VAF: 5.05%; c.2510C\u0026thinsp;\u0026gt;\u0026thinsp;G, VAF: 5.09%), ARID1B (c.974_985delGAGGAGGAGGAG, VAF: 29.66%), BCL10 (c.403A\u0026thinsp;\u0026gt;\u0026thinsp;T, VAF: 1.13%), FBXO11 (c.161_169dupAGCAGCAGC, VAF: 30.03%), KMT2A (c.9452delC, VAF: 4.65%), MYD88 (c.649G\u0026thinsp;\u0026gt;\u0026thinsp;T, VAF: 5.86%), and SAMHD1 (c.895G\u0026thinsp;\u0026gt;\u0026thinsp;T, VAF: 7.53%). No pathogenic TP53 mutations appeared. Staging included a whole-body CT, showing no abnormalities. Blood tests revealed hepatitis B virus carrier status with a viral load of 1.17\u0026times;10⁴ copies/mL (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). IGHV gene analysis revealed clonal IGHV3-64*01, IGHV3-64*02, and IGHV3-64*07 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The patient was diagnosed with Rai stage 0 CLL and hepatitis B carrier. Early CLL stage led to low suspicion for CNS involvement. Initial management was limited to entecavir antiviral therapy. No CLL-specific treatment was started then.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of Diagnostic and Laboratory Findings\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTest / Assessment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResults\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral blood flow cytometry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMonoclonal B-cells (24.7% of total cells):\u003c/p\u003e \u003cp\u003eCD19+, CD20+, CD5 (partial+), CD10\u0026ndash;,\u003c/p\u003e \u003cp\u003eKappa+, Lambda\u0026ndash; (See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow smear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHypercellular marrow with 31% mature lymphocytes;\u003c/p\u003e \u003cp\u003e23% lymphocytes in peripheral blood;\u003c/p\u003e \u003cp\u003eno lineage suppression noted\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiffuse infiltration by small B-cells expressing:\u003c/p\u003e \u003cp\u003eCD20, CD79a; scattered Kappa/Lambda positivity;\u003c/p\u003e \u003cp\u003eCyclinD1\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow flow pattern\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMonoclonal B-cell population consistent with CLL\u003c/p\u003e \u003cp\u003e(See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFISH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo TP53, CEP12, or ATM mutations;\u003c/p\u003e \u003cp\u003eIGH/CCND1 fusion\u0026ndash;; D13S319 deletion\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMutations detected:\u003c/p\u003e \u003cp\u003e\u0026bull; APC (c.2507C\u0026thinsp;\u0026gt;\u0026thinsp;G, VAF 5.05%; c.2510C\u0026thinsp;\u0026gt;\u0026thinsp;G, VAF 5.09%)\u003c/p\u003e \u003cp\u003e\u0026bull; ARID1B (c.974_985del, VAF 29.66%)\u003c/p\u003e \u003cp\u003e\u0026bull; BCL10 (c.403A\u0026thinsp;\u0026gt;\u0026thinsp;T, VAF 1.13%)\u003c/p\u003e \u003cp\u003e\u0026bull; FBXO11 (c.161_169dup, VAF 30.03%)\u003c/p\u003e \u003cp\u003e\u0026bull; KMT2A (c.9452delC, VAF 4.65%)\u003c/p\u003e \u003cp\u003e\u0026bull; MYD88 (c.649G\u0026thinsp;\u0026gt;\u0026thinsp;T, VAF 5.86%)\u003c/p\u003e \u003cp\u003e\u0026bull; SAMHD1 (c.895G\u0026thinsp;\u0026gt;\u0026thinsp;T, VAF 7.53%)\u003c/p\u003e \u003cp\u003e\u0026bull; TP53 mutation not detected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLumbar puncture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNormal intracranial pressure\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eScattered lymphocytes and monocytes;\u003c/p\u003e \u003cp\u003eno monoclonal B-cells detected;\u003c/p\u003e \u003cp\u003eflow cytometry: 0% B-cells, IGHV rearrangement\u0026ndash;, NGS\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft paraventricular lesion: NAA/Cr 1.2, Cho/Cr 1.9;\u003c/p\u003e \u003cp\u003eright paraventricular region: NAA/Cr 1.7, Cho/Cr 1.1;\u003c/p\u003e \u003cp\u003esuggests neoplastic process\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMultiple paraventricular demyelinating lesions\u003c/p\u003e \u003cp\u003ewith mild ring enhancement;\u003c/p\u003e \u003cp\u003esome non-neoplastic features, possibly influenced\u003c/p\u003e \u003cp\u003eby prior steroid therapy (See Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePET-CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMultiple hypermetabolic CNS lesions (SUVmax 8.2);\u003c/p\u003e \u003cp\u003ebilateral temporal hypodense shadows (SUVmax 7.6);\u003c/p\u003e \u003cp\u003efocal hypometabolism in left basal ganglia and thalamus;\u003c/p\u003e \u003cp\u003emild mediastinal lymph node uptake (SUVmax 2.09);\u003c/p\u003e \u003cp\u003espleen normal (SUVmax 2.61) (See Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDense perivascular lymphocytic infiltration,\u003c/p\u003e \u003cp\u003emyelin loss, reactive gliosis, vascular hyperplasia;\u003c/p\u003e \u003cp\u003eIHC: CD20+, CD79a+, CD23+/\u0026ndash;, CD5\u0026ndash;, CD38+,\u003c/p\u003e \u003cp\u003eKappa+/\u0026ndash;, Lambda\u0026ndash;, LFB+ (See Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIGH Gene Clonal Rearrangement Analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSample\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIGHV Gene Usage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIGHV mutation rate (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIGHV3-64*01/*02/*07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;9.