Fulminant recurrent intracerebral hemorrhage in neurofibromatosis type 1: A case report with clinical insights

Fulminant recurrent intracerebral hemorrhage in neurofibromatosis type 1: A case report with clinical insights | 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 Fulminant recurrent intracerebral hemorrhage in neurofibromatosis type 1: A case report with clinical insights Yuhua Wang, Quanfu Fan, Ce Wang, Qian Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9212728/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cerebrovascular abnormalities, including an increased risk of intracranial hemorrhage. We present a 44-year-old male with confirmed NF1 who developed fulminant recurrent bilateral frontal intracerebral hemorrhage, requiring three emergency craniotomies over a 22-day period. Despite aggressive surgical and medical management, he developed recurrent hemorrhages and refractory cerebral edema, ultimately leading to death after the family elected to transition to comfort measures only. Serial coagulation profiles showed dynamic changes consistent with acute hemorrhage, postoperative reparative responses, and terminal consumptive coagulopathy. This case highlights the complex management challenges in NF1 patients with intracranial hemorrhage, where underlying vascular dysplasia may contribute to refractory hemorrhage and edema, requiring specialized approaches. Early recognition of NF1-associated cerebrovascular complications, aggressive multidisciplinary care, and serial coagulation monitoring are crucial for optimizing outcomes in these high-risk patients. Neurofibromatosis type 1 Intracerebral hemorrhage Vascular dysplasia Decompressive craniectomy Figures Figure 1 Figure 2 Figure 3 Introduction Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting approximately 1 in 2,500–3,000 individuals worldwide [ 1 ], caused by mutations in the NF1 gene resulting in loss of neurofibromin function [ 2 ]. Cerebrovascular abnormalities are a concerning complication of NF1, with patients having significantly increased risk of cerebrovascular disease [ 3 ]. Manifestations include stenosis, occlusion, aneurysms, and arteriovenous malformations [ 4 ], resulting from abnormal neurofibromin function leading to excessive proliferation of vascular smooth muscle cells and vessel wall dysplasia [ 5 , 6 ]. Intracranial hemorrhage in NF1 patients presents unique management challenges due to underlying vascular dysplasia, which may lead to increased bleeding tendency, difficulty achieving hemostasis during surgery, and higher risk of rebleeding [ 7 ]. Cerebral edema in these patients may also be refractory to conventional therapies [ 5 ]. Despite increasing recognition of NF1-associated cerebrovascular complications, optimal management strategies in the neurocritical care setting remain poorly defined. Here, we report a challenging case of a patient with NF1 who developed refractory intracranial hemorrhage and cerebral edema requiring three surgical interventions. Methods This case report was prepared in accordance with the CARE (Case Reports) guidelines [ 14 ]. The patient's medical records, including daily progress notes, operative reports, imaging studies, and laboratory results, were retrospectively reviewed. Serial coagulation testing was performed at clinically indicated time points throughout the hospital course. All data were de-identified to protect patient privacy. A literature search was conducted using PubMed and Web of Science databases (up to March 2026) with the following keywords: "neurofibromatosis type 1", "intracranial hemorrhage", "cerebral edema", "vascular dysplasia", and "decompressive craniectomy". Only peer-reviewed articles published in English were considered. Case presentation Note All days are counted from admission (Day 1 = January 31, 2026). A 44-year-old male with known NF1 since childhood presented with acute neurological deterioration. His medical history included multiple café-au-lait spots, cutaneous neurofibromas, and learning disabilities consistent with NF1 [ 2 , 13 ]. Family history was notable for his mother having NF1, confirming autosomal dominant inheritance [ 2 ]. Physical examination revealed multiple café-au-lait spots (> 15 mm) on the trunk and extremities, numerous cutaneous neurofibromas, and axillary freckling (Fig. 1 G-H). Neurological examination showed a Glasgow Coma Scale (GCS) score of 8 (E2V2M4), with decorticate posturing on the right side and purposeful movements on the left. Emergency non-contrast head CT revealed bilateral frontal intracerebral hematomas (Fig. 2 A-B). The right frontal hematoma measured approximately 40 mL with significant mass effect, including compression of the right frontal horn and midline shift of 8 mm to the left. The left frontal hematoma measured approximately 25 mL with mild mass effect. CT angiography showed no evidence of aneurysms, vascular malformations, or large vessel occlusion (Fig. 1 E-F). Three-dimensional reconstructed CT images of the skull revealed a congenital defect/absence of the left parietal bone (red arrows, Fig. 1 A-D), a characteristic skeletal manifestation of NF1 [ 13 ], and bilateral parietal bone fractures (white arrows) resulting from the fall. Initial laboratory investigations showed normal coagulation parameters except for mild hypofibrinogenemia (FIB 1.48 g/L) and marked elevation of FDP (99.37 µg/mL) and D-dimer (42.16 µg/mL) (Table 1 ), consistent with local consumption following acute hemorrhage rather than a primary coagulopathy. Table 1 Serial coagulation profiles during the clinical course Parameter (Unit) Normal Range Day 1 Day 5 Day 13 Day 23 APTT (s) 24.5–42.5 30.6 25.7 27.5 36.9 PT (s) 8.8–14.4 12.30 12.50 13.60 10.90 INR 0.8–1.4 1.10 1.12 1.22 