Utility of serum lactate on differential diagnosis of seizure-like activity: A systematic review and meta-analysis

  • Jigar Patel
    Department of Emergency Medicine, George Washington University School of Medicine and Health Sciences, Washington DC, United States
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  • Quincy K. Tran
    Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America

    Program in Trauma, The R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, United States
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  • Santiago Martinez
    Department of Emergency Medicine, George Washington University School of Medicine and Health Sciences, Washington DC, United States
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  • Halley Wright
    Department of Emergency Medicine, George Washington University School of Medicine and Health Sciences, Washington DC, United States
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  • Ali Pourmand
    Corresponding author at: Department of Emergency Medicine, George Washington University School of Medicine and Health Sciences, 2120L St. Washington, DC, 20037, United States.
    Department of Emergency Medicine, George Washington University School of Medicine and Health Sciences, Washington DC, United States
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Published:October 06, 2022DOI:


      • Transient loss of consciousness has a diverse etiology including syncope, orthostatic hypotension, seizures, psychogenic non-epileptic seizures.
      • Serum lactate can be a valuable tool to differentiate generalized tonic-clonic seizures from other forms of transient loss of consciousness.
      • In our study, we found no difference in serum lactate levels in patients with non- generalized tonic-clonic seizure types of transient loss of consciousness, such as syncope, and psychogenic non-epileptic seizures.
      • Serum lactate levels in patients with generalized tonic-clonic seizures were significantly higher than any other cause of transient loss of consciousness, including syncope.


      Introduction: Differentiating epileptic seizures from other causes of Transient Loss of Consciousness (TLOC) remains a challenge in the Emergency Department (ED), where it may lead to erroneous administration of anti-epileptic drugs. Although video electroencephalography (EEG) is the gold standard for diagnosing epileptic seizures, it is not widely available in ED settings. Therefore, simple and quick diagnostic techniques for patients with TLOC in ED are needed. We performed a meta-analysis to review relevant literature and determine the efficacy of serum lactate in differentiating epileptic seizures from other causes of TLOC in the ED setting.
      Methods: We performed a literature search of PubMed and Scopus from inception up to April 2022. Randomized trials and observational (prospective or retrospective) studies reporting lactate levels in adults ≤ 3 h after a TLOC episode were included. The primary outcome of interest was the serum lactate level difference between patients with a generalized tonic-clonic seizures (GTCS) and those with other forms of TLOC. Other outcomes were the differences in serum lactate levels among patients with other types of TLOC, such as psychogenic nonepileptic seizures (PNES), syncope, and non-GTCS. Random-effects meta-analysis was performed to compare the mean difference in serum lactate levels among different types of TLOC. The PROSPERO registration is CRD42022316163.
      Results: We included eight studies (1348 patients) in our analysis. Serum lactate levels from patients who had GTCS were significantly higher than those from patients who had TLOC from any other cause (mean difference 5.27 mmol/L, 95% CI 1.73, 8.81, P = 0.004). Similarly, there was statistically a significant difference in serum lactate between patients with GTCS and non-GTCS (2.96 mmol/L, 95% CI 1.68, 4.24, P = 0.001), and patients with GTCS and syncope (4.29 mmol/L, 95% CI 2.48, 6.10, P = 0.001). However, there was no difference in mean lactate between syncope and PNES, and between syncope and non-GTCS, demonstrating that the serum lactate levels between other forms of TLOC other than GTCS were similar. A serum lactate concentration of 2.4 mmol/L provided a good capability to differentiate between GTCS and non-GTCS, with AUROC ranging from 0.94 - 0.97.
      Conclusion: Serum lactate can be a valuable tool to differentiate GTCS from other forms of TLOC, but it is not valuable in distinguishing non-GTCS types of TLOC from each other. However, lactate level should not be used as an absolute diagnostic tool and should be interpreted along with proper clinical context.


