The post-traumatic confusional state (PTCS) is a period of recovery that follows traumatic brain injury (TBI), characterized by post-traumatic amnesia (PTA), impairments in attention, and behavioral dysregulation, among other clinical symptoms. The pathophysiology of PTCS is unknown, contributing to the absence of neurobiologically based diagnostic criteria, prognostic models, and treatments. The workgroup conducted a scoping review of the literature in MEDLINE/PubMed database and manual searches of references to synthesize the existing knowledge on structural, functional, electroencephalographic (EEG), molecular, and genetic biomarkers underlying PTCS diagnosis and prognosis through five Population, Intervention, Comparison, and Outcome (PICO) questions. The search yielded 3,333 abstracts of which 69 were retained and included. Teams of two workgroup members independently reviewed abstracts and articles. Most articles addressed whether biomarkers differentiated patients with PTCS/PTA from those not in PTCS/PTA, and whether biomarkers were associated with severity or duration of PTCS/PTA. Our findings suggest that transition through PTCS/PTA from lower to higher states of consciousness involves increased thalamic function, restoration of default mode network dynamics, and normalizing of excessive slow wave activity on quantitative EEG. For patients with mild TBI, PTCS/PTA was associated with greater TBI lesion burden on structural imaging. PTCS/PTA severity and duration were associated with lesion burden, reduced white matter integrity, and electrophysiological signatures. Results across studies were variable with many finding no relationship between PTCS/PTA and biomarkers. In summary, while it is premature to include biomarkers in the definition of PTCS/PTA, our findings provide avenues for future research that is designed specifically to address the pathophysiology of this condition.
ShererM, KatzDI, BodienYG, et al.Post-traumatic confusional state: A case definition and diagnostic criteria. Arch Phys Med Rehabil, 2020; 101(11):2041–2050.
2.
PovlishockJT, KatzDI. Update of neuropathology and neurological recovery after traumatic brain injury. J Head Trauma Rehabil, 2005; 20(1):76–94.
3.
GiacinoJT, FinsJJ, LaureysS, et al.Disorders of consciousness after acquired brain injury: The state of the science. Nat Rev Neurol, 2014; 10(2):99–114.
4.
KatzDI, PolyakM, CoughlanD, et al.Natural history of recovery from brain injury after prolonged disorders of consciousness: Outcome of patients admitted to inpatient rehabilitation with 1-4 year follow-up. Prog Brain Res, 2009; 177:73–88.
5.
PonsfordJ, CarrierS, HicksA, et al.Assessment and management of patients in the acute stages of recovery after traumatic brain injury in adults: A worldwide survey. J Neurotrauma, 2021; 38(8):1060–1067.
6.
HagenC, MalkmusD, DurhamP. Levels of cognitive functioning. Downey, CA: Ranchos Los Amigos Hospital; 1972.
7.
StussDT, BinnsMA, CarruthFG, et al.The acute period of recovery from traumatic brain injury: Posttraumatic amnesia or posttraumatic confusional state? J Neurosurg, 1999; 90(4):635–643.
8.
TriccoAC, LillieE, ZarinW, et al.PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Ann Intern Med, 2018; 169(7):467–473.
ShererM, Nakase-ThompsonR, YablonSA, et al.Multidimensional assessment of acute confusion after traumatic brain injury. Arch Phys Med Rehabil, 2005; 86(5):896–904.
11.
OldhamMA, MacLullichA, SlooterAJC. Posttraumatic confusional state: Delirium by another name. Arch Phys Med Rehabil, 2021; 102(2):338–339.
12.
ShererM, KatzDI, BodienYG. Seeking clarity about confusion. Arch Phys Med Rehabil, 2021; 102(2):339–340.
13.
PetersMD, GodfreyCM, KhalilH, et al.Guidance for conducting systematic scoping reviews. Int J Evid Based Healthc, 2015; 13(3):141–146.
14.
StenderJ, KupersR, RodellA, et al.Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients. J Cereb Blood Flow Metab, 2015; 35(1):58–65.
15.
García-PanachJ, LullN, LullJJ, et al.A voxel-based analysis of FDG-PET in traumatic brain injury: Regional metabolism and relationship between the thalamus and cortical areas. J Neurotrauma, 2011; 28(9):1707–1717.
16.
LullN, NoéE, LullJJ, et al.Voxel-based statistical analysis of thalamic glucose metabolism in traumatic brain injury: Relationship with consciousness and cognition. Brain Inj, 2010; 24(9):1098–1107.
