
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

39029046
MD-D-23-11764
00048
10.1097/MD.0000000000038974
3
5300
Research Article
Observational Study
Incidence of seizures in ICU patients with diffuse encephalopathy and its predictors
https://orcid.org/0000-0001-8310-1875
Alkhotani Amal M MBBS a*
Al sulaimi Jwana Faisal BSc jwanah1991@gmail.com
b
Bana Afaf Ali Dip b
Abu Alela Hanadi MBBS, FRCPC Abualela.h@kamc.med.sa
b
a Department of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
b Department of Neurology, King Abdulla Medical City, Makkah, Saudi Arabia.
* Correspondence: Amal M Alkhotani, Department of Medicine, College of Medicine, Umm al-Qura University, Makkah 21421, Saudi Arabia (e-mail: amkhotani@uqu.edu.sa, dr.amalkhotani@hotmail.com).
19 7 2024
19 7 2024
103 29 e3897426 12 2023
26 6 2024
27 6 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Encephalopathy is a diffuse brain dysfunction that results from systemic disorder. Patients with diffuse encephalopathy are at risk of developing clinical and electrographic seizures. The aim of this study is to assess the prevalence of electrographic seizures in a setting of encephalopathy and the clinical and electroencephalogram predictors. We retrospectively reviewed all continuous electroencephalograms done between 2019 and 2022. Continuous electroencephalograms with diffuse encephalopathy were included in the study. A total of 128 patients with diffuse encephalopathy were included in this study. Patients’ ages ranged from 18 to 96 years old with a mean age of 55.3 ± 19.2 years old. Nine out of 128 patients had seizures with an incidence of 7%. Sixty-six point six percent were nonconvulsive electrographic seizures. Fourteen point three percent of the female patients with diffuse encephalopathy had seizures as compared to none of the male patients (P = .002). Also, 12% of patients with a history of epilepsy experienced seizures versus 5.8% of patients without this history (P = .049). Among electrographic features, 25% of patients with delta background had seizures versus 2.3% of the other patients (P = .048). Likewise, 90% of patients with periodic discharges developed seizures in comparison with none of the patients without (P = .001). Seizures are seen in 7% of patients with diffuse encephalopathy. Female gender, past history of epilepsy, delta background and periodic discharges are significant predictors of seizure development in patients with diffuse encephalopathy.

cEEG
encephalopathy
ICU
seizure
OPEN-ACCESSTRUE
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pmc1. Introduction

Encephalopathy is a diffuse brain dysfunction that results from systemic disorder. Encephalopathy is one of the most common causes of altered mental status in the hospital.[1,2] Several causes can cause encephalopathy and result in an altered mental status. Those include septic, anoxic-hypoxic, or metabolic etiology. Elderly patients and patients with preexisting dementia or neurological problems are more likely to develop an altered mental status in response to systemic disorders.

In a setting of altered mental status, an electroencephalogram (EEG) helps to establish the cause of the altered mental status by excluding nonconvulsive status epilepticus and confirming the diagnosis of encephalopathy. However, it does not provide specific clues as to the cause of encephalopathy.

In a patient with encephalopathy, several EEG changes can occur, including background slowness (theta and delta frequencies) as well as a more severe pattern of suppression according to the severity.[3–7] Triphasic waves are another common finding in patients with diffuse encephalopathy. A study of triphasic wave etiology found an infectious cause (56%), renal (50%) and liver insufficiency (12%), and respiratory failure (20%).[8] Periodic discharges, which are stereotypical epileptiform discharges, are described in patients with encephalopathy. They can be generalized or focal.[7,9] An electrographic seizure has been described in patients with encephalopathy with no significant risk factors.[9]

King Abdulla Medical City is a tertiary care center in Makkah with a large intensive care unit (ICU), cardiac care unit and neuro intensive care unit. Encephalopathy is one of the major causes of consultation to the neurology department. We aim in this study to evaluate the risk factors of developing electrographic seizures in a patient with diffuse encephalopathy.

