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Open research questions in Intracerebral and Subarachnoid Hemorrhage Research

44 unresolved questions extracted from the limitations and future-work sections of 184 Intracerebral and Subarachnoid Hemorrhage Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Cognitive impairment (CI) is a major contributor to long-term disability following ICH, yet the molecular mechanisms underlying CI in hypertensive ICH remain poorly understood.

    Transcriptome sequencing and validation of potential biomarkers associated with cognitive impairment after hypertensive intracerebral hemorrhage · 2026 · DOI

  • ABSTRACT Background Cerebral microbleeds (CMBs) are a key imaging marker of cerebral amyloid angiopathy (CAA), but their individual spatial distribution and potential clustering remain poorly understood.

    Clustering of Cerebral Microbleeds in Cerebral Amyloid Angiopathy: A Flow Territory‐Based Analysis · 2026 · DOI

  • The arterial flow territory subdivision was chosen, considering the predilection of CMB location in the posterior cortex—not limited to the occipital lobe—and the prominent vascular role in CAA.

    Clustering of Cerebral Microbleeds in Cerebral Amyloid Angiopathy: A Flow Territory‐Based Analysis · 2026 · DOI

  • A neuroimaging-based diagnosis of cerebral amyloid angiopathy can inform decisions about blood-pressure control and judicious use or avoidance of antithrombotic therapies. Similar considerations of risks and benefits apply to the incorporation of cerebral amyloid angiopathy markers into decisions about whether to initiate immunotherapy in patients with Alzheimer's disease. The limited treatment options for cerebral amyloid angiopathy highlight the importance of identifying new approaches to disease modification. The decades-long pathogenic pathway and insidious effects on physiological properties of blood vessel, cognitive function, and intracerebral hemorrhage risk provide a long time window for slowing progression, but only if the early pathogenic steps can be detected and blocked. Potential approaches to slowing the progression of cerebral amyloid angiopathy include reducing Aβ production, enhancing Aβ clearance, and protecting vessels from destructive remodeling triggered by Aβ. Data on blocking production of Aβ may emerge from an ongoing phase 2 trial (ClinicalTrials.gov number, NCT06393712) of a C16-conjugated short interfering RNA targeted to APP, a trial involving persons with symptomatic sporadic cerebral amyloid angiopathy as well as those with presymptomatic or symptomatic Dutch-type cerebral amyloid angiopathy. Determining  Journals (/journals) 53   how and when cerebral amyloid angiopathy can be slowed will inform future progress in ® developing treatments for this small-vessel brain disease.

    Cerebral Amyloid Angiopathy · 2026 · DOI

  • Whether its elevation is related to a compensatory protective mechanism during central nervous system inflammation remains to be further clarified. Several limitations of this study should be acknowledged. Therefore, future prospec- tive multicenter studies with larger sample sizes are warranted to further verify the robustness, external generalizability, and clinical applicability of the proposed model, and to further develop subtype- specific prediction models.

    Development and internal validation of a nomogram for predicting neurobrucellosis in hospitalized patients with brucellosis: a single-center retrospective study · 2026 · DOI

  • However, it remains unclear whether neurovascular barrier dysfunction can be captured by routinely available fluid biomarkers and whether such markers identify clinically relevant hemorrhage-prone CAA phenotypes.

    Blood-brain barrier dysfunction in cerebral amyloid angiopathy is associated with disseminated cortical superficial siderosis · 2026 · DOI

  • The novelty of this study lies in its focus on older adults, a clinically vulnerable popula- tion in whom early HE prediction remains insufficiently character- ized, and in its emphasis on variables that can be obtained rapidly in routine stroke care without reliance on advanced imaging, radiomics, or computationally intensive workflows.

    Risk factors and development of a prediction model for hematoma expansion in elderly patients with spontaneous intracerebral hemorrhage · 2026 · DOI

  • Third, methodological inconsistencies in defining risk factors mean that their association with DVT in patients with intracerebral hem- orrhage remains uncertain.

    Risk factors for lower limb deep vein thrombosis in patients with intracerebral hemorrhage: a retrospective study using LASSO regression to develop a nomogram · 2026 · DOI

  • This study is the first to systematically and simultaneously evaluate both the NLR and the CAR, examining their combined predictive value that has not been previously explored.