17.
ThrelkeldZD, BodienYG, RosenthalES, et al.Functional networks reemerge during recovery of consciousness after acute severe traumatic brain injury. Cortex, 2018; 106:299–308.
18.
BodartO, GosseriesO, WannezS, et al.Measures of metabolism and complexity in the brain of patients with disorders of consciousness. Neuroimage Clin, 2017; 14:354–362.
19.
EdlowBL, ChatelleC, SpencerCA, et al.Early detection of consciousness in patients with acute severe traumatic brain injury. Brain, 2017; 140(9):2399–2414.
20.
HaugerSL, OlafsenK, SchnakersC, et al.Cognitive event-related potentials during the sub-acute phase of severe traumatic brain injury and their relationship to outcome. J Neurotrauma, 2017; 34(22):3124–3133.
21.
DietrichAM, BowmanMJ, Ginn-PeaseME, et al.Pediatric head injuries: Can clinical factors reliably predict an abnormality on computed tomography? Ann Emerg Med, 1993; 22(10):1535–1540.
22.
De SimoniS, GroverPJ, JenkinsPO, et al.Disconnection between the default mode network and medial temporal lobes in post-traumatic amnesia. Brain, 2016; 139(Pt 12):3137–3150.
23.
ShahSA, MohamadpourM, AskinG, et al.Focal electroencephalographic changes index post-traumatic confusion and outcome. J Neurotrauma, 2017; 34(19):2691–2699.
24.
MallasEJ, GorgoraptisN, DautricourtS, et al.Pathological slow-wave activity and impaired working memory binding in post-traumatic amnesia. J Neurosci, 2022; 42(49):9193–9210.
25.
PapanicolaouAC, LevinHS, EisenbergHM, et al.Evoked potential correlates of posttraumatic amnesia after closed head injury. Neurosurgery, 1984; 14(6):676–678.
26.
OlbrichHM, NauHE, LodemannE, et al.Evoked potential assessment of mental function during recovery from severe head injury. Surg Neurol, 1986; 26(2):112–118.
27.
NekrosiusD, KaminskaiteM, JokubkaR, et al.Association of COMT Val(158)Met polymorphism with delirium risk and outcomes after traumatic brain injury. J Neuropsychiatry Clin Neurosci, 2019; 31(4):298–305.
28.
LapierreA, ProulxA, GélinasC, et al.Association between pupil light reflex and delirium in adults with traumatic brain injury: Preliminary findings. J Neurosci Nurs, 2024; 56(4):107–112.
29.
KinuyaK, KakudaK, NobataK, et al.Role of brain perfusion single-photon emission tomography in traumatic head injury. Nucl Med Commun, 2004; 25(4):333–337.
30.
SmitsM, HuninkMGM, NederkoornPJ, et al.A history of loss of consciousness or post-traumatic amnesia in minor head injury: “conditio sine qua non” or one of the risk factors? J Neurol Neurosurg Psychiatry, 2007; 78(12):1359–1364.
31.
UchinoY, OkimuraY, TanakaM, et al.Computed tomography and magnetic resonance imaging of mild head injury–Is it appropriate to classify patients with Glasgow Coma Scale score of 13 to 15 as “mild injury”? Acta Neurochir (Wien), 2001; 143(10):1031–1037.
32.
FotakopoulosG, MakrisD, TsianakaE, et al.The value of the identification of predisposing factors for post-traumatic amnesia in management of mild traumatic brain injury. Brain Inj, 2018; 32(5):563–568.
33.
KumagawaT, OtakiR, MaedaT, et al.Consideration of brain CT imaging standard for mild head injuries. Neurol Med Chir (Tokyo), 2024; 64(6):247–252.
34.
SakkasA, WeißC, WildeF, et al.Justification of indication for cranial CT imaging after mild traumatic brain injury according to the current national guidelines. Diagnostics (Basel), 2023; 13(11):1826.
35.
HaydelMJ, PrestonCA, MillsTJ, et al.Indications for computed tomography in patients with minor head injury. N Engl J Med, 2000; 343(2):100–105.
36.
HuangS, LiM, HuangC, et al.Acute limbic system connectivity predicts chronic cognitive function in mild traumatic brain injury: An individualized differential structural covariance network study. Pharmacol Res, 2024; 206:107274.
37.