2. Methods

We retrospectively evaluated all continuous EEG (cEEG) in the ICU, cardiac care unit, and neuro intensive care unit from January 2019 to December 2022. All cEEGs with the diagnosis of diffuse encephalopathy were included in the study. An EEG was excluded if it was done under sedation or if it was <24 hours in duration. Patients with epilepsy who were admitted secondary to status epilepticus were also excluded from analysis. We included epilepsy patients if their EEG showed diffuse encephalopathy and a clear etiology of encephalopathy was obtained. cEEG was obtained according to the International 10 to 20 System by certified EEG. Two independent physicians with EEG certifications reviewed all cEEG. Ethical approval was obtained from the Institutional Review Board of King Abdullah Medical City (23-1072).

Data included in the analysis consists of the patients’ demographic data, history of epilepsy and antiseizure medication uses, systemic co-morbidities, presence of neurological diseases, clinical seizure development prior to EEG hooking, EEG features (i.e., background rhythm, presence of sharp waves and periodic discharges), and the cause of encephalopathy.

The cause of encephalopathy was categorized into metabolic that include: electrolyte abnormalities; liver, renal or respiratory failure; septic in the presence of sepsis as indicated with presence of high white cell counts; and positive blood culture, anoxic if it happened in setting of post cardiac or respiratory arrest, and toxic if in the presence of toxic or drug exposure.

2.1. Data analysis

The data were collected, reviewed, and then fed to Statistical Package for Social Sciences version 21 (SPSS: An IBM Company, Chicago, IL). All statistical methods used were 2 tailed and an alpha level of 0.05 was considered significant if the P value was less than or equal to .05. Descriptive analysis was done by prescribing frequency distribution and percentage for study variables including patient’s demographic data, medical data, encephalopathy causes and history of seizures and epilepsy. Also, EEG related data and pattern, and seizure frequency and types, were tabulated. Finally, cross tabulation was used to show factors associated with seizures among patients and also to assess EEG association with seizure development using Pearson chi-square test for significance and exact probability test if there were small frequency distributions.

3. Results

A total of 128 patients with diffuse encephalopathy were included in this study. Table 1 shows patient demographic data. Patients’ ages ranged from 18 to 96 years old with a mean age of 55.3 ± 19.2 years old. The most reported cause of encephalopathy included septic (65.6%), metabolic (27.3%) and hypoxic (24.9%). Only 23 (18%) of the study patients had a history of clinical seizures, 25 (19.5%) had a history of epilepsy and 26 (20.3%) received antiseizure drugs treatment.

Table 1 Bio-demographic data of study patients with diffuse encephalopathy.

Bio-demographic data	No.	%	
Age in years			
  < 40	24	18.8%	
 40-59	43	33.6%	
 60+	61	47.7%	
Gender			
 Male	65	50.8%	
 Female	63	49.2%	
Co-morbidities			
 None	29	22.7%	
 DM	45	35.2%	
 HTN	59	46.1%	
 IHD	28	21.9%	
 Tumor	11	8.6%	
 Others	19	14.8%	
Cause of encephalopathy			
 Infectious	84	65.6%	
 Metabolic	35	27.3%	
 Hypoxic	33	24.9%	
Underlying neurological diseases			
 No	47	36.7%	
 Stroke	36	28.2%	
 Hemorrhage	23	18.0%	
 Brain tumor	10	7.8%	
 Inflammation	7	5.5%	
 Infiltration	4	3.1%	
 Others	4	3.1%	
History of clinical seizures			
 Yes	23	18.0%	
 No	105	82.0%	
History of epilepsy			
 Yes	25	19.5%	
 No	103	80.5%	
Treatment with AED			
 Yes	26	20.3%	
 No	102	79.7%	

Table 2 shows EEG-related data and patterns among study patients with diffuse encephalopathy. As for background, it was suppressed among 43 (33.6%) patients, theta among 77 (60.2%) and delta among 8 (6.3%) patients. Exactly 45 (35.2%) of the patients had a focal sharp wave, 19 (14.8%) had a triphasic wave, and 6 (4.7%) had a generalized sharp wave.

Table 2 EEG-related data and pattern of study patients with diffuse encephalopathy.

EEG data	No.	%	
Background			
 Delta	8	6.3%	
 Suppressed	43	33.6%	
 Theta	77	60.2%	
Sharp Wave			
 None	58	45.3%	
 Focal	45	35.2%	
 Triphasic	19	14.8%	
 Generalized	6	4.7%	

Table 3 shows the seizures and their types and duration among study patients with diffuse encephalopathy. A total of 9 (7%) patients had seizures due to encephalopathy, of which 3 (33.3%) cases were nonconvulsive focal status, 3 (33.3%) were nonconvulsive generalized status, 2 (22.2%) were myoclonic status, and 1 (11.1%) was generalized convulsive.