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        • NICE
        CG109: Transient loss of consciousness (’blackouts’) in over 16s.
        National Institute for Health and Clinical Excellence, 2010 (Accessed June 4, 2022)
        • Rogers G.
        • O'Flynn N.
        NICE guideline: transient loss of consciousness (blackouts) in adults and young people.
        Br J Gen Pract. 2011; 61: 40-42
        • Griffith N.M.
        • Szaflarski J.P.
        Epidemiology and classification of psychogenic nonepileptic seizures.
        in: Gates J.R. Rowan A.J. Nonepileptic seizures. Cambridge University Press, Cambrigde2010: P3-16
        • Chadwick D.
        • Smith D.
        The misdiagnosis of epilepsy.
        BMJ. 2002; 324: 495-496
        • Leach J.P.
        • Lauder R.
        • Nicolson A.
        • Smith D.F.
        Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project.
        Seizure. 2005; 14: 514-520
        • Williamson C.
        • Reed M.J.
        Syncope: the emergency department and beyond.
        Intern Emerg Med. 2015; 10: 843-850
        • Shen W.K.
        • Sheldon R.S.
        • Benditt D.G.
        • et al.
        ACC/AHA/HRS Guideline for the evaluation and management of patients with syncope: executive Summary: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
        Circulation. 2017; 136 ([published correction appears in Circulation. 2017 Oct 17;136(16):e269-e270]) (2017): e25-e59
        • Baron-Esquivias G.
        • Martínez-Alday J.
        • Martín A.
        • et al.
        Epidemiological characteristics and diagnostic approach in patients admitted to the emergency room for transient loss of consciousness: group for Syncope Study in the Emergency Room (GESINUR) study.
        Europace. 2010; 12: 869-876
        • Pallin D.J.
        • Goldstein J.N.
        • Moussally J.S.
        • Pelletier A.J.
        • Green A.R.
        • Camargo Jr., C.A.
        Seizure visits in US emergency departments: epidemiology and potential disparities in care.
        Int J Emerg Med. 2008; 1: 97-105
        • Elger C.E.
        • Baumgartner C.
        • Beyenburg S.
        • Dennig D.
        • Donati F.
        • Ebner A.
        • et al.
        Guideline: first epileptic seizure and epilepsy in adult.
        in: Diener H.C. Weimar C. Guidelines for diagnosis and therapy in neurology. ThiemeStuttgart, 2012: 28-47
        • Fowle A.J.
        • Binnie C.D.
        Uses and abuses of the EEG in epilepsy.
        Epilepsia. 2000; 41: S10-S18
        • Chesson A.L.
        • Kasarskis E.J.
        • Small V.W.
        Postictal elevation of serum creatine kinase level.
        Arch Neurol. 1983; 40: 315-317
        • Brivet F.
        • Bernardin M.
        • Cherin P.
        • Chalas J.
        • Galanaud P.
        • Dormont J
        Hyperchloremic acidosis during grand mal seizure lactic acidosis.
        Intensive Care Med. 1994; 20: 27-31
        • Nass R.D.
        • Sassen R.
        • Elger C.E.
        • Surges R.
        The role of postictal laboratory blood analyses in the diagnosis and prognosis of seizures.
        Seizure. 2017; 47: 51-65
        • BRODER G.
        • WEIL M.H
        Excess lactate: an index of reversibility of shock in human patients.
        Science. 1964; 143: 1457-1459
        • Orringer C.E.
        • Eustace J.C.
        • Wunsch C.D.
        • Gardner L.B.
        Natural history of lactic acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis not associated with hyperkalemia.
        N Engl J Med. 1977; 297: 796-799
        • Matz O.
        • Zdebik C.
        • Zechbauer S.
        • et al.
        Lactate as a diagnostic marker in transient loss of consciousness.
        Seizure. 2016; 40: 71-75
        • Matz O.
        • Heckelmann J.
        • Zechbauer S.
        • et al.
        Early postictal serum lactate concentrations are superior to serum creatine kinase concentrations in distinguishing generalized tonic-clonic seizures from syncopes.
        Intern Emerg Med. 2018; 13: 749-755
        • Doğan E.A.
        • Ünal A.
        • Ünal A.
        • Erdoğan Ç.
        Clinical utility of serum lactate levels for differential diagnosis of generalized tonic-clonic seizures from psychogenic nonepileptic seizures and syncope.
        Epilepsy Behav. 2017; 75: 13-17
        • Olaciregui Dague K.
        • Surges R.
        • Litmathe J.
        • et al.
        The discriminative value of blood gas analysis parameters in the differential diagnosis of transient disorders of consciousness.
        J Neurol. 2018; 265: 2106-2113
        • Magnusson C.
        • Herlitz J.
        • Höglind R.
        • et al.
        Prehospital lactate levels in blood as a seizure biomarker: a multi-center observational study.
        Epilepsia. 2021; 62: 408-415
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372 (Published 2021 Mar 29)
      1. Wells G., Shea B., O'Connell D., Peterson J., Welch V., TT Losos M. The Newcastle- Ottawa scale (NOS) for assessing the quality of nonrandomised studies in metaanalyse. Published online. Accessed May 12, 2019.;2000.