0.98 FIB (g/L) 2.0–4.0 1.48 ↓ 4.62 ↑ 4.76 ↑ 2.07 TT (s) 10.3–18.0 16.9 11.7 12.0 19.8 ↑ FDP (µg/mL) 0–5 99.37↑ 10.90↑ 10.96↑ 109.42↑ D-dimer (µg/mL) 0–0.5 42.16↑ 4.77↑ 5.62↑ 39.92↑ ↑: above normal range; ↓: below normal range. Abbreviations: APTT, activated partial thromboplastin time; PT, prothrombin time; INR, international normalized ratio; FIB, fibrinogen; TT, thrombin time; FDP, fibrinogen/fibrin degradation products. On Day 2, the patient underwent bilateral frontal craniotomies and hematoma evacuation. Intraoperatively, the dura was thickened and adherent to the underlying brain, consistent with NF1-related dural abnormalities [ 8 ]. Approximately 45 mL of clot was removed from the right frontal lobe and 30 mL from the left. Postoperatively, he was transferred to the neurocritical care unit with an intracranial pressure (ICP) monitor. Initial ICP readings were 25–30 mmHg, managed with propofol sedation and mannitol. Coagulation testing on Day 5 showed a rebound in fibrinogen to 4.62 g/L (Table 1 ), consistent with a postoperative acute-phase reparative response [ 9 ]. On Day 4 (two days after the first surgery), the patient developed acute deterioration with right pupillary dilation to 5 mm. CT revealed recurrent bilateral frontal hematomas (right 35 mL, left 20 mL) with significant midline shift (10 mm) (Fig. 2 C-D). He underwent emergent reoperation; bleeding originated from multiple small vessels within friable brain tissue, possibly related to NF1-associated parenchymal abnormalities [ 5 , 6 ]. In addition to hematoma evacuation, a right frontal decompressive craniectomy was performed [ 11 ]. Postoperatively, ICP remained elevated (25–35 mmHg) despite hyperosmolar therapy, sedation, and neuromuscular blockade. CT on Day 10 showed progressive bilateral frontal edema, more severe on the right (Fig. 2 G-H). Of note, coagulation parameters on Days 5 and 13 were within normal ranges (Table 1 ), underscoring that rebleeding occurred despite adequate systemic hemostasis—further implicating local vascular fragility as the primary driver [ 7 , 8 ]. On Day 21, the patient acutely deteriorated again. CT revealed new hemorrhages in the right frontal lobe (30 mL) and left frontal lobe (15 mL), with worsening edema and midline shift (12 mm) (Fig. 2 K-L). A third surgical intervention was performed, with evacuation of bilateral frontal hematomas. The brain tissue was extremely friable with diffuse oozing. A bilateral frontal decompressive craniectomy was performed for maximal brain relaxation [ 11 ]. Postoperatively, ICP remained elevated despite maximal therapy, and the patient developed progressive multi-organ failure. After extensive discussion with the family, the decision was made to transition to comfort measures only [ 12 ]. The patient was extubated and passed away peacefully the following day (Day 22). Coagulation testing on Day 23 showed prolonged thrombin time (19.8 s), decreased FIB (2.07 g/L), and marked re-elevation of FDP (109.42 µg/mL) and D-dimer (39.92 µg/mL) (Table 1 ), indicating acute consumptive coagulopathy secondary to massive recurrent hemorrhage [ 9 ]. Discussion The pathophysiology of intracranial hemorrhage in NF1 patients involves NF1 gene mutations leading to loss of neurofibromin function, resulting in constitutive activation of the Ras-MAPK signaling pathway [ 2 ]. This causes excessive proliferation of vascular smooth muscle cells and vessel wall dysplasia [ 5 , 6 ], affecting both large and small vessels and leading to abnormalities including stenosis, aneurysms, and arteriovenous malformations [ 4 , 8 ]. In our patient, recurrent hemorrhages likely resulted from underlying vascular dysplasia, which increased vessel fragility and impaired hemostasis [ 7 ]. Intraoperative findings of friable brain tissue and difficulty achieving hemostasis support this. Serial coagulation profiles provided critical insights: initial changes (decreased FIB, elevated FDP/D-dimer) reflected local consumption from acute hemorrhage, ruling out primary coagulopathy. The terminal coagulopathy (prolonged TT, decreased FIB, marked elevation of FDP/D-dimer) indicated acute consumptive coagulopathy secondary to massive recurrent hemorrhage, exacerbating bleeding and contributing to irreversible deterioration. Refractory cerebral edema may be related to blood-brain barrier disruption, increased vascular permeability, and impaired astrocytic function in NF1 [ 5 ]. Surgical management of intracranial hemorrhage in NF1 patients presents unique challenges. First, abnormal anatomy—thickened and adherent dura—complicates dural opening and closure [ 8 ]. Second, vascular dysplasia leads to friable vessels that are difficult to coagulate, resulting in increased intraoperative bleeding [ 7 , 8 ]. Third, NF1 patients have an increased risk of rebleeding due to underlying vascular abnormalities [ 9 , 10 ]. Notably, despite normalization of coagulation parameters after the first surgery (Table 1 , Days 5 and 13), rebleeding still occurred—strongly suggesting that local vascular fragility, rather than systemic coagulopathy, was the predominant mechanism [ 7 ]. Decompressive craniectomy was ultimately necessary to address refractory ICP elevation [ 11 ]. Medical management of increased ICP in NF1 patients is particularly challenging. Conventional therapies—osmotic diuretics, hypertonic saline, sedation—may be less effective due to underlying pathophysiology [ 5 ]. Contributing factors likely include impaired cerebrovascular autoregulation [ 5 ], blood-brain barrier disruption leading to vasogenic edema resistant to therapy [ 5 ], and hydrocephalus requiring external ventricular drainage. Our case shares similarities with previously reported NF1 patients with intracranial hemorrhage. Hayashi