GowdaNK, AgrawalD, BalC, et al.Technetium Tc-99m ethyl cysteinate dimer brain single-photon emission CT in mild traumatic brain injury: A prospective study. AJNR Am J Neuroradiol, 2006; 27(2):447–451.
38.
NariaiT, SuzukiR, OhtaY, et al.Focal cerebral hyperemia in postconcussive amnesia. J Neurotrauma, 2001; 18(12):1323–1332.
39.
MettingZ, RodigerLA, de JongBM, et al.Acute cerebral perfusion CT abnormalities associated with posttraumatic amnesia in mild head injury. J Neurotrauma, 2010; 27(12):2183–2189.
40.
ReyesJ, SpitzG, MajorBP, et al.Utility of acute and subacute blood biomarkers to assist diagnosis in CT-negative isolated mild traumatic brain injury. Neurology, 2023; 101(20):e1992–e2004.
41.
FlesherMR, DelahantyDL, RaimondeAJ, et al.Amnesia, neuroendocrine levels and PTSD in motor vehicle accident victims. Brain Inj, 2001; 15(10):879–889.
42.
MitraB, RauTF, SurendranN, et al.Plasma micro-RNA biomarkers for diagnosis and prognosis after traumatic brain injury: A pilot study. J Clin Neurosci, 2017; 38:37–42.
43.
SabooriM, AhmadiJ, FarajzadeganZ. Indications for brain CT scan in patients with minor head injury. Clin Neurol Neurosurg, 2007; 109(5):399–405.
44.
BorgaroSR, PrigatanoGP, KwasnicaC, et al.Cognitive and affective sequelae in complicated and uncomplicated mild traumatic brain injury. Brain Inj, 2003; 17(3):189–198.
45.
PalchakMJ, HolmesJF, VanceCW, et al.Does an isolated history of loss of consciousness or amnesia predict brain injuries in children after blunt head trauma? Pediatrics, 2004; 113(6):e507-13–e513.
46.
HaugE, MinerJ, DannehyM, et al.Bispectral electroencephalographic analysis of head-injured patients in the emergency department. Acad Emerg Med, 2004; 11(4):349–352.
47.
YueJK, RobinsonCK, BurkeJF, et al.; TRACK‐TBI Investigators. Apolipoprotein E epsilon 4 (APOE-epsilon4) genotype is associated with decreased 6-month verbal memory performance after mild traumatic brain injury. Brain Behav, 2017; 7(9):e00791.
48.
AldossaryNM, KotbMA, KamalAM. Predictive value of early MRI findings on neurocognitive and psychiatric outcomes in patients with severe traumatic brain injury. J Affect Disord, 2019; 243:1–7.
49.
ChoiJY, HartT, WhyteJ, et al.Myelin water imaging of moderate to severe diffuse traumatic brain injury. Neuroimage Clin, 2019; 22:101785.
50.
HåbergAK, OlsenA, MoenKG, et al.White matter microstructure in chronic moderate-to-severe traumatic brain injury: Impact of acute-phase injury-related variables and associations with outcome measures. J of Neuroscience Research, 2015; 93(7):1109–1126.
51.
ChoMJ, JangSH. Relationship between post-traumatic amnesia and white matter integrity in traumatic brain injury using tract-based spatial statistics. Sci Rep, 2021; 11(1):6898.
52.
LevinHS, O’DonnellVM, GrossmanRG. The Galveston orientation and amnesia test: A practical scale to assess cognition after head injury. J Nerv Ment Dis, 1979; 167(11):675–684.
53.
TellierA, MarshallSC, WilsonKG, et al.The heterogeneity of mild traumatic brain injury: Where do we stand? Brain Inj, 2009; 23(11):879–887.
54.
BrezovaV, MoenKG, SkandsenT, et al.Prospective longitudinal MRI study of brain volumes and diffusion changes during the first year after moderate to severe traumatic brain injury. Neuroimage Clin, 2014; 5:128–140.
55.
MazwiNL, IzzyS, TanCO, et al.Traumatic microbleeds in the hippocampus and corpus callosum predict duration of posttraumatic amnesia. J Head Trauma Rehabil, 2019; 34(6):E10–E18.
56.
GerberDJ, WeintraubAH, CusickCP, et al.Magnetic resonance imaging of traumatic brain injury: Relationship of T2*SE and T2GE to clinical severity and outcome. Brain Inj, 2004; 18(11):1083–1097.
57.
WilsonLD, MaigaAW, LombardoS, et al.Prevalence and risk factors for intensive care unit delirium after traumatic brain injury: A retrospective cohort study. Neurocrit Care, 2023; 38(3):752–760.