    Predictive value of NLR combined with CAR in patients with cerebral hemorrhage undergoing maintenance hemodialysis · 2026 · DOI

  • BACKGROUNGBisphenol A (BPA) has been linked to hypertension and disturbances in lipid metabolism; however, limited evidence is available regarding its association with hypertensive intracerebral hemorrhage (ICH).

    The Impact of Dysregulated Lipid Metabolism on the Gut-Brain Axis in Patients with Intracerebral Hemorrhage · 2026 · DOI

  • There are some methodological limitations to be considered. First, this study is an exploratory post hoc analysis. While our results demonstrate strong associations between m-cSVD burden and recurrent stroke risk in hemorrhageprone patients, they should be interpreted as suggesting potential relationships rather than establishing causality. Furthermore, as most prospective clinical trials including PICASSO largely excluded patients who are in poor medical condition or in a functionally dependent state, our study population might not reflect a real-world setting. Second, significant baseline imbalances existed across m-cSVD groups; patients with higher scores were older and had greater clinical and vascular frailty. This disparity, potentially reflecting clinical caution regarding intensive therapy in patients with high hemorrhagic burden, is noteworthy given the established role of statins in secondary prevention. Although we performed multivariable adjustments to mitigate these imbalances, the possibility of residual confounding remains, necessitating a cautious interpretation of the independent prognostic value attributed to the m-cSVD score. Third, the relatively low incidence of hemorrhagic stroke compared to ischemic events might have resulted in insufficient statistical power to provide precise estimates of the association with m-cSVD scores. Consequently, the findings regarding hemorrhagic risk should be interpreted with caution, and larger-scale studies are warranted to further validate these associations. Forth, given that the phenotypes of cSVD markers are heterogeneous and vary according to their numbers, simple scoring of total cSVD by adding a point may jeopardizes the precision of estimates for assessing recurrent stroke risk. A detailed cSVD scoring approach that quantitatively incorporated the severity of each phenotype may be more informative. Fifth, our study did not distinguish between the anatomical locations (deep vs. lobar) of ICH or CMBs, which could reflect different underlying etiologies such as hypertensive arteriopathy and CAA. However, since approximately nine out of ten participants had hypertension, our results may reflect the outcomes of a population with hypertensive arteriopathy. Lastly, the use of a m-cSVD score that excludes EPVS was necessitated by data availability within the PICASSO database, and this modified score has not undergone full external validation. However, WMH, CMBs/ICH, and lacune are considered the core imaging markers in predicting vascular outcomes, which may mitigate the potential impact of excluding EPVS on our primary findings regarding stroke recurrence risk.

    Differential impact of cumulative cerebral small-vessel disease burden on ischemic versus hemorrhagic stroke recurrence in hemorrhage-prone patients · 2026 · DOI

  • Our study has several limitations. First, we did not include SAH-negative head CT scans during the study period, which precluded comprehensive assessment of diagnostic performance. For both Annalise and RapidAI, such analysis would require evaluation of a large number of head CT scans, which is challenging in our hospital’s ED, where approximately 20,000 head CT scans are performed annually. The false-positive rate of Annalise for SAH has been estimated, with a reported specificity of 96.6%.3 During head-to-head comparison, positive results from Annalise may be due to concurrent non-SAH haemorrhage rather than SAH itself, which could inflate the SAH detection rate. Meanwhile, for RapidAI, because the module does not provide ICH segmentation, it is difficult to determine the specific abnormality associated with a positive AI result, thereby hindering accurate assessment of the false-positive rate. Second, the retrospective design may introduce bias and limit the generalisability of our results. Additionally, all scans were acquired from a single CT scanner. Third, the cohort may not fully represent routine clinical imaging because only one scan contained a major artefact; none demonstrated clinically significant motion artefacts, other substantial artefacts, or prior neurosurgical intervention.

    Commercial Artificial Intelligence for Detection of Subarachnoid Haemorrhage on Head Computed Tomography Scans · 2026 · DOI

  • Several limitations of this study should be acknowledged First, the large exclusion rate (73.6%) raises concerns about selection bias. The majority of exclusions were due to missing APACHE IV scores, which require complete physiological data within the first 24 h of ICU admission. Patients with very short ICU stays, rapid deterioration, or transfers may be underrepresented, potentially limiting generalizability to the broader ICH population. The final cohort may overrepresent patients with more stable clini- cal courses who remained in ICU long enough for complete data capture. Second, the retrospective observational design precludes causal inference, and residual confounding cannot be fully excluded. Important clinical variables such as hemorrhage volume, anatomical location, surgical interventions, pre-ICH anticoagulation use, and NIHSS scores were not available. Although we adjusted for GCS and APACHE score, these are imperfect surrogates for neurological sever- ity and ICH characteristics. Third, certain VTE risk factors including prior VTE history and inherited thrombophilia were not available in the database, which may contribute to residual confounding.