et al. described a patient with NF1 who developed repeated intracerebral hemorrhage due to quasi-moyamoya disease [ 9 ], and Uchida et al. reported a patient with NF1 and subarachnoid hemorrhage due to multiple de novo aneurysms [ 10 ]. A recent pediatric case series further characterized the spectrum of vascular abnormalities in NF1 [ 15 ]. Moreover, emerging evidence on surgical revascularization in children with NF1-associated moyamoya syndrome suggests that timely intervention may prevent neurological complications in selected cases, underscoring the potential benefits of early detection of cerebrovascular pathology [ 16 ]. This case offers several key clinical insights. First, early recognition of NF1 and its cerebrovascular complications is crucial; patients with NF1 should undergo regular screening for vascular abnormalities [ 3 , 7 ]. Second, surgical management requires expertise in handling abnormal anatomy, increased bleeding risk, and difficulty achieving hemostasis [ 7 , 8 ]; decompressive craniectomy should be considered early if medical ICP management fails [ 11 ]. Third, multi-modal ICP management is often necessary, and refractory intracranial hypertension should prompt early surgical intervention [ 11 ]. Fourth, serial coagulation monitoring helps distinguish local consumption from terminal consumptive coagulopathy, guiding targeted hemostatic interventions. Fifth, prognosis for NF1 patients with severe intracranial hemorrhage is generally poor; early involvement of palliative care and honest communication with families are essential [ 12 ]. Limitations This case report has several limitations. First, post-mortem examination was not performed due to religious reasons, precluding histopathological confirmation of the underlying vascular pathology. Second, molecular testing of the resected tissue was not available, which could have provided insights into potential genotype-phenotype correlations. Third, while serial coagulation monitoring was performed, intracranial pressure monitoring was not continuous throughout the entire hospital course due to removal of the ICP monitor after the second surgery. Conclusion This case describes a challenging NF1 patient with refractory intracranial hemorrhage and cerebral edema requiring three craniotomies. The clinical course highlights the unique challenges in managing NF1 patients with intracranial hemorrhage, including increased bleeding risk, difficulty achieving hemostasis, and poor response to conventional therapies. Serial coagulation profiles provided critical insights into dynamic coagulation changes associated with acute hemorrhage, surgical intervention, and terminal deterioration. The pathophysiology involves vascular dysplasia, increased vessel fragility, and impaired blood-brain barrier function [ 5 ]. Optimal management requires a multidisciplinary approach with expertise in vascular dysplasia, coagulopathy, and neurocritical care. Declarations Ethics approval and consent to participate: This study was reviewed and approved by the Institutional Review Board of Cangzhou People's Hospital (Approval No. K2025-156-05, approved January 13, 2026). All procedures adhered to the ethical standards of the institutional committee and the 1964 Helsinki Declaration. Consent for publication: Written informed consent was obtained from the patient's legal next-of-kin for the publication of this case report and any accompanying images. Competing interests: The authors declare no competing interests. Funding: This work was supported by the 2026 Medical Science Research Project of Hebei Provincial Health Commission (Grant No. 20261342). The funder had no role in the study design, data collection, analysis, or manuscript preparation. Author Contribution YW conceptualized the study, collected and analyzed the clinical data, performed the literature review, and drafted and revised the manuscript. QF and CW contributed to data collection and manuscript revision. ZQ contributed to the analysis of imaging data and provided critical review of the radiological findings. All authors approved the final version. Data Availability All data generated or analysed during this study are included in this published article. References Lee TJ, Chopra M, Kim RH, Parkin PC, Barnett-Tapia C. Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis. Orphanet J Rare Dis. 2023;18(1):292. 10.1186/s13023-023-02911-2 . Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017;3:17004. 10.1038/nrdp.2017.4 . Terry AR, Jordan JT, Schwamm L, Plotkin SR. Increased Risk of Cerebrovascular Disease Among Patients With Neurofibromatosis Type 1: Population-Based Approach. Stroke. 2016;47(1):60–5. 10.1161/STROKEAHA.115.011406 . Santoro C, Di Rocco F, Kossorotoff M, et al. Moyamoya syndrome in children with neurofibromatosis type 1: Italian-French experience. Am J Med Genet A. 2017;173(6):1521–30. 10.1002/ajmg.a.38212 . Lehman LL, Ullrich NJ. Cerebral Vasculopathy in Children with Neurofibromatosis Type 1. Cancers (Basel). 2023;15(20):5111. 10.3390/cancers15205111 . Hamilton SJ, Friedman JM. Insights into the pathogenesis of neurofibromatosis 1 vasculopathy. Clin Genet. 2000;58(5):341–4. 10.1034/j.1399-0004.2000.580501.x . Sheerin UM, Holmes P, Childs L, et al. Neurovascular complications in adults with Neurofibromatosis type 1: A national referral center experience. Am J Med Genet A. 2022;188(10):3009–15. 10.1002/ajmg.a.62931 . Oderich GS, Sullivan TM, Bower TC, et al. Vascular abnormalities in patients with neurofibromatosis syndrome type I: clinical spectrum, management, and results. J Vasc Surg. 2007;46(3):475–84. 10.1016/j.jvs.2007.03.055 . Hayashi K, Morofuji Y, Horie N, Izumo T. A Case of Neurofibromatosis Type 1 Complicated with Repeated Intracerebral Hemorrhage due to Quasi-Moyamoya Disease. J Stroke Cerebrovasc Dis. 2015;24(5):e109–113. 