Copeptin as a predictor of seizure diagnosis and seizure type in emergency department patients

Abstract

Objective

To evaluate the diagnostic utility of serum copeptin (CPT) levels in distinguishing epileptic seizures from Pseudo or functional/dissociative seizures (FDS) in adult patients presenting to the emergency department, and to investigate possible differences in CPT levels among various seizure types.

Methods

This prospective, observational study was conducted at a tertiary research hospital between September 2023 and September 2024. Adult patients presenting to the emergency department with seizure complaints were screened and, after applying exclusion criteria, 59 patients were included. Patients were classified based on clinical, laboratory, and EEG findings into epileptic seizure or FDS groups. Serum CPT and interleukin-6 (IL-6) levels were measured using ELISA.

Results

Of the 59 patients, 24 were diagnosed with epileptic seizures and 35 with FDS. No statistially significant difference was found in serum CPT levels between the epileptic seizure and FDS groups (p = 0.755). Glucose, base deficit, CRP (C-reactive protein), and IL-6 levels were significantly elevated in the epileptic seizure group relative to FDS. Serum CPT values were not predictive of clinical outcomes or the need for intensive care admission.

Conclusion

Serum CPT levels are not useful for differentiating between epileptic seizures and FDS in adult emergency patients. Further multicenter studies with larger cohorts and standardized sampling times are warranted to clarify the diagnostic and prognostic value of CPT in seizure disorders.

Introduction

A seizure is the manifestation of altered cerebral function due to excessive and abnormal electrical discharges of brain cells. It is a common event, affecting approximately 8% to 10% of the population over a lifetime [1, 2]. Seizures account for 1% to 2% of all emergency department admissions, and about a quarter of these are first-time seizures [3]. Functional/dissociative seizures (FDS), also known as psychogenic non-epileptic seizures (PNES; formerly pseudoseizures), are episodes that must be considered in the differential diagnosis of epileptic seizures or syncope attacks. FDS are involuntary, experiential, and behavioral responses to internal or external triggers [4]. There are no pathological changes in brain physiology (such as epileptiform EEG activity or cerebral oligemia) accompanying these events. Although FDS superficially resemble epileptic seizures, they are characterized by a typical subjective and observable seizure profile that distinguishes them from these episodic disorders.

An acute symptomatic seizure refers to a seizure occurring at the time of a systemic injury or documented brain injury [5]. Such injuries include acute neurological disorders such as metabolic imbalance, drug or alcohol withdrawal, stroke, encephalitis, or head trauma [6, 7]. This condition itself constitutes a significant stressor for the body or is observed following a stress event. Arginine vasopressin (AVP), a neuropeptide stored in the posterior pituitary, and copeptin (CPT) are released in response to acute and life-threatening situations. AVP is an important part of the endocrine stress response, resulting in the release of adrenocorticotropic hormone (ACTH) and cortisol [8–10]. As a biomarker, CPT is thought to reflect individual stress levels [8, 11–13]. CPT concentrations are correlated with vasopressin levels in both healthy volunteers and critically ill patients who have had seizures [10, 14, 15]. Therefore, measuring CPT may provide insight into the underlying vasopressin response in the differentiation between epileptic seizure and FDS.

The aim of this study is to evaluate the diagnostic value of serum CPT levels measured in patients admitted to the emergency department with seizures, in distinguishing seizure types and diagnoses. We also aimed to assess the utility of serum CPT values in differentiating between epileptic seizure and FDS, and to examine differences in CPT levels among patients diagnosed with different types of epilepsy.

Methods

Study design

This prospective, observational, and analytical study was conducted between 15.09.2023 and 15.09.2024 at the Emergency Medicine and Neurology Departments of Atatürk University Research Hospital. The study commenced after receiving approval from the local ethics committee (date: 07/09/2023, protocol code: B.30.2.ATA.0.01.00/1). Written informed consent was obtained from all volunteers participating in the study. For patients who arrived unconscious, consent was obtained from their legal guardians. The study was conducted in accordance with the Declaration of Helsinki and good clinical practices. All patients presenting to the emergency department with seizure or FDS during the study period were included as participants.