Table 3 Seizures and their types and durations in study patients with diffuse encephalopathy.

Seizures	No.	%	
Seizures			
 Yes	9	7.0%	
 No	119	93.0%	
Seizure type (n = 9)			
 Nonconvulsive focal status	3	33.3%	
 Nonconvulsive generalized status	3	33.3%	
 Myoclonic status	2	22.2%	
 Generalized convulsive	1	11.1%	

Table 4 shows factors associated with seizures among patients with diffuse encephalopathy. Exactly 14.3% of the female patients with diffuse encephalopathy had seizures, as compared with none of the male patients, with recorded statistical significance (P = .002). Also, 12% of patients with a history of epilepsy experienced seizures versus 5.8% of others without this history (P = .049). All other factors showed insignificant association with experiencing seizures among study patients.

Table 4 Factors associated with seizures among patient with diffuse encephalopathy.

Factors	Seizures	P-value	
Yes	No	
No	%	No	%	
Age in years					.474	
 < 40	3	12.5%	21	87.5%	
 40-59	2	4.7%	41	95.3%	
 60+	4	6.6%	57	93.4%	
Gender					.002*	
 Male	0	0.0%	65	100.0%	
 Female	9	14.3%	54	85.7%	
Co-morbidities					.974	
 Yes	7	7.1%	92	92.9%	
 No	2	6.9%	27	93.1%	
Cause of encephalopathy					.690	
 Infectious	5	6.0%	79	94.0%	
 Metabolic	4	11.4%	31	88.6%	
 Hypoxic	4	12%	29	88%	
Underlying CNS problem					.841	
 No	5	10.6%	42	89.4%	
 Stroke	3	8.3%	33	91.7%	
 Hemorrhage	1	4.3%	22	95.7%	
 Brain tumor	0	0.0%	10	100.0%	
 Inflammation	0	0.0%	7	100.0%	
 Infiltration	0	0.0%	4	100.0%	
 Others	0	0.0%	4	100.0%	
History of epilepsy					.049*	
 Yes	3	12.0%	22	88.0%	
 No	6	5.8%	97	94.2%	
Treatment with ASD					.314	
 Yes	3	11.5%	23	88.5%	
 No	6	5.9%	96	94.1%	
P: Exact probability test.

* P < .05 (significant)

Table 5 shows EEG association with seizure development in patients with diffuse encephalopathy. 25% of patients with a delta background had seizures versus 2.3% of others with a suppressed background (P = .048). Likewise, 90% of patients with periodic discharges developed seizures in comparison with none of the others without this history (P = .001).

Table 5 EEG association with seizure development in study patients with diffuse encephalopathy.

EEG	Seizures	P-value	
Yes	No	
No.	%	No.	%	
Background					.048*	
 Delta	2	25.0%	6	75.0%	
 Suppressed	1	2.3%	42	97.7%	
 Theta	6	7.8%	71	92.2%	
Sharp Wave					.470	
 Focal	4	8.9%	41	91.1%	
 Generalized	1	16.7%	5	83.3%	
 Triphasic	0	0.0%	19	100.0%	
 None	4	6.9%	54	93.1%	
Generalized periodic discharges (GPDs)					.001*	
 Yes	9	90.0%	1	10.0%	
 No	0	0.0%	118	100.0%	
P: Exact probability test.

* P < .05 (significant).