10.1016/j.jstrokecerebrovasdis.2014.12.029 . Uchida T, Amagasaki K, Hosono A, Nakaguchi H. Neurofibromatosis type 1 with subarachnoid hemorrhage due to multiple and de novo aneurysms: a case report. J Med Case Rep. 2021;15(1):411. 10.1186/s13256-021-02967-3 . Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension. N Engl J Med. 2016;375(12):1119–30. 10.1056/NEJMoa1605215 . Frontera JA, Curtis JR, Nelson JE, et al. Integrating palliative care into the care of neurocritically ill patients: a report from the Improving Palliative Care in the ICU Project. Crit Care Med. 2015;43(9):1964–71. 10.1097/CCM.0000000000001131 . Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506–13. 10.1038/s41436-021-01170-5 . Riley DS, Barber MS, Kienle GS, et al. CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol. 2017;89:218–35. 10.1016/j.jclinepi.2017.04.026 . Currao P, Balzarini M, Pruna D, et al. Vascular Abnormalities and Neurofibromatosis Type 1: A Paediatric Case Series. J Child Neurol. 2025;40(1):49–60. 10.1177/08830738241284081 . Morello A, Scala M, Schiavetti I, et al. Surgical revascularization as a procedure to prevent neurological complications in children with moyamoya syndrome associated with neurofibromatosis I: a single institution case series. Childs Nerv Syst. 2024;40(6):1731–41. 10.1007/s00381-024-06304-z . Additional Declarations No competing interests reported. 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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-9212728","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":619716459,"identity":"b1ed6f4d-99e8-46a4-9702-cfce0c4d5cd4","order_by":0,"name":"Yuhua Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYPCCAwwMzIwNh/9USMjxE6+FnbnxAc8ZC2PJBqK18LM3G/C2VSRuIKTF4PjZw6952+4k9jcztklIzpNg3MDA/PDRDXxazuSlWfO2PUuccRioxXCbBLM5A5uxcQ4eLWYHcsyMedsOJzaAtCRuk2CzbOBhk8ar5fwbiJb5IC0H50jwGBwgpOVGjvFjkJYNhxmbDRsbJCQIarG/8caMcc65w8YbDzM2PmY4JmEg2UzAL5L9OcYf3pQdlp13/viDwww1dfX97M0PH+PTAgRsUjwofGb8ysFKPv4grGgUjIJRMApGMgAAhsZSQA9o2eAAAAAASUVORK5CYII=","orcid":"","institution":"People's Hospital of Cangzhou","correspondingAuthor":true,"prefix":"","firstName":"Yuhua","middleName":"","lastName":"Wang","suffix":""},{"id":619716460,"identity":"b00bbbf8-ec1d-4a2f-8258-370e3806805f","order_by":1,"name":"Quanfu Fan","email":"","orcid":"","institution":"People's Hospital of Cangzhou","correspondingAuthor":false,"prefix":"","firstName":"Quanfu","middleName":"","lastName":"Fan","suffix":""},{"id":619716463,"identity":"71603afb-19b6-423d-8a1a-121c5bb9f360","order_by":2,"name":"Ce Wang","email":"","orcid":"","institution":"People's Hospital of Cangzhou","correspondingAuthor":false,"prefix":"","firstName":"Ce","middleName":"","lastName":"Wang","suffix":""},{"id":619716464,"identity":"a41aeba5-aed1-4039-adef-032ef312c8d5","order_by":3,"name":"Qian Zhang","email":"","orcid":"","institution":"People's Hospital of Cangzhou","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2026-03-24 13:41:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9212728/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9212728/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106596522,"identity":"ec97cf02-7321-4563-a928-d08418cc5529","added_by":"auto","created_at":"2026-04-10 09:37:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":9171605,"visible":true,"origin":"","legend":"\u003cp\u003eNeurofibromatosis type 1 (NF1)-related manifestations. (A-D) Three-dimensional reconstructed CT images of the skull. Red arrows indicate a congenital defect/absence of the left parietal bone, a characteristic skeletal manifestation of NF1 (bone dysplasia). White arrows indicate acute bilateral parietal bone fractures resulting from the fall. (E-F) Three-dimensional reconstructed CT angiography images showing no evidence of aneurysm, stenosis, or vascular malformation. (G) Clinical photograph of the trunk showing multiple café-au-lait spots (black arrowheads) and cutaneous neurofibromas (black arrows). (H) Clinical photograph of the scalp showing a raised lesion (arrow), consistent with a cutaneous or plexiform neurofibroma.\u003c/p\u003e","description":"","filename":"Fig11.png","url":"https://assets-eu.researchsquare.com/files/rs-9212728/v1/0c7e781bcbb75e019912c858.png"},{"id":106728696,"identity":"8622233c-7500-470e-bb86-40454fbcba14","added_by":"auto","created_at":"2026-04-12 18:43:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5880307,"visible":true,"origin":"","legend":"\u003cp\u003eSerial non-contrast head CT scans illustrating the asymmetric evolution of bilateral frontal lesions. Images are arranged chronologically (top to bottom) with right frontal level (left column) and left frontal level (right column). White arrows: hematoma/hemorrhage; red arrows: compression of right frontal horn and/or midline shift; blue arrows: edema/swelling. (A-B) Day 1: bilateral frontal hematomas. (C-D) Day 4: enlargement of hematomas with mass effect. (E-F) Day 5: post-operative day 1 after first surgery, satisfactory evacuation. (G-H) Day 10: progressive right frontal edema. (I-J) Day 13: post-operative day 1 after second surgery, no re-hemorrhage. (K-L) Day 21 (morning): right frontal re-hemorrhage. (M-N) Day 22: post-operative day 1 after third surgery, cavity clear. (O-P) Day 23: massive right frontal re-hemorrhage with brain herniation.