Participants

During the study period, 189 seizure patients presented to the emergency department. Inclusion criteria were being at least 18 years old, not pregnant, and presenting to the emergency department with a seizure complaint. Patients were divided into two groups based on clinical, laboratory, and EEG findings. The first group comprised patients consistent with epileptic seizures. The second group included patients presenting with seizures but without supportive EEG, clinical, or laboratory findings, and were diagnosed as FDS. Fifty-two patients were excluded due to seizures secondary to coronary artery disease, acute coronary syndrome, or arrhythmia. Twenty-eight patients with ischemic/hemorrhagic cerebrovascular events or cerebral/cerebellar mass compressing the brainstem were also excluded. Thirteen patients with sepsis (per qSOFA) and altered consciousness/hypotension were not included. Five patients diagnosed with eclampsia during pregnancy were excluded. Twenty-seven post-traumatic seizure patients and 15 patients who did not consent were not included. A total of 59 patients met the study criteria and were included (Fig. 1).

Fig. 1.

Case collection flow chart. (Clinical conditions affecting CPT levels, such as cardiovascular system diseases, central nervous system pathologies, sepsis accompanied by hypovolemia, the presence of trauma, and seizures characterized by eclampsia during pregnancy, were excluded from the study [8, 9, 16])

Individuals aged < 18 years, pregnant patients, and those with systemic conditions—including cardiovascular and central nervous system disorders, sepsis, or trauma—that could potentially effect CPT levels were excluded from the study. In addition, patients receiving medications other than antiepileptic drugs that may affect osmotic homeostasis or circulating blood volume were not included. These medications occured diuretics, antihypertensive agents (with or without inotropic support), as well as pharmacological agents and hormones used in the management of hypo- or hyperglycemia, and therapies involving blood, albumin, or electrolyte replacement. Furthermore, patients with chronic comorbidities—such as chronic heart failure, diabetes mellitus, chronic kidney disease, ischemic cerebrovascular disease, chronic anemia, and liver failure or cirrhosis—were excluded due to their potential effects on circulating blood volume and osmotic regulation. Patients with acute/chronic alcohol consumption or a history of active smoking were excluded from the study. These exclusion criteria were applied to minimize potential confounding arising from both acute and chronic alterations in CPT levels.

Intervention

Upon hospital admission, patients had blood samples drawn for diagnostic tests, including calcium, magnesium, glucose, pH, pCO2, HCO3, lactate, LDH, base deficit, and CRP. Laboratory analyses were performed on serum separated by centrifugation. Additionally, 2 cc of serum was stored at −80 °C for batch analysis of CPT and IL-6. Epidemiological, medical history, number of seizures, time from seizure to hospital admission, seizure types (absence, generalized tonic–clonic, partial), presence of trauma/incontinence, underlying causes, length of hospital stay, and type of admission (ward/ICU) were recorded.

Biochemical analysis

Blood samples were centrifuged at 3,000 rpm for 10 min to separate the serum. After routine tests, the remaining serum was stored at −80 °C for CPT and IL-6 analysis. All analyses were performed at the Medical Biochemistry Laboratory of XXX University Health Research and Application Center. On the analysis day, samples were thawed, and serum CPT levels were measured using a commercially available ELISA kit (Cat. No. ABT1470Hu, Atlas Biotechnology Ltd., Ankara, Turkey) according to the manufacturer's protocol. Measurements were performed using an ELISA reader (BioTek PowerWave XS, USA). All samples were tested in duplicate, and the means were used for statistical analysis. The intra- and inter-assay coefficients of variation for the kit were less than 10%.

Statistical analysis

Statistical analyses were performed using SPSS 20.0 (SPSS, Chicago, IL, United States). The normality of parameters was assessed with the Kolmogorov–Smirnov test. Parameters with normal distribution were compared using the independent samples t-test and ANOVA. Categorical data were compared using the chi-square test. Results are presented as mean ± standard deviation (mean ± SD) and minimum–maximum values. A p-value of < 0.05 was considered statistically significant for differences between groups.

Results

There was no statistical difference in age distribution among participants (p = 0.256). The female/male ratio was 32/27, with 14 female patients in the epileptic seizure group. Epidemiological and clinical variables of the participants are shown in Table 1.

Table 1.

Epidemiological and clinical variables of participants

	Epileptic Seizures	FDS
Age (year)	36.18 ± 18.92	41.43 ± 19.85
Gender (%)
Male	10 (17%)	17 (28.8%)
Female	14 (23.7%)	18 (30.5%)
Hospital arrival time (n) (%)
< 1 Hour	14 (23.7%)	17 (28.8%)
1–2 Hour	6 (10.2%)	10 (17%)
> 2 Hour	4 (6.8%)	8 (13.5)
Outcome (n) (%)
Discharge	22 (37.3%)	28 (47.5%)
Inpatient admission	1 (1.7%)	6 (10.1%)
ICU admission	1 (1.7%)	1 (1.7%)
Condition upon arrival at hospital (n) (%)
Conscious	22 (37.3%)	31 (52.5%)
Postictal	2 (3.4%)	4 (6.8%)
Incontinence (n) (%)
None	20 (34%)	31 (52.5%)
Urine	4 (6.8%)	4 (6.8%)
Associate trauma (n)* (%)
Trauma present	1 (1.7%)	7 (11.9%)
No trauma	23 (38.9%)	28 (47.5%)