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIGHV3-64*01/*02/*07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;9.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Re-evaluation and Multidisciplinary Diagnosis\u003c/h2\u003e \u003cp\u003eDue to worsening clinical symptoms, a lumbar puncture was performed. CSF pressure was normal. Tests for demyelination, infection, and autoimmunity were negative. CSF flow cytometry showed 0% B cells and anIGH rearrangement. IL-8 and IL-6 were higher in the CSF. IL-10 was higher in the blood. MRI in August 2021 showed ongoing, persistent paraventricular lesions with mild ring enhancement. Previous images showed new 'soft' foci, sometimes linked to non-neoplastic inflammation. Recent high-dose steroids may have altered these changes, as treatment can affect the evolution of imaging findings. The effects of both the inflammatory and neoplastic processes were considered (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Magnetic resonance spectroscopy (MRS) revealed metabolic changes suggestive of a tumor. The NAA/Cr ratio was1.2 on the lesion side and 1.7 on the contralateral side, indicating neuronal loss. The Cho/Cr ratio was 1.9 versus 1.1 contralaterally, and increased cell membrane production was seen in aggressive tumors. A whole-body 18F-FDG PET-CT subsequently revealed a key finding: hypermetabolic left occipital white matter with an SUVmax of 8.2. This result strongly suggested malignancy and outweighed the inconclusive MRI findings (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGiven the difference between the clinical course and the initial diagnosis, and guided by the hypermetabolic PET-CT findings, an MDT discussion was held. A decision was made to proceed with a stereotactic biopsy of the left paraventricular lesion. Histopathology of the brain tissue showed a dense perivascular lymphocytic infiltrate. Immunohistochemistry was atypical for CLL (CD20+, CD79a+, but CD5-) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). To definitively establish clonality and origin, IGH gene clonal rearrangement analysis was on both the brain biopsy and bone marrow specimens. This analysis showed an identical clonal sequence (IGHV3-64*01/02/07) in both tissues, with a 90.83% degree of homology. This finding confirmed that the CNS infiltrate was clonally identical to the systemic CLL and established the definitive diagnosis of CNS-CLL[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Treatment and Outcome\u003c/h2\u003e \u003cp\u003eThe patient was started on oral ibrutinib (560 mg/day) in combination with antiviral therapy. Over a five-year follow-up, his disease remained stable. While his visual and hearing deficits persisted (suggesting irreversible structural damage). Follow-up MRI showed a reduction in lesion size. His MMSE score increased to 16/30 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eCNS-CLL is identified in a significant proportion of autopsy studies of CLL patients, with reported prevalence rates ranging from 7% to 71% [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, the incidence of clinically significant CNS involvement is markedly lower, estimated at only 0.8% to 2%[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This pronounced discrepancy shows that although seeding of the CNS by CLL cells may be a common event, it rarely culminates in symptomatic disease, which directly accounts for the low rate of clinical diagnosis. The diagnostic challenge is additionally complicated by the limitations of CSF analysis. Although sensitive, detection of CLL cells in the CSF is not pathognomonic for CNS-CLL, as contamination from peripheral blood during lumbar puncture can yield false-positive results. Conversely, as demonstrated in our case, the absence of CLL cells in the CSF does not exclude the diagnosis, yielding false-negative results. Therefore, A definitive diagnosis of CNS-CLL requires integration of clinical presentation, neuroimaging, and histopathological evidence, rather than relying on CSF analysis alone.The differentiation of CNS-CLL from other neurological disorders in CLL patients is clinically challenging due to the highly nonspecific nature of the symptoms, which overlap with a wide spectrum of conditions, including infections, metabolic disorders, autoimmune diseases, treatment-related complications, and other malignancies. Crucially, the detection of clonal B cells in the CSF does not definitively establish CNS-CLL as the symptomatic cause, necessitating a broad diagnostic evaluation. This is exemplified by a study of 172 CLL patients with neurological symptoms, in which only 33% had CNS-CLL, while 67% had alternative diagnoses such as opportunistic infections or other cancers[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Therefore, neurological decline in CLL mandates a systematic investigation of all potential etiologies rather than presumptive attribution to leukemic involvement.