\u003c/p\u003e","description":"","filename":"FIg21.png","url":"https://assets-eu.researchsquare.com/files/rs-9212728/v1/66493ee5c9d1826a408e2e2e.png"},{"id":106596523,"identity":"0e268de3-d2a6-4860-a1d9-8722c8cba2cf","added_by":"auto","created_at":"2026-04-10 09:37:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":8484642,"visible":true,"origin":"","legend":"\u003cp\u003eDiffusion tensor imaging (DTI) showing the relationship between bilateral frontal hematomas and adjacent white matter tracts. (A-D) Axial DTI images with fiber tracking. White arrows indicate hematomas. Colored spheres represent regions of interest (ROIs): red spheres—right-sided ROIs, blue spheres—left-sided ROIs. Red and blue arrows point to corresponding white matter tracts. (E-H) Corresponding fiber tractography images demonstrating that the white matter fibers (red and blue tracts) are displaced and encased by the hematomas but remain structurally intact, without frank disruption. This finding suggests that neurological deficits (right-sided weakness) were primarily due to mass effect and tract compression rather than irreversible axonal injury.\u003c/p\u003e","description":"","filename":"Fig31.png","url":"https://assets-eu.researchsquare.com/files/rs-9212728/v1/b972defcbb51625f6ed95342.png"},{"id":108005971,"identity":"b2913d1b-c469-40c9-8d93-d72a5ed250d0","added_by":"auto","created_at":"2026-04-28 12:51:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2208738,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9212728/v1/18c3fa9e-c6b8-4614-9027-23f474250c7a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Fulminant recurrent intracerebral hemorrhage in neurofibromatosis type 1: A case report with clinical insights","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting approximately 1 in 2,500–3,000 individuals worldwide [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e], caused by mutations in the NF1 gene resulting in loss of neurofibromin function [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. Cerebrovascular abnormalities are a concerning complication of NF1, with patients having significantly increased risk of cerebrovascular disease [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. Manifestations include stenosis, occlusion, aneurysms, and arteriovenous malformations [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e], resulting from abnormal neurofibromin function leading to excessive proliferation of vascular smooth muscle cells and vessel wall dysplasia [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIntracranial hemorrhage in NF1 patients presents unique management challenges due to underlying vascular dysplasia, which may lead to increased bleeding tendency, difficulty achieving hemostasis during surgery, and higher risk of rebleeding [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. Cerebral edema in these patients may also be refractory to conventional therapies [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]. Despite increasing recognition of NF1-associated cerebrovascular complications, optimal management strategies in the neurocritical care setting remain poorly defined. Here, we report a challenging case of a patient with NF1 who developed refractory intracranial hemorrhage and cerebral edema requiring three surgical interventions.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eThis case report was prepared in accordance with the CARE (Case Reports) guidelines [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. The patient's medical records, including daily progress notes, operative reports, imaging studies, and laboratory results, were retrospectively reviewed. Serial coagulation testing was performed at clinically indicated time points throughout the hospital course. All data were de-identified to protect patient privacy.\u003c/p\u003e\u003cp\u003eA literature search was conducted using PubMed and Web of Science databases (up to March 2026) with the following keywords: \"neurofibromatosis type 1\", \"intracranial hemorrhage\", \"cerebral edema\", \"vascular dysplasia\", and \"decompressive craniectomy\". Only peer-reviewed articles published in English were considered.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003e \u003cstrong\u003eNote\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eAll days are counted from admission (Day 1 = January 31, 2026).\u003c/p\u003e\u003cp\u003eA 44-year-old male with known NF1 since childhood presented with acute neurological deterioration. His medical history included multiple café-au-lait spots, cutaneous neurofibromas, and learning disabilities consistent with NF1 [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. Family history was notable for his mother having NF1, confirming autosomal dominant inheritance [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. Physical examination revealed multiple café-au-lait spots (\u0026gt; 15 mm) on the trunk and extremities, numerous cutaneous neurofibromas, and axillary freckling (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eG-H). Neurological examination showed a Glasgow Coma Scale (GCS) score of 8 (E2V2M4), with decorticate posturing on the right side and purposeful movements on the left.\u003c/p\u003e\u003cp\u003eEmergency non-contrast head CT revealed bilateral frontal intracerebral hematomas (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA-B). The right frontal hematoma measured approximately 40 mL with significant mass effect, including compression of the right frontal horn and midline shift of 8 mm to the left. The left frontal hematoma measured approximately 25 mL with mild mass effect. CT angiography showed no evidence of aneurysms, vascular malformations, or large vessel occlusion (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eE-F). Three-dimensional reconstructed CT images of the skull revealed a congenital defect/absence of the left parietal bone (red arrows, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA-D), a characteristic skeletal manifestation of NF1 [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e], and bilateral parietal bone fractures (white arrows) resulting from the fall.