FDS Functional/dissociative seizures

^*The seizures in these cases are witnessed seizures. The trauma experienced is the trauma observed in the patient during/after the seizure. First, the seizure is discussed, then the trauma resulting from it

Laboratory analysis showed that glucose, base deficit, IL-6, and CRP were the only statistically significant parameters differentiating seizure patients (p = 0.030, p = 0.020, p = 0.001, p = 0.001, respectively). Mean glucose levels in epileptic seizure patients were higher than those with FDS. Serum CRP and IL-6 levels were significantly higher in patients experiencing epileptic seizures, and the difference between the groups was statistically significant. Age, routine laboratory parameters, and CPT levels of patients are presented in Table 2 as mean ± SD and p values.

Table 2.

Comparison of laboratory parameters according to presence of epileptic seizure

Parameters	Patients with Epileptic Seizures (n = 24)	Patients with FDS (n = 35)	p value	Normal Reference Ranges
Age	36.18 ± 18.92	41.43 ± 19.85	0.250
Serum Glucose level (mg/dL)	107.41 ± 25.42	95.38 ± 21.96	0.030	74–106 mg/dL
Serum Ca level (mg/dL)	9.24 ± 0. 68	9.07 ± 0.72	0.330	8,8–10,6 mg/dL
Serum Mg level (mg/dL)	1.86 ± 0.22	1.86 ± 0.22	0.930	1,8–2,6 mg/dL
Serum LDH Activity (U/L)	235.48 ± 140.62	246.74 ± 102.17	0.200	0–250 U/L
Serum Lactat Level (mmol/L)	3.82 ± 2.75	2.73 ± 2.2	0.060	0,5–1,6 mmol/L
pH	7.35 ± 0.06	7.31 ± 0.33	0.470	7,35–7,45
PCO2 (mmHg)	39.45 ± 6.95	40.24 ± 8.3	0.670	35–48
HCO3- (mmol/L)	20.91 ± 3.24	22.24 ± 3.2	0.080	21,2–28,3 mmol/L
Base deficite	−2.55 ± 4.03	−0.74 ± 3	0.020	0–1
Serum CRP Level (mg/L)	5.30 ± 4.09	1.48 ± 0.72	0.001	0–5 mg/dL
Serum IL-6 (pg/mL)	11.99 ± 6.07	2.24 ± 0.77	0.001	*
Serum Copeptin Level (pg/mL)	498.62 ± 95.32	492.29 ± 81.23	0.750	*

Bold values indicate p value's are < 0,05

Ca Calcium, Mg Magnesium, pCO₂ Partial carbon dioxide, HCO₃ Bicarbonate, LDH Lactate dehydrogenase, CRP C Reactive Protein ve IL-6:İnterleukin-6, FDS Functional/dissociative seizures

^* Since IL-6 and CPT were measured using the ELISA method, no reference range was specified

There was no statistically significant difference in serum CPT levels between FDS and epileptic seizure patients (p = 0.755). Mean ± SD values for both groups are shown in Table 2 and Fig. 2.

Fig. 2.

The mean ± SD values of serum CPT levels (FDS: Functional/dissociative seizures)

CPT levels appeared to be higher in patients with absence seizures (661.77 ± 15.45 pg/mL); however, given the limited number of patients in this subgroup, the observed difference did not reach statistical significance. Therefore, CPT levels could not be demonstrated to serve as a reliable biomarker for differential diagnosis among seizure subtypes. CPT levels by seizure type are detailed in Table 3 and Fig. 3.

Table 3.

CPT levels by seizure type

Seizure Type	N	Mean	Minimum	Maximum	P value
Absence	2	661.77 ± 15.45	650.84	672.70	0.80a 0.11b 0.16c
Focal	10	512.86 ± 76.38	427.93	664.22	0.80a 0.51d 0.70e
Generalized	12	486.33 ± 91.63	356.32	631.67	0.11b 0.51d 0.96f
FDS	35	483.11 ± 77.64	375.28	685.58	0.16c 0.70e 0.96f

^aAbsence vs Focal

^bAbsence vs Generalized

^cAbsence vs FDS

^dFocal vs Generalized

^eFocal vs FDS

^fGeneralized vs FDS, FDS: Functional/dissociative seizure

Fig. 3.

