BRIEF NOTE
Dear Editor,
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide in all ages. While much is known about the acute and subacute phases of TBI, a critical dimension remains underexplored: the brain’s vulnerability to re-injury1,2, particularly in individuals with preexisting brain damage, either due to prior trauma or underlying medical conditions. Emerging evidence suggests that traumatic brain injury induces persistent neuroinflammatory, glymphatic, and neurovascular alterations that may increase susceptibility to subsequent neurological insults3-5. In clinical practice, some patients present not only with a new neurotrauma but with a brain that has already been structurally or functionally compromised. The interaction between the prior insult and a new traumatic event may lead to disproportionate neurological deterioration, delayed recovery, or persistent deficits1,2. Persistent axonal injury, chronic microglial priming, and impaired metabolic clearance may amplify secondary injury cascades even after relatively minor trauma6-8. Yet, current neurotrauma guidelines rarely address this vulnerability. This paper aims to introduce and define the concept of “vulnerability to reinjury” in neurotrauma, propose a classification framework, and discuss its implications for prevention, monitoring, and clinical decision-making.
Dear Editor,
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide in all ages. While much is known about the acute and subacute phases of TBI, a critical dimension remains underexplored: the brain’s vulnerability to re-injury1,2, particularly in individuals with preexisting brain damage, either due to prior trauma or underlying medical conditions. Emerging evidence suggests that traumatic brain injury induces persistent neuroinflammatory, glymphatic, and neurovascular alterations that may increase susceptibility to subsequent neurological insults3-5. In clinical practice, some patients present not only with a new neurotrauma but with a brain that has already been structurally or functionally compromised. The interaction between the prior insult and a new traumatic event may lead to disproportionate neurological deterioration, delayed recovery, or persistent deficits1,2. Persistent axonal injury, chronic microglial priming, and impaired metabolic clearance may amplify secondary injury cascades even after relatively minor trauma6-8. Yet, current neurotrauma guidelines rarely address this vulnerability. This paper aims to introduce and define the concept of “vulnerability to reinjury” in neurotrauma, propose a classification framework, and discuss its implications for prevention, monitoring, and clinical decision-making.
2. Laurer HL, Bareyre FM, Lee VM, et al. Mild head injury increasing the brain’s vulnerability to a second concussive impact. J Neurosurg. 2001;95(5):859-70. https://doi.org/10.3171/jns.2001.95.5.0859. PMid:11702878.
3. Yang Z, Li P, Wei J. Perceiving traumatic brain injury from glymphatic system. Mol Psychiatry. 2025;30(11):5546-62. https://doi.org/10.1038/ s41380-025-03126-6. PMid:40745390.
4. Kaniuk JK, Kumar D, Mazurek C, et al. From acute injury to chronic neurodegeneration: molecular mechanisms linking secondary brain injury to long-term pathology. Int J Mol Sci. 2025;26(15):7191. https://doi.org/10.3390/ijms2615719 . PMid:40806328.
5. Katramadou A, Bender ES, Kanakis D. from traumatic brain injury to Alzheimer’s disease: multilevel biomechanical, neurovascular, and molecular mechanisms with emerging therapeutic directions. Int J Mol Sci. 2026;27(3):1570. https://doi.org/10.3390/ijms27031570. PMid:41683989.
6. Bi D, Gao B, Shen Y, Dai Z, Yang S, Wang L. Traumatic brain injury and neurodegenerative diseases: the role of axonal injury and amyloid-β. Brain Res. 2025;1865:149873. https://doi.org/10.1016/j. brainres.2025.149873. PMid:40784618.
7. Zhu L, Huang S, Chen W, Li K, Sheng J. Cytokines and related signaling pathways in traumatic brain injury. Front Immunol. 2026;17:1738589. https://doi.org/10.3389/fimmu.2026.1738589. PMid:41756282.
8. Barker RB, Karakaya E, Baran D, et al. The glymphatic and meningeal lymphatic systems may converge, connecting traumatic brain injury progression with chronic traumatic encephalopathy onset. Mol Cell Neurosci. 2025;134:104031. https://doi.org/10.1016/j.mcn.2025.104031. PMid:40713001.
9. Simmonds E, Han J, Kirov G, Sharp DJ, Massey TH, Escott-Price V. Dementia risk due to traumatic brain injury in subtypes of dementia in the welsh population. Neurology. 2025;105(3):e213866. https://doi. org/10.1212/WNL.0000000000213866. PMid:40609060.
10. Edwards S, Corrigan F, Collins-Praino L. Lasting impact: exploring the brain mechanisms that link traumatic brain injury to Parkinson’s Disease. Mol Neurobiol. 2025;62(6):7421-44. https://doi.org/10.1007/ s12035-025-04706-x. PMid:39891816.
11. Howarth NE, Ji C, Batten J, et al. Neurodegenerative Disease and Association Football (NDAF): systematic review and meta-analysis. Int J Environ Res Public Health. 2025;22(5):806. https://doi.org/10.3390/ ijerph22050806. PMid:40427919.
12. Brett BL, Sullivan ME, Asken BM, Terry DP, Meier TB, McCrea MA. Long-term neurobehavioral and neuroimaging outcomes in athletes with prior concussion(s)and head impact exposure. Clin Neuropsychol. 2025;39(8):2220-48. https://doi.org/10.1080/13854046.2024.2442427.
PMid:39797596.
1Department of Neurosurgery, AV Healthcare Innovators, LLC; Madison, WI, United States.
2 The National Brain Aneurysm & Tumor Center, Minneapolis, United States.
3 Department of Neurosurgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India.
4 Neurosurgery Research, Mahatma Gandhi Mission Institute of Health Sciences, Maharashtra, Mumbai, India.
Department of Neurosurgery, AV Healthcare Innovators, LLC; Madison, WI, United States.
The National Brain Aneurysm & Tumor Center, Minneapolis, United States.
Department of Neurosurgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India.
Neurosurgery Research, Mahatma Gandhi Mission Institute of Health Sciences, Maharashtra, Mumbai, India.