\u003c/p\u003e\u003cp\u003eInitial laboratory investigations showed normal coagulation parameters except for mild hypofibrinogenemia (FIB 1.48 g/L) and marked elevation of FDP (99.37 µg/mL) and D-dimer (42.16 µg/mL) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), consistent with local consumption following acute hemorrhage rather than a primary coagulopathy.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab1\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerial coagulation profiles during the clinical course\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003eParameter (Unit)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eNormal Range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eDay 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eDay 5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eDay 13\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eDay 23\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAPTT (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e24.5–42.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e30.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e25.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e27.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e36.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003ePT (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e8.8–14.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e12.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e13.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e10.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.8–1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFIB (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e2.0–4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e1.48 ↓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4.62 ↑\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4.76 ↑\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e2.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eTT (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e10.3–18.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e16.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e11.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e12.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e19.8 ↑\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFDP (µg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0–5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e99.37↑\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e10.90↑\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e10.96↑\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e109.42↑\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eD-dimer (µg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0–0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e42.16↑\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e4.77↑\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e5.62↑\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e39.92↑\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e↑: above normal range; ↓: below normal range.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: APTT, activated partial thromboplastin time; PT, prothrombin time; INR, international normalized ratio; FIB, fibrinogen; TT, thrombin time; FDP, fibrinogen/fibrin degradation products.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOn Day 2, the patient underwent bilateral frontal craniotomies and hematoma evacuation. Intraoperatively, the dura was thickened and adherent to the underlying brain, consistent with NF1-related dural abnormalities [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Approximately 45 mL of clot was removed from the right frontal lobe and 30 mL from the left. Postoperatively, he was transferred to the neurocritical care unit with an intracranial pressure (ICP) monitor. Initial ICP readings were 25–30 mmHg, managed with propofol sedation and mannitol. Coagulation testing on Day 5 showed a rebound in fibrinogen to 4.62 g/L (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), consistent with a postoperative acute-phase reparative response [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOn Day 4 (two days after the first surgery), the patient developed acute deterioration with right pupillary dilation to 5 mm. CT revealed recurrent bilateral frontal hematomas (right 35 mL, left 20 mL) with significant midline shift (10 mm) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC-D). He underwent emergent reoperation; bleeding originated from multiple small vessels within friable brain tissue, possibly related to NF1-associated parenchymal abnormalities [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition to hematoma evacuation, a right frontal decompressive craniectomy was performed [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. Postoperatively, ICP remained elevated (25–35 mmHg) despite hyperosmolar therapy, sedation, and neuromuscular blockade. CT on Day 10 showed progressive bilateral frontal edema, more severe on the right (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eG-H). Of note, coagulation parameters on Days 5 and 13 were within normal ranges (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), underscoring that rebleeding occurred despite adequate systemic hemostasis—further implicating local vascular fragility as the primary driver [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOn Day 21, the patient acutely deteriorated again. CT revealed new hemorrhages in the right frontal lobe (30 mL) and left frontal lobe (15 mL), with worsening edema and midline shift (12 