\u003c/p\u003e \u003cp\u003eThe diagnosis of CNS-CLL requires a high index of suspicion and an MDT approach, as no single investigation is definitive. Neuroimaging plays a pivotal role in the initial evaluation. On MRI, CNS-CLL often presents with diverse features, including demyelinating and ring-enhancing lesions, which typically appear isointense on T1-weighted images (T1WI) and hypointense on T2-weighted images (T2WI).[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] These imaging characteristics, when considered alongside clinical and CSF findings, help distinguish CNS-CLL from other CNS disorders. 18F-FDG PET-CT scans are highly sensitive for detecting aggressive lymphomas. Most hematological malignancies exhibit increased glycolytic activity, enabling detection with 18F-FDG-PET imaging. PET-CT was instrumental in our case. The high SUVmax (8.2) within a CNS lesion was a critical red flag, strongly suggesting a neoplastic process over inflammation and providing a precise target for biopsy. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eBrain biopsy remains the diagnostic cornerstone. However, as seen in our case, the immunohistochemical profile can be atypical (e.g., CD5 negativity). To further determine the clonality and origin of the lymphocytic infiltrate, IGH gene clonal rearrangement analysis was performed as a diagnostic adjunct, demonstrating identical clonal sequences in the brain tissue and bone marrow, confirming that the intracerebral lesions resulted from CNS involvement by systemic CLL. As CLL arises from the unconstrained expansion of a single transformed B cell and is characterized by the presence of clonal rearrangements of immunoglobulin (IG). In B cell lymphoma, gene fragments are rearranged, and random nucleotide insertions and deletions occur, thereby generating unique sequences for each B lymphocyte.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThere is no standard of therapy for CNS-CLL; evidence is derived from case reports and small series. The advent of novel agents has improved prospects. Bruton's tyrosine kinase (BTK) inhibitors, such as ibrutinib, form a cornerstone of this modern therapeutic approach due to their favorable central nervous system penetration and potent inhibition of B-cell receptor (BCR) and NF-κB signaling. Ibrutinib has demonstrated efficacy in CNS-CLL across various IGHV mutational subgroups [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Current treatments for CNS-CLL that have been shown to be effective include Ibrutinib[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], Venetoclax[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], Venetoclax with Ibrutinib[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], Ibrutinib with rituximab and methotrexate [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], Venetoclax with high-dose methotrexate and rituximab[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Regimens such as venetoclax-obinutuzumab-ibrutinib, venetoclax-rituximab, and venetoclax-obinutuzumab have shown comparable patient survival outcomes, with all demonstrating superior efficacy compared to chemotherapy alone.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eThis case highlights the diagnostic challenges associated with CNS-CLL. It reinforces several critical lessons. CNS-CLL can occur in patients with low-grade or previously undiagnosed systemic CLL. A negative CSF flow cytometry result cannot rule out the diagnosis.18F-FDG PET-CT is a valuable tool for identifying suspicious lesions and guiding biopsy. Molecular confirmation of clonal identity between CNS and systemic disease is the gold standard for diagnosis, especially when pathology is atypical. BTK inhibitors like ibrutinib are effective treatment options that aim for disease control and functional preservation, albeit with the understanding that some deficits may be permanent. A high index of suspicion and a structured, multidisciplinary algorithm incorporating advanced imaging and molecular techniques are essential for the timely and accurate diagnosis of this rare but serious complication.