4. Discussion

Generalized and focal convulsive and nonconvulsive seizures have been reported in association with several causes of diffuse encephalopathy.[9–14] In this study, we looked at the incidence of seizures detected by cEEG in patients with diffuse encephalopathy. Out of 128 patients who had diffuse encephalopathy in the ICU setting, 9 patients had seizures detected on cEEG with incidence of 7%. 66.6% were nonconvulsive electrographic seizures. Among those, 33.3% were focal and 33.3% were generalized in onset. Our findings are similar to other studies where nonconvulsive seizures were the most common type of seizure noted in critically ill patients with sepsis.[14] In the subset of patients who had myoclonic status, all were post cardiac arrest hypoxic anoxic encephalopathy. Myoclonic status within 24 hours or within 7 days of cardiac arrest is considered to be a bad prognostic variable.[15]

We studied different clinical and electrographic factors in association with seizure development in a setting of diffuse encephalopathy. Female patients with encephalopathy are more likely to develop seizures in comparison with male patients (P value .002). In a study of generalized periodic discharges (GPDs) in critically ill patients, female patients were more likely to have GPD than male patients.[16] There was no definitive explanation for which woman may have a higher risk of developing seizures in the setting of encephalopathy. There is a well-known gender difference in relation to epilepsy. Generalized epilepsy and cryptogenic epilepsy are more common in women whereas focal epilepsy is more common in men.[17] However, the exact molecular mechanism behind this difference is unknown. Different explanations include hormonal effects, neurogenesis, and glial response to injury.[17]

Patients with epilepsy (PWE) were more likely to develop seizures in a setting of diffuse encephalopathy. Stress, lack of sleep, and poor compliance to medications are common triggers of seizures in epileptic patients.[18,19] Infections are also a well-known trigger to breakthrough seizure in PWE. Infections can trigger seizures though affection blood brain barrier permeability, induction of inflammatory response, cytokine, and affection of vascular permeability.[19–21] Since PWE have a low seizure threshold, they are likely to develop seizures in a setting of metabolic or septic encephalopathy. Nonconvulsive status should be ruled out in PWE who are admitted with altered mental status even in the presence of clear etiology like renal or hepatic encephalopathy. Nonconvulsive status should be ruled out by cEEG.

No significant relationship was found between the cause of encephalopathy, presence of structural CNS diseases, the use of antiseizure drugs or the clinical seizure prior to cEEG and the risk of detecting electrographic seizure. One possible explanation is that patients who already had a clinical seizure would be started on antiseizure medications before or with the cEEG attachment, which would reduce the chance of detecting electrographic seizure.

Among different electrographic features, patients with a delta background are more likely to develop seizures in comparison to other background features. Triphasic waves and sharp waves also were not associated with the finding of a seizure.

Generalized periodic discharges (GPDS) are frequently recorded in a setting of metabolic, toxic or septic encephalopathy.[16,22] A stroke is the second most likely cause of GPDs, after encephalopathy.[16] Lateralized periodic discharges are commonly seen in a setting of acute or subacute cerebral injury.[23] Patients with periodic discharges were found to have an increased risk of seizure development.[16,24,25] In our study, we had a similar finding of a positive relationship between periodic discharges and seizure developments.

Our study was limited by being a retrospective study. We accessed data from patients’ records. Patients with a lack of information were excluded from the analysis. Another limitation of our study was that EEG reactivity was excluded from analysis, as it was not assessed in all patients. Also, we did not look at the effect of seizure on the prognosis of patients with encephalopathy.

5. Conclusion

In critically ill patients with altered mental status, EEG should be performed to help assess the cause of this altered mental status. In a subset of encephalopathy patients who have high risk of seizure (which include a positive history of epilepsy, presence of periodic discharges and delta background), more prolonged monitoring is required.

Author contributions

Conceptualization: Amal M Alkhotani.

Data curation: Jwana Faisal Al sulaimi, Afaf Ali Bana.

Formal analysis: Amal M Alkhotani.

Investigation: Amal M Alkhotani, Jwana Faisal Al sulaimi.

Methodology: Amal M Alkhotani.

Project administration: Afaf Ali Bana.

Resources: Hanadi Abu Alela.

Supervision: Hanadi Abu Alela.

Validation: Amal M Alkhotani, Hanadi Abu Alela.

Writing – original draft: Amal M Alkhotani, Jwana Faisal Al sulaimi, Afaf Ali Bana.

Writing – review & editing: Amal M Alkhotani, Hanadi Abu Alela.

Abbreviations:

cEEG continuous EEG

EEG electroencephalogram

GPDS generalized periodic discharges

ICU intensive care unit

PWE patient with epilepsy

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Alkhotani AM, Al sulaimi JF, Bana AA, Abu Alela H. Incidence of seizures in ICU patients with diffuse encephalopathy and its predictors. Medicine 2024;103:29(e38974).
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