    Atrial fibrillation as an independent risk factor for venous thromboembolism in intracerebral hemorrhage patients: a multicenter retrospective cohort study · 2026 · DOI

  • Several methodological and practical limitations should be considered when interpreting the findings of this study. Although the dual-center retrospective design enhanced case ascertainment, the sample size remained relatively small (n = 14), which limits statistical power for subgroup comparisons and may affect the generalizabil- ity of our observations to all phenotypic presentations of Ji et al. BMC Neurology (2026) 26:271 Page 11 of 11 10. Kumar N. Superficial siderosis: a clinical review. Ann Neurol. 2021;89(6):1068–79. 11. Flores Martin A, Shanmugarajah P, Hoggard N, Hadjivassiliou M. Treatment response of deferiprone in infratentorial superficial siderosis: a systematic review. Cerebellum. 2021;20(3):454–61. 12. Gangadharan JS, Vani; Bharath R, Pandey. Paritosh;: Spinal ependymoma pre- senting with visual and hearing impairment – An unusual sequelae. Indian J Neurosurg. 2012;01(02):169–71. 13. Xu L, Hu MJ, Li YY, Qu HD, Qian WD, Liu XL. Superficial siderosis of the central nervous system caused by myxopapillary ependymoma of conus medullaris and cauda equine: a case report and literature review. Beijing Da Xue Xue Bao Yi Xue Ban. 2019;51(4):769–74. 14. Rudrabhatla P, Sabarish S, Nair SS, George T, Divakar G, Sylaja PN. Superficial siderosis due to spinal myxopapillary ependymoma mimicking idiopathic intracranial hypertension. Ann Indian Acad Neurol. 2022;25(1):156–7. 15. Choi KE, Na SH, Jeong HS, Im JJ, Kim YD. Superficial siderosis of the central nervous system due to spinal ependymoma. Ann Geriatr Med Res. 2018;22(1):43–5. 16. Chen H, Raza HK, Jing J, Ye X, Zhang Z, Hua F, Cui G. Superficial siderosis of central nervous system with unknown cause: report of 2 cases and review of the literature. Br J Neurosurg. 2019;33(3):305–8. 17. Kharytaniuk N, Cowley P, Sayal P, Eleftheriou P, Farmer SF, Chan E, Bamiou DE, Werring DJ. Classical infratentorial superficial siderosis of the central nervous system: pathophysiology, clinical features and management. Pract Neurol. 2022;22(4):274-84. 18. Katoh H, Shibukawa S, Yamaguchi K, Hiyama A, Horie T, Sato M, Watanabe M. A combination of magnetic resonance imaging techniques to localize the dural defect in a case of superficial siderosis-a case report. Med (Basel). 2020;7(6):36. 19. Fragoso YD, Adoni T, Brooks JB, Gomes S, Goncalves MV, Jovem CL, Matta AP, Oliveira JF, Siquinelli F, Tauil CB, et al. Superficial siderosis of the central nervous system is a rare and possibly underdiagnosed disorder. Arq Neurop- siquiatr. 2017;75(2):92–5. 20. Cossu G, Abbruzzese G, Forni GL, Matta G, Pinto V, Ruffinengo U, Oppo V, Marchese R. Efficacy and safety of deferiprone for the treatment of superficial siderosis: results from a long-term observational study. Neurol Sci. 2019;40(7):1357–61. 21. Deng L, Lin Y, Lin Y, Huang W. Infratentorial superficial siderosis: report of six cases and review of the literature. Front Neurosci. 2024;18:1373358. 22. Levy M, Llinas RH. Deferiprone reduces hemosiderin deposits in the brain of a patient with superficial siderosis. AJNR Am J Neuroradiol. 2011;32(1):E1–2. 23. Kessler RA, Li X, Schwartz K, Huang H, Mealy MA, Levy M. Two-year obser- vational study of deferiprone in superficial siderosis. CNS Neurosci Ther. 2018;24(3):187–92. 24. Sammaraiee Y, Banerjee G, Farmer S, Hylton B, Cowley P, Eleftheriou P, Porter J, Werring DJ. Risks associated with oral deferiprone in the treatment of infratentorial superficial siderosis. J Neurol. 2020;267(1):239–43. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

    Clinical retrospective analysis of 14 cases of superficial siderosis of the central nervous system · 2026 · DOI

  • The drivers of treatment selection to manage ICH should be further investigated in a separate multicenter study with questionnaires.