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eCLL\u003c/strong\u003e: Chronic lymphocytic leukemia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCNS-CLL\u003c/strong\u003e: Central nervous system involvement by chronic lymphocytic leukemia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEM-CLL\u003c/strong\u003e: Extramedullary manifestations of chronic lymphocytic leukemia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFISH\u003c/strong\u003e: Fluorescence in situ hybridization\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMDT\u003c/strong\u003e: Multidisciplinary collaborative treatment mode\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI\u003c/strong\u003e: Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePET\u003c/strong\u003e: Positron emission tomography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNGS\u003c/strong\u003e: Next-generation sequencing\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank TOPEDIT for their assistance with language editing and proofreading of this manuscript. We are grateful to the patient and the families for their contributions to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY.X.G,W.L.S conceptualized and developed the study.W.N.S. collected materials and wrote the article. Y.M.W. performed the stereotactic biopsy surgery; D.W.L.managed the neurology treatment ;D.D.W.conducted the pathological examination;Z.L.Z performed the cranial MRI examination;T.B.S. conducted the PET-CT examination；Y.X.G managed the hematology treatment and revised the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUndergraduate Scientific Research Training Program of Capital Medical University (XSKY2024)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this case report is available. The next-generation sequencing (NGS) results generated by this case have been deposited in an open database. For further information, you can inquire with the corresponding author .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. Based on international ethical standards and Chinese laws and regulations, case reports are not classified as clinical studies and, consequently, do not necessitate ethical review. Written informed consent has been provided by the patient.Written informed consent has been obtained from the patient to publish this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient has granted written informed consent for the publication of this case report and any associated photos.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWeining Sun, Yixian Guo, Wanling Sun: Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China\u003c/p\u003e\n\u003cp\u003eYaming Wang: Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China\u003c/p\u003e\n\u003cp\u003eDawei Li: Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China\u003c/p\u003e\n\u003cp\u003eDandan Wang: Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China\u003c/p\u003e\n\u003cp\u003eZhilian Zhao: Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China\u003c/p\u003e\n\u003cp\u003eTianbin Song: Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eEichhorst, B., et al., Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2021. 32(1): p. 23-33.\u003c/li\u003e\n \u003cli\u003eCramer, P., et al., Extramedullary manifestations of chronic lymphocytic leukaemia are not unusual. Leuk Res, 2014. 38(3): p. 284-5.\u003c/li\u003e\n \u003cli\u003eAlbakr, A., et al., Central Nervous System Lymphoma in a Patient with Chronic Lymphocytic Leukemia: A Case Report and Literature Review. Cureus, 2018. 10(11): p. e3660.\u003c/li\u003e\n \u003cli\u003eTimmers, N., et al., Central nervous system localisation of chronic lymphocytic leukaemia, description of two very distinct cases and a review of the literature. Ann Hematol, 2018. 97(9): p. 1627-1632.\u003c/li\u003e\n \u003cli\u003eAgathangelidis, A., et al., Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: the 2022 update of the recommendations by ERIC, the European Research Initiative on CLL. Leukemia, 2022. 36(8): p. 1961-1968.\u003c/li\u003e\n \u003cli\u003eBarcos, M., et al., An autopsy study of 1206 acute and chronic leukemias (1958 to 1982). Cancer, 1987. 60(4): p. 827-837.\u003c/li\u003e\n \u003cli\u003eBojsen-M\u0026oslash;ller, M. and J.L. Nielsen, CNS involvement in leukaemia. An autopsy study of 100 consecutive patients. Acta Pathol Microbiol Immunol Scand A, 1983. 91(4): p. 209-16.\u003c/li\u003e\n \u003cli\u003eHanse, M.C.J., et al., Incidence of central nervous system involvement in chronic lymphocytic leukemia and outcome to treatment. Journal of Neurology, 2008. 255(6): p. 828-830.\u003c/li\u003e\n \u003cli\u003eStrati, P., et al., Prevalence and characteristics of central nervous system involvement by chronic lymphocytic leukemia. Haematologica, 2016. 101(4): p. 458-65.\u003c/li\u003e\n \u003cli\u003eGuo, R., et al., Primary central nervous system small lymphocytic lymphoma in the bilateral ventricles: two case reports. BMC Neurol, 2019. 19(1): p. 200.