58.
FujimotoG, UbukataS, SugiharaG, et al.A model for estimating the brainstem volume in normal healthy individuals and its application to diffuse axonal injury patients. Sci Rep, 2023; 13(1):33.
59.
SchonbergerM, PonsfordJ, ReutensD, et al.The Relationship between age, injury severity, and MRI findings after traumatic brain injury. J Neurotrauma, 2009; 26(12):2157–2167.
60.
WildeEA, BiglerED, PedrozaC, et al.Post-traumatic amnesia predicts long-term cerebral atrophy in traumatic brain injury. Brain Inj, 2006; 20(7):695–699.
61.
van der NaaltJ, van ZomerenAH, SluiterWJ, et al.Acute behavioural disturbances related to imaging studies and outcome in mild-to-moderate head injury. Brain Inj, 2000; 14(9):781–788.
62.
LevinHS, AmparoE, EisenbergHM, et al.Magnetic resonance imaging and computerized tomography in relation to the neurobehavioral sequelae of mild and moderate head injuries. J Neurosurg, 1987; 66(5):706–713.
63.
SidarosA, SkimmingeA, LiptrotMG, et al.Long-term global and regional brain volume changes following severe traumatic brain injury: A longitudinal study with clinical correlates. Neuroimage, 2009; 44(1):1–8.
64.
WareJB, DoluiS, DudaJ, et al.Relationship of cerebral blood flow to cognitive function and recovery in early chronic traumatic brain injury. J Neurotrauma, 2020; 37(20):2180–2187.
65.
LorberboymM, LamplY, GerzonI, et al.Brain SPECT evaluation of amnestic ED patients after mild head trauma. Am J Emerg Med, 2002; 20(4):310–313.
66.
GarnettMR, BlamireAM, CorkillRG, et al.Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. Brain, 2000; 123 (Pt 10):2046–2054.
67.
StulemeijerM, VosPE, van der WerfS, et al.How mild traumatic brain injury may affect declarative memory performance in the post-acute stage. J Neurotrauma, 2010; 27(9):1585–1595.
68.
WattSE, ShoresEA, BaguleyIJ, et al.Protein S-100 and neuropsychological functioning following severe traumatic brain injury. Brain Inj, 2006; 20(10):1007–1017.
69.
BogoslovskyT, WilsonD, ChenY, et al.Increases of plasma levels of Glial fibrillary acidic protein, tau, and amyloid beta up to 90 days after traumatic brain injury. J Neurotrauma, 2017; 34(1):66–73.
70.
HanksR, MillisS, ScottS, et al.The relation between cognitive dysfunction and diffusion tensor imaging parameters in traumatic brain injury. Brain Inj, 2019; 33(3):355–363.
71.
MohammadianM, RoineT, HirvonenJ, et al.High angular resolution diffusion-weighted imaging in mild traumatic brain injury. Neuroimage Clin, 2017; 13:174–180.
72.
ShererM, StruchenMA, YablonSA, et al.Comparison of indices of traumatic brain injury severity: Glasgow coma scale, length of coma and post-traumatic amnesia. J Neurol Neurosurg Psychiatry, 2008; 79(6):678–685.
73.
Holli-HeleniusK, LuotoTM, BranderA, et al.Structural integrity of medial temporal lobes of patients with acute mild traumatic brain injury. J Neurotrauma, 2014; 31(13):1153–1160.
74.
LevinHS, WilliamsDH, EisenbergHM, et al.Serial MRI and neurobehavioural findings after mild to moderate closed head injury. J Neurol Neurosurg Psychiatry, 1992; 55(4):255–262.
75.
KoufenH, HagelKH. Systematic EEG follow-up study of traumatic psychosis. Eur Arch Psychiatry Neurol Sci, 1987; 237(1):2–7.
76.
PonsfordJ, RudzkiD, BaileyK, et al.Impact of apolipoprotein gene on cognitive impairment and recovery after traumatic brain injury. Neurology, 2007; 68(8):619–620.
77.
PonsfordJ, McLarenA, SchönbergerM, et al.The association between apolipoprotein E and traumatic brain injury severity and functional outcome in a rehabilitation sample. J Neurotrauma, 2011; 28(9):1683–1692.
78.
NoeE, FerriJ, ColomerC, et al.APOE genotype and verbal memory recovery during and after emergence from post-traumatic amnesia. Brain Inj, 2010; 24(6):886–892.