        • Hozo S.P.
        • Djulbegovic B.
        • Hozo I.
        Estimating the mean and variance from the median, range, and the size of a sample.
        BMC Med Res Methodol. 2005; 5 (Published 2005 Apr 20)
        • Barbella G.
        • Barras P.
        • Rossetti A.O.
        • Novy J.
        Hypophosphatemia compared to classical biomarkers of tonic clonic seizures.
        Epilepsy Res. 2020; 163106326
        • Shimmura M.
        • Takase K.I.
        Clinical utility of serum prolactin and lactate concentrations to differentiate epileptic seizures from non-epileptic attacks in the emergency room.
        Seizure. 2022; 95: 75-80
        • Nass R.D.
        • Zur B.
        • Elger C.E.
        • Holdenrieder S.
        • Surges R.
        Acute metabolic effects of tonic-clonic seizures.
        Epilepsia Open. 2019; 4 (Published 2019 Oct 22): 599-608
        • Benzon H.T.
        • Toleikis J.R.
        • Meagher L.L.
        • Shapiro B.A.
        • Ts'ao C.H.
        • MJ Avram
        Changes in venous blood lactate, venous blood gases, and somatosensory evoked potentials after tourniquet application.
        Anesthesiology. 1988; 69: 677-682
        • Kaplan L.J.
        • Kellum J.A.
        Initial pH, base deficit, lactate, anion gap, strong ion difference, and strong ion gap predict outcome from major vascular injury.
        Crit Care Med. 2004; 32: 1120-1124
        • Puskarich M.A.
        • Trzeciak S.
        • Shapiro N.I.
        • et al.
        Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation.
        Acad Emerg Med. 2012; 19: 252-258
        • Chioléro R.L.
        • Revelly J.P.
        • Leverve X.
        • et al.
        Effects of cardiogenic shock on lactate and glucose metabolism after heart surgery.
        Crit Care Med. 2000; 28: 3784-3791
        • Stang M.
        • Wysowski D.K.
        • Butler-Jones D.
        Incidence of lactic acidosis in metformin users.
        Diabetes Care. 1999; 22: 925-927
        • Record C.O.
        • Chase R.A.
        • Williams R.
        • Appleton D.
        Disturbances of lactate metabolism in patients with liver damage due to paracetamol overdose.
        Metabolism. 1981; 30: 638-643
        • Almenoff P.L.
        • Leavy J.
        • Weil M.H.
        • Goldberg N.B.
        • Vega D.
        • Rackow E.C.
        Prolongation of the half-life of lactate after maximal exercise in patients with hepatic dysfunction.
        Crit Care Med. 1989; 17: 870-873
        • Khan F.Y.
        Rhabdomyolysis: a review of the literature.
        Neth J Med. 2009; 67: 272-283
        • Mahmoud A.T.
        • El Deghady A.A.
        Serum prolactin and cre- atine kinase levels in epileptic and non epileptic seizures.
        Alex J Pediatr. 2005; 19: 217-222
        • Libman M.D.
        • Potvin L.
        • Coupal L.
        • Grover S.A.
        Seizure vs. syncope: measuring serum creatine kinase in the emergency department.
        J Gen Intern Med. 1991; 6: 408-412
        • Glötzner F.L.
        • Planner M.
        • Gaab M.
        Creatine kinase in serum after grand mal seizures.
        Eur Neurol. 1979; 18: 399-404
        • Wani A.A.
        • Shabir S.
        • Bhat I.A.
        Study of serum prolactin levels in seizures List of authors in order.
        Int J Med Sci Curr Res. 2019; 2: 275-287
        • Wang Y.Q.
        • Wen Y.
        • Wang M.M.
        • Zhang Y.W.
        • Fang Z.X.
        Prolactin levels as a criterion to differentiate between psychogenic non-epileptic seizures and epileptic seizures: a systematic review.
        Epilepsy Res. 2021; 169106508
        • Ahmad S.
        • Beckett M.W.
        Value of serum prolactin in the management of syncope.
        Emerg Med J. 2004; 21: e3
        • Malkowicz D.E.
        • Legido A.
        • Jackel R.A.
        • Sussman N.M.
        • Eskin B.A.
        • Harner R.N.
        Prolactin secretion following repetitive seizures.
        Neurology. 1995; 45: 448-452
        • Aydin S.
        • Dag E.
        • Ozkan Y.
        • et al.
        Time-dependent changes in the serum levels of prolactin, nesfatin-1 and ghrelin as a marker of epileptic attacks young male patients.
        Peptides. 2011; 32: 1276-1280
        • Oribe E.
        • Amini R.
        • Nissenbaum E.
        • Boal B.
        Serum prolactin concentrations are elevated after syncope.
        Neurology. 1996; 47: 60-62
        • Theodorakis G.N.
        • Markianos M.
        • Livanis E.G.
        • Zarvalis E.
        • Flevari P.
        • Kremastinos D.T.
        Hormonal responses during tilt-table test in neurally mediated syncope.
        Am J Cardiol. 1997; 79: 1692-1695