\u003c/li\u003e\n \u003cli\u003eZirakchian Zadeh, M., Clinical Application of (18)F-FDG-PET Quantification in Hematological Malignancies: Emphasizing Multiple Myeloma, Lymphoma and Chronic Lymphocytic Leukemia. Clin Lymphoma Myeloma Leuk, 2023. 23(11): p. 800-814.\u003c/li\u003e\n \u003cli\u003eDewaide, R. and K. Saevels, Treatment strategy in chronic lymphocytic leukemia with symptomatic central nervous system involvement: A case report. Clin Case Rep, 2023. 11(11): p. e7965.\u003c/li\u003e\n \u003cli\u003eDudley, D.D., et al., Mechanism and control of V(D)J recombination versus class switch recombination: similarities and differences. Adv Immunol, 2005. 86: p. 43-112.\u003c/li\u003e\n \u003cli\u003eScheijen, B., et al., Next-generation sequencing of immunoglobulin gene rearrangements for clonality assessment: a technical feasibility study by EuroClonality-NGS. Leukemia, 2019. 33(9): p. 2227-2240.\u003c/li\u003e\n \u003cli\u003eMousinho, F., et al., Treatment Sequencing in a Chronic Lymphocytic Leukemia Patient with Central Nervous System Involvement. Case Rep Hematol, 2018. 2018: p. 7817918.\u003c/li\u003e\n \u003cli\u003eMart\u0026iacute;n-Moro, F., et al., Intracranial hemorrhage as presentation of chronic lymphocytic leukemia successfully treated with ibrutinib. Annals of Hematology, 2021. 101(1): p. 213-215.\u003c/li\u003e\n \u003cli\u003eReda, G., et al., Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica, 2019. 104(5): p. e222-e223.\u003c/li\u003e\n \u003cli\u003eSoumerai, J.D., et al., Venetoclax activity in a patient with central nervous system involvement by chronic lymphocytic leukaemia. The Lancet Haematology, 2022. 9(10).\u003c/li\u003e\n \u003cli\u003eWang, W., et al., Richter\u0026rsquo;s syndrome in central nervous system with MYD88L265P and CD79b mutation responded well to ibrutinib containing chemotherapy: a case report and review of the literature. Annals of Hematology, 2022. 101(8): p. 1869-1872.\u003c/li\u003e\n \u003cli\u003eBeziat, G., et al., Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report. Clin Case Rep, 2020. 8(2): p. 269-273.\u003c/li\u003e\n \u003cli\u003eEichhorst, B., et al., First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med, 2023. 388(19): p. 1739-1754.\u003c/li\u003e\n\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":"Central nervous system, Chronic lymphocyte leukemia, Multidisciplinary diagnosis, Immunoglobulin heavy chain variable regionmutations, Positron emission tomography-computed tomography","lastPublishedDoi":"10.21203/rs.3.rs-8631569/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8631569/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCentral nervous system involvement by chronic lymphocyte leukemia (CNS-CLL) without Richter transformation is a rare and hard-to-diagnose condition. Nonspecific symptoms and the need for a brain biopsy complicate diagnosis. We report a 58-year-old male with Rai stage 0 CLL who had severe neurological signs. His initial MRI suggested autoimmune-related demyelinating disease. However, high-dose steroids and intravenous immunoglobulin (IVIG) did not help. His neurological status continued to worsen. A multidisciplinary team used advanced imaging (PET-CT showing a hypermetabolic lesion with SUVmax 8.2) and stereotactic brain biopsy. Immunoglobulin heavy chain (IGH) gene clonal rearrangement showed identical clones (IGHV3-64*01/02/07) in both cerebral tissue and bone marrow. This confirmed CNS-CLL. Treatment with ibrutinib stabilized the disease and led to partial cognitive recovery. The patient survived five years without progression. This case and a literature review show that CNS-CLL can have atypical imaging and occur even in early-stage disease. Under targeted therapy, this rare condition may have a better prognosis than previously reported. The report highlights the importance of molecular studies for diagnosis and recommends a multidisciplinary diagnostic approach.\u003c/p\u003e","manuscriptTitle":"CNS Involvement by CLL Mimicking Demyelinating Disease: A Five-Year Case Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-16 06:03:27","doi":"10.21203/rs.3.rs-8631569/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-03-11T12:03:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-09T09:04:58+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-17T07:12:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-14T13:31:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-02-14T13:27:44+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":"b79d6117-e208-4e56-9509-dc242a9b8afb","owner":[],"postedDate":"March 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-16T06:03:27+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-16 06:03:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8631569","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8631569","identity":"rs-8631569","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}