CPT levels in seizure type (FDS: Functional/dissociative seizures)

Following the end of a epileptic seizure, there is a period of transition from the ictal state back to the preseizure baseline level of awareness and function, referred to as the postictal period. 37.3% of patients presented after an epileptic seizure with preserved consciousness, while 6.8% appeared postictal but were actually diagnosed with FDS. No statistical difference in CPT levels was detected between these groups (p = 0.982). Time to hospital admission was earlier in the FDS group (Table 1). Patients in this group had a shorter time to reach the hospital. However, no statistically significant relationship was found between hospital arrival times and CPT levels (Table 4).

Table 4.

The correlation between the time of Hospital arrival time and CPT levels

Hospital arrival time	n	Mean ± SD (25–75 Percentiles)	95% Confidence Interval for Mean		P value
			Lower Bound	Upper Bound
< 1 Houra	31	491.99 ± 81.76 (423.95–561.79)	461.46	522.53	0.83a−b 0.51a−c
1–2 Hourb	16	477.40 ± 78.82 (413.31–524.48)	435.40	519.40	0.83a−b 0.31b−c
> 2 Hourc	12	523.44 ± 90.06 (438.31–610.37)	466.22	580.67	0.51a−c 0.31b−c

Etiological analysis revealed that psychogenic causes (strong emotions, stress, mood disorder) were the most frequent in both groups, with dehydration as the second most common cause in the FDS group (n = 7). Other etiologies are shown in Fig. 4.

Fig. 4.

Underlying causes of epileptic seizures and FDS (FDS: Functional/dissociative seizures)

Discussion

In this study, we investigated the utility of serum CPT levels as a diagnostic and prognostic marker in patients presenting to the hospital with seizures. This is the first study in the literature to evaluate the role of CPT in differentiating seizure and FDS diagnoses. Our findings showed that serum CPT levels are not diagnostic in distinguishing between seizure and FDS.

A review of the literature reveals five studies related to seizures and CPT levels: two in adults and three in pediatric populations. One study compared CPT levels in focal and generalized tonic–clonic seizures; others assessed CPT in febrile convulsions, fever without seizures, and epileptic seizures. Our study is the first to compare CPT levels across epileptic seizure types other than febrile convulsions.

A major limitation of the study is the relatively small and imbalanced sample size, particularly within the seizure subgroup. Of the 59 patients included, only 24 had epileptic seizures, and subgroup distribution was uneven (absence n = 2, focal n = 10, generalized n = 12). Given the extremely small number of patients with absence seizures, subgroup comparisons lack sufficient statistical power. Therefore, any apparent elevation observed in this subgroup should be interpreted strictly as descriptive and hypothesis-generating rather than inferential. No definitive conclusions regarding seizure subtype classification can be drawn from these data.

Another important limitation concerns potential confounding factors. Although patients with sepsis, cardiac disease, or other known conditions affecting CPT levels were excluded, trauma was present in a subset of patients. Trauma is a well-recognized physiological stressor capable of independently increasing CPT levels. In particular, the two patients requiring intensive care admission had post-traumatic seizures, making it difficult to disentangle the relative contributions of seizure activity and traumatic stress to CPT elevation. This confounding effect limits causal interpretation of CPT changes in relation to seizure etiology. The trauma patients included in the study were those who experienced trauma during or after a witnessed seizure. These patients had no observed trauma before the seizure.

Freund Y et al. investigated CPT and S100B levels for evaluating post-seizure outcomes, finding that elevated CPT predicted poor outcomes like seizure recurrence, hospital admission, death or return visit to hospital within seven days [17]. Within the scope of this study, a record-keeping and follow-up system was not established regarding the short- and long-term outcomes and neurological survival of the patients. Only data related to the patients' emergency department outcomes, discharge, and ward/ICU admissions were recorded. The study population included two patients who could be considered to have a poor outcome. Both of these patients, who were admitted to the intensive care unit (one in each group), had CPT levels above the mean. It was determined that these patients had experienced trauma after a seizure and were admitted to the ICU due to trauma-related pathologies. Literature suggests that CPT is influenced by trauma severity [16]. We agree with Westermann et al. that elevated CPT in our patients may reflect trauma rather than seizure/FDS differentiation [18].