    Clinical characteristics and outcomes of intracranial hemorrhage in geriatric patients receiving non–vitamin K antagonist oral anticoagulants: a multicenter observational study · 2026 · DOI

  • Although our study has a multicenter design, and data from different hospitals increased generalizability by covering a wider range of the population, it had some limitations. First, the retrospective design contained the risk of selection bias that may affect the accuracy of the data. The relatively small patient size limited the statistical power, especially in the evaluation of secondary outcomes such as mortality rates. In addition, the lack of standardization of variables such as the timing of 4 F-PCC administration and dose differences of 4 F-PCC may make it difficult to interpret the results. Dif- ferences in the timing of CT scans also limited the objective assessment of hemorrhage volume changes. Lastly, due to Irish Journal of Medical Science (1971 -)1 3 the very small number of patients using Edoxaban and Dab- igatran in our cohort, a detailed comparison of outcomes across all NOAC types could not be performed.

    Clinical characteristics and outcomes of intracranial hemorrhage in geriatric patients receiving non–vitamin K antagonist oral anticoagulants: a multicenter observational study · 2026 · DOI

  • Postoperative ICP management represents a potentially modifiable target, and standardized protocols for ICP control may improve cognitive outcomes, although this hypothesis requires prospective validation.

    Risk factors and nomogram for cognitive impairment after stereotactic drainage of spontaneous intracerebral hemorrhage · 2026 · DOI

  • To validate our results, a prospective multicenter clinical trial involving multiple CT systems from different vendors is needed to assess the generalizability and robustness of the AI algorithm in diverse clinical settings. Similarly, the confidence level adaptation for other diagnostic sites must be reevaluated.

    Diagnostic performance and confidence of an optimized deep-learning algorithm for the detection of intracranial hemorrhages · 2026 · DOI

  • Background: Conflicting data exist regarding the relationship between prior statin use and perihematomal edema (PHE) in patients with intracerebral hemorrhage (ICH).

    Abstract WP122: Effect Of Prior Exposure To Statin Therapy On Clinical And Radiological Features Of Intracerebral Hemorrhage: A Post-hoc Analysis Of The I-def Trial · 2023 · DOI

  • RESULTS: The relationship between low-middle alcohol consumption and ICH remains controversial for various reasons, whereas chronic heavy drinking increases the incidence of ICH and exerts worse outcome.

    Cerebral Hemorrhage and Alcohol Exposure: A Review · 2019 · DOI

  • Criteria for a short-term vital and functional prognosis for cerebral hemorrhagic supratentorial stroke (CHSS) acute period, that would take into account the secondary IVH severity in the onset of the disease, are currently lacking.

    Prediction of cerebral hemorrhagic supratentorial stroke acute period outcome on the basis of the assessment of secondary intraventricular hemorrhage severity in the onset of the disease · 2017 · DOI

  • Background While randomized trials have demonstrated noninferiority of tenecteplase compared with alteplase in terms of functional outcomes and symptomatic intracranial hemorrhage (sICH), differences in hemorrhagic imaging phenotypes remain insufficiently explored in real-world practice.

    Imaging patterns of hemorrhagic transformation after tenecteplase versus alteplase in real-world practice · 2026 · DOI

  • Although pooled data suggest a potential treatment benefit across various types of intracranial hemorrhages and anticoagulants, most hemorrhage subtypes remain insufficiently studied.

    Effect on Mortality of Anticoagulant Reversal in Acute Intracranial Hemorrhage: A Systematic Review and Meta-analysis · 2026 · DOI

  • The dataset does not contain patient outcomes and is limited to adults in the US with Medicare coverage.

    Investigating Intracerebral Hemorrhage Evacuation Procedure Volumes Before and After the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation III (MISTIE III) Trial · 2026 · DOI

  • When critical inputs are missing or uncertain, the agent returns an “insufficient data” state with an explicit list of required variables and assumptions rather than extrapolating.

    An agentic AI framework for integrated decision support and surgical planning in intracerebral hemorrhage · 2026 · DOI

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44 open questions have been extracted from the limitations and future-work passages of 184 Intracerebral and Subarachnoid Hemorrhage Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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