79.
ChamelianL, ReisM, FeinsteinA. Six-month recovery from mild to moderate traumatic brain injury: The role of APOE-epsilon4 allele. Brain, 2004; 127(Pt 12):2621–2628.
80.
WillmottC, WithielT, PonsfordJ, et al.COMT Val158Met and cognitive and functional outcomes after traumatic brain injury. J Neurotrauma, 2014; 31(17):1507–1514.
81.
WilsonJT, PettigrewLE, TeasdaleGM. Structured interviews for the glasgow outcome scale and the extended glasgow outcome scale: Guidelines for their use. J Neurotrauma, 1998; 15(8):573–585.
82.
ShererM, HartT, WhyteJ, et al.Neuroanatomic basis of impaired self-awareness after traumatic brain injury: Findings from early computed tomography. J Head Trauma Rehabil, 2005; 20(4):287–300.
83.
LeskinenS, MehtaNH, ShahHA, et al.Functional connectivity changes in traumatic brain injury: A systematic review and coordinate-based meta-analysis of fMRI studies. Neurology, 2025; 105(9):e214298.
84.
Falletta CaravassoC, de PasqualeF, CiurliP, et al.The default mode network connectivity predicts cognitive recovery in severe acquired brain injured patients: A longitudinal study. J Neurotrauma, 2016; 33(13):1247–1262.
85.
Fernández-EspejoD, SodduA, CruseD, et al.A role for the default mode network in the bases of disorders of consciousness. Ann Neurol, 2012; 72(3):335–343.
86.
SchiffND. Posterior medial corticothalamic connectivity and consciousness. Ann Neurol, 2012; 72(3):305–306.
87.
FleischmannR, TraenknerS, KraftA, et al.Delirium is associated with frequency band specific dysconnectivity in intrinsic connectivity networks: Preliminary evidence from a large retrospective pilot case-control study. Pilot Feasibility Stud, 2019; 5:2.
88.
van MontfortSJT, van DellenE, van den BoschAMR, et al.Resting-state fMRI reveals network disintegration during delirium. Neuroimage Clin, 2018; 20:35–41.
89.
ChoiS-H, LeeH, ChungT-S, et al.Neural network functional connectivity during and after an episode of delirium. Am J Psychiatry, 2012; 169(5):498–507.
90.
KoponenH, PartanenJ, PaakkonenA, et al.EEG spectral analysis in delirium. J Neurol Neurosurg Psychiatry, 1989; 52(8):980–985.
91.
PantelatosRI, SkandsenT, FollestadT, et al.Prediction of outcome in moderate and severe traumatic brain injury: The value of pragmatic estimation of the duration of posttraumatic confusional state. Arch Rehabil Res Clin Transl, 2025; 7(3):100446.
92.
HartT, NovackTA, TemkinN, et al.Duration of posttraumatic amnesia predicts neuropsychological and global outcome in complicated mild traumatic brain injury. J Head Trauma Rehabil, 2016; 31(6):E1–E9.
93.
PonsfordJL, SpitzG, McKenzieD. Using post-traumatic amnesia to predict outcome after traumatic brain injury. J Neurotrauma, 2016; 33(11):997–1004.
94.
WalkerWC, StrombergKA, MarwitzJH, et al.Predicting long-term global outcome after traumatic brain injury: Development of a practical prognostic tool using the traumatic brain injury model systems national database. J Neurotrauma, 2018; 35(14):1587–1595.
95.
ShererM, YablonSA, Nakase-RichardsonR, et al.Effect of severity of post-traumatic confusion and its constituent symptoms on outcome after traumatic brain injury. Arch Phys Med Rehabil, 2008; 89(1):42–47.
96.
TuureJ, MohammadianM, TenovuoO, et al.Late blood levels of neurofilament light correlate with outcome in patients with traumatic brain injury. J Neurotrauma, 2024; 41(3–4):359–368.
97.
PianconeF, La RosaF, HernisA, et al.Neuroinflammatory signature of post-traumatic confusional state: The role of cytokines in moderate-to-severe traumatic brain injury. Int J Mol Sci, 2025; 26(17):8593.
98.
ManleyGT, Dams-O’ConnorK, AloscoML, et al.; NIH-NINDS TBI Classification and Nomenclature Initiative. A new characterisation of acute traumatic brain injury: The NIH-NINDS TBI classification and nomenclature initiative. Lancet Neurol, 2025; 24(6):512–523.
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