Autonomic symptoms during epileptic seizures result from the activation of the central autonomic network by epileptic discharges [19]. This network includes the insular cortex, anterior cingulate cortex, amygdala, hypothalamus, periaqueductal gray, parabrachial nucleus, solitary nucleus, ventrolateral reticular formation of the medulla oblongata, and the medullary raphe. The interaction of these centers regulates autonomic, endocrine, and motor responses to visceral and somatosensory information [20, 21]. The resulting responses affect CPT release from the posterior pituitary. Cardiac manifestations, respiratory changes, gastrointestinal symptoms, skin findings, and genitourinary symptoms during seizures result from this network's systemic interaction [22]. Laboratory parameters such as glucose, pH, pCO2, HCO3, lactate, LDH, base deficit, CRP, and IL-6 measured in our study are thought to be affected by this systemic response.

A 2018 study by Robert D. Nass et al. demonstrated that CPT levels significantly increased after generalized convulsive seizures due to cardiac stress during seizures [23]. In their study of focal and generalized tonic–clonic seizures, mean CPT levels in generalized tonic–clonic seizure patients were 143.5 pg/mL, markedly lower than the mean CPT level in our group (486.33 ± 91.63 pg/mL). The same study noted that CPT levels declined within 2 h and returned to baseline 6 h after a seizure [24]. In our study, only two patients presented more than 2 h after seizure onset, and their CPT levels were below the mean for generalized tonic–clonic seizures, consistent with this decline. The absence of standardized timing for blood sampling represents an additional methodological constraint. In our study, the interval between seizure onset and blood sampling varied among patients. To standardize the time elapsed after a seizure for blood samples collected from patients, the arrival time to the hospital has been designated as the blood collection time. Because serial measurements were not performed, we were unable to assess temporal changes in CPT concentrations. Consequently, intergroup differences may partially reflect variability in sampling time rather than true biological differences, thereby limiting comparability across patients.

Abdel Salam et al. reported that IL-6 and CPT were elevated in febrile convulsions, sepsis, and hypotension, highlighting the interplay between anti-inflammatory processes, decreased circulating volume, and AVP/CPT [24]. In our study, 21% of epileptic seizure patients had infection as a trigger, but none were hypotensive or septic, so the diagnostic value of elevated IL-6 needs further investigation.

Base deficit, derived from arterial CO2, pH, and bicarbonate, indicates metabolic stress. In our study, base deficit was higher in seizure patients, reflecting hypoxia and acidosis associated with actual seizures.

Overall, our findings primarily support a negative but clinically important conclusion: CPT does not appear to have diagnostic value in differentiating epileptic seizures from FDS in the emergency setting. This negative finding contributes to the literature by clarifying the limited clinical applicability of CPT for this specific purpose.

Conclusion

Serum CPT levels measured in the emergency department do not reliably differentiate epileptic seizures from functional/dissociative seizures. Subgroup observations, particularly regarding absence seizures, are based on extremely limited sample sizes and should be considered preliminary and hypothesis-generating only. Larger, prospective, multicenter studies with standardized sampling protocols and balanced subgroup distributions are required to determine whether CPT has any clinically meaningful role in seizure subtype characterization or prognostication.

Abbreviations

CPT

Copeptin

FDS

Functional/dissociative seizures

EEG

Electroencephalography

IL-6

Interleukin-6

CRP

C-reactive protein

PNES

Psychogenic non-epileptic seizures

AVP

Arginine vasopressin

ACTH

Adrenocorticotropic hormone

qSOFA

Quick SOFA

Ca

Kalsiyum,

Mg

Magnezyum

pCO₂

Parsiyel karbondioksit

HCO₃

Bikarbonat

LDH

Laktat dehidrogenaz

SPSS

Statistical Package for the Social Sciences

ANOVA

ANalysis Of VAriance

Authors’ contributions

AÇ, STAG, MMÇ, NÖ, FŞ: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work AÇ, MMÇ, NÖ: Drafting the work or reviewing it critically for important intellectual content AÇ, MMÇ, STAG: Final approval of the version to be published AÇ, FŞ, STAG: Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

This study received financial support from the Scientific Research Projects Coordination Unit of XXX University under project number 13129 and project code TCD-2023–13129. The funding for the Copeptin Elisa kits used in the study was covered by this support.

Data availability

Data are available on reasonable request.

Declarations

Ethics approval and consent to participate

The study commenced after receiving approval from the Atatürk University Faculty of Medicine Scientific Research Ethics Committee on 07.09.2023 Date and B.30.2.ATA.0.01.00/1 Decision No. The study was conducted in accordance with the Declaration of Helsinki and good clinical practices. Written informed consent was obtained from all volunteers participating in the study. For patients who arrived unconscious, consent was obtained from their legal guardians.

Consent for publication

There is not any identifying images or other personal or clinical details of participants are presented that compromise anonymity.

Competing interests

The authors declare no competing interests.