mm) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eK-L). A third surgical intervention was performed, with evacuation of bilateral frontal hematomas. The brain tissue was extremely friable with diffuse oozing. A bilateral frontal decompressive craniectomy was performed for maximal brain relaxation [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. Postoperatively, ICP remained elevated despite maximal therapy, and the patient developed progressive multi-organ failure. After extensive discussion with the family, the decision was made to transition to comfort measures only [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. The patient was extubated and passed away peacefully the following day (Day 22). Coagulation testing on Day 23 showed prolonged thrombin time (19.8 s), decreased FIB (2.07 g/L), and marked re-elevation of FDP (109.42 µg/mL) and D-dimer (39.92 µg/mL) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), indicating acute consumptive coagulopathy secondary to massive recurrent hemorrhage [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe pathophysiology of intracranial hemorrhage in NF1 patients involves NF1 gene mutations leading to loss of neurofibromin function, resulting in constitutive activation of the Ras-MAPK signaling pathway [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This causes excessive proliferation of vascular smooth muscle cells and vessel wall dysplasia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], affecting both large and small vessels and leading to abnormalities including stenosis, aneurysms, and arteriovenous malformations [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In our patient, recurrent hemorrhages likely resulted from underlying vascular dysplasia, which increased vessel fragility and impaired hemostasis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Intraoperative findings of friable brain tissue and difficulty achieving hemostasis support this.\u003c/p\u003e \u003cp\u003eSerial coagulation profiles provided critical insights: initial changes (decreased FIB, elevated FDP/D-dimer) reflected local consumption from acute hemorrhage, ruling out primary coagulopathy. The terminal coagulopathy (prolonged TT, decreased FIB, marked elevation of FDP/D-dimer) indicated acute consumptive coagulopathy secondary to massive recurrent hemorrhage, exacerbating bleeding and contributing to irreversible deterioration. Refractory cerebral edema may be related to blood-brain barrier disruption, increased vascular permeability, and impaired astrocytic function in NF1 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSurgical management of intracranial hemorrhage in NF1 patients presents unique challenges. First, abnormal anatomy\u0026mdash;thickened and adherent dura\u0026mdash;complicates dural opening and closure [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Second, vascular dysplasia leads to friable vessels that are difficult to coagulate, resulting in increased intraoperative bleeding [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Third, NF1 patients have an increased risk of rebleeding due to underlying vascular abnormalities [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Notably, despite normalization of coagulation parameters after the first surgery (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Days 5 and 13), rebleeding still occurred\u0026mdash;strongly suggesting that local vascular fragility, rather than systemic coagulopathy, was the predominant mechanism [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Decompressive craniectomy was ultimately necessary to address refractory ICP elevation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMedical management of increased ICP in NF1 patients is particularly challenging. Conventional therapies\u0026mdash;osmotic diuretics, hypertonic saline, sedation\u0026mdash;may be less effective due to underlying pathophysiology [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Contributing factors likely include impaired cerebrovascular autoregulation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], blood-brain barrier disruption leading to vasogenic edema resistant to therapy [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and hydrocephalus requiring external ventricular drainage.\u003c/p\u003e \u003cp\u003eOur case shares similarities with previously reported NF1 patients with intracranial hemorrhage. Hayashi et al. described a patient with NF1 who developed repeated intracerebral hemorrhage due to quasi-moyamoya disease [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and Uchida et al. reported a patient with NF1 and subarachnoid hemorrhage due to multiple de novo aneurysms [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A recent pediatric case series further characterized the spectrum of vascular abnormalities in NF1 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Moreover, emerging evidence on surgical revascularization in children with NF1-associated moyamoya syndrome suggests that timely intervention may prevent neurological complications in selected cases, underscoring the potential benefits of early detection of cerebrovascular pathology [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis case offers several key clinical insights. First, early recognition of NF1 and its cerebrovascular complications is crucial; patients with NF1 should undergo regular screening for vascular abnormalities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Second, surgical management requires expertise in handling abnormal anatomy, increased bleeding risk, and difficulty achieving hemostasis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]; decompressive craniectomy should be considered early if medical ICP management fails [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Third, multi-modal ICP management is often necessary, and refractory intracranial hypertension should prompt early surgical intervention [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Fourth, serial coagulation monitoring helps distinguish local consumption from terminal consumptive coagulopathy, guiding targeted hemostatic interventions. Fifth, prognosis for NF1 patients with severe intracranial hemorrhage is generally poor; early involvement of palliative care and honest communication with families are essential [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003eThis case report has several limitations. First, post-mortem examination was not performed due to religious reasons, precluding histopathological confirmation of the underlying vascular pathology. Second, molecular testing of the resected tissue was not available, which could have provided insights into potential genotype-phenotype correlations. Third, while serial coagulation monitoring was performed, intracranial pressure monitoring was not continuous throughout the entire hospital course due to removal of the ICP monitor after the second surgery.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case describes a challenging NF1 patient with refractory intracranial hemorrhage and cerebral edema requiring three craniotomies. The clinical course highlights the unique challenges in managing NF1 patients with intracranial hemorrhage, including increased bleeding risk, difficulty achieving hemostasis, and poor response to conventional therapies. Serial coagulation profiles provided critical insights into dynamic coagulation changes associated with acute hemorrhage, surgical intervention, and terminal deterioration. The pathophysiology involves vascular dysplasia, increased vessel fragility, and impaired blood-brain barrier function [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Optimal management requires a multidisciplinary approach with expertise in vascular dysplasia, coagulopathy, and neurocritical care.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e \u003cp\u003eThis study was reviewed and approved by the Institutional Review Board of Cangzhou People's Hospital (Approval No. K2025-156-05, approved January 13, 2026). All procedures adhered to the ethical standards of the institutional committee and the 1964 Helsinki Declaration.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from the patient's legal next-of-kin for the publication of this case report and any accompanying images.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests:\u003c/strong\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis work was supported by the 2026 Medical Science Research Project of Hebei Provincial Health Commission (Grant No. 20261342). The funder had no role in the study design, data collection, analysis, or manuscript preparation.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYW conceptualized the study, collected and analyzed the clinical data, performed the literature review, and drafted and revised the manuscript. QF and CW contributed to data collection and manuscript revision. ZQ contributed to the analysis of imaging data and provided critical review of the radiological findings. All authors approved the final version.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLee TJ, Chopra M, Kim RH, Parkin PC, Barnett-Tapia C. Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis. 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Childs Nerv Syst. 2024;40(6):1731\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00381-024-06304-z\u003c/span\u003e\u003cspan address=\"10.1007/s00381-024-06304-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neurofibromatosis type 1, Intracerebral hemorrhage, Vascular dysplasia, Decompressive craniectomy","lastPublishedDoi":"10.21203/rs.3.rs-9212728/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9212728/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cerebrovascular abnormalities, including an increased risk of intracranial hemorrhage. We present a 44-year-old male with confirmed NF1 who developed fulminant recurrent bilateral frontal intracerebral hemorrhage, requiring three emergency craniotomies over a 22-day period. Despite aggressive surgical and medical management, he developed recurrent hemorrhages and refractory cerebral edema, ultimately leading to death after the family elected to transition to comfort measures only. Serial coagulation profiles showed dynamic changes consistent with acute hemorrhage, postoperative reparative responses, and terminal consumptive coagulopathy. This case highlights the complex management challenges in NF1 patients with intracranial hemorrhage, where underlying vascular dysplasia may contribute to refractory hemorrhage and edema, requiring specialized approaches. Early recognition of NF1-associated cerebrovascular complications, aggressive multidisciplinary care, and serial coagulation monitoring are crucial for optimizing outcomes in these high-risk patients.\u003c/p\u003e","manuscriptTitle":"Fulminant recurrent intracerebral hemorrhage in neurofibromatosis type 1: A case report with clinical insights","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 09:37:11","doi":"10.21203/rs.3.rs-9212728/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f1c5b3da-b725-41cb-998a-24265ab1eb34","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-22T08:26:51+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 09:37:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9212728","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9212728","identity":"rs-9212728","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}