a b s t r a c t

Objective: Central nervous system (CNS) infections are often suspected in adult patients with fever-associated seizures. However, it is unclear whether lumbar puncture is routinely required in patients with fever- associated seizures. This study aimed to examine the prevalence of meningitis and encephalitis in adult patients with fever-associated seizures and to evaluate whether LP is routinely required.

Methods: We retrospectively studied patients aged >=16 years who presented to the emergency department with complaints of seizures and fever above 37.5 ?C who were admitted to the hospital between January 2017 and December 2019. LP was performed when the emergency physician suspected meningitis or encephalitis. Neurol- ogists assessed patients with normal cerebrospinal fluid (CSF) findings and those admitted without LP after hospitalization. A neurologist confirmed the diagnoses of meningitis and encephalitis.

Results: The study included 148 patients. Ninety-seven patients (65.5%) were male, and the median age was 60 years. LP was performed in 105 patients (70.9%), and 14 (13.4%) had CSF pleocytosis. Meningitis and encephalitis were diagnosed in nine patients (6.1%), of whom four (2.8%) had CNS infections. Patients diagnosed with men- ingitis and encephalitis were more likely to have Glasgow Coma Scale <13 (P = 0.03) and less likely to have a history of seizures or epilepsy (P = 0.04) and had higher C-reactive protein levels than the other patients (P = 0.02).

Conclusion: The prevalence of meningitis or encephalitis is relatively low in adult patients with fever-associated seizures. Lumbar puncture is considered unnecessary to be performed routinely, but its indication should be care- fully considered with reference to the clinical course, comorbidities, and blood tests. Further validation studies with larger sample sizes are needed to confirm the findings of this study.

(C) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Approximately 1% of all patients present to the emergency depart- ment (ED) with seizures and related symptoms [1]. Central nervous sys- tem (CNS) infections must be considered in the differential diagnosis of patients with fever-associated seizures, and Diagnostic lumbar puncture

Abbreviations: BT, body temperature; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; CT, computed tomography; ED, emergency department; EEG, electroencephalography; GCS, Glasgow coma scale; HIV, human immunodeficiency virus; IQR, interquartile range; LP, lumbar puncture; PCR, polymerase chain reaction; MRI, magnetic resonance imaging; WBC, white blood cell.

* Corresponding author.

E-mail address: [email protected] (D. Mizu).

(LP) is indicated in these patients. However, Wachtel et al. reported that most fevers in patients with tonic-clonic seizures were not caused by in- fection and were resolved within 48 h [2]. Thus, the evaluation of whether the clinical observation is appropriate for these patients is clin- ically valuable. It is well known that LP is not necessary for all pediatric patients with febrile seizures [3,4]; however, the necessity of LP in all adult patients with fever-associated seizures is unclear. Since there is no consensus on whether to perform LP in adult patients with fever- associated seizures, the decision to perform LP remains physician- dependent. LP is an invasive procedure, and there are many complica- tions, including cerebral and spinal herniation, neuropathies, headache, low back pain, infections, and Bleeding complications. Especially post- LP headaches occur in approximately 30% of patients [5,6]; therefore, its indications should be carefully evaluated. This study aimed to

https://doi.org/10.1016/j.ajem.2022.05.055

0735-6757/(C) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

examine the prevalence of meningitis and encephalitis in adult emer- gency patients with fever-associated seizures and to evaluate the neces- sity of LP in these patients.

1. Methods
   1. Study design

This was a single-center retrospective cohort study. We performed a chart review of patients aged >=16 years who presented to the ED with convulsive seizures (including suspected cases) between January 2017 and December 2019. We checked whether the following information was recorded in the EMS transport and the medical records: (1) pres- ence of a witness to the seizure and (2) the condition of the seizure (e.g., eye position, limb movements), and determined the patients with seizure to be verified. Our institution is a tertiary care hospital lo- cated in the center of a city with approximately 1.5 million people, and approximately 30,000 patients visit the hospital ED annually. Emer- gency physicians initially evaluated all the patients who visited the ED. This study was approved by the appropriate ethics review board (registration number: zn200810), which waived the requirement for

informed consent.

• 1. Study setting and population

Patients aged >=16 years who presented to the ED with convulsive seizures (including suspected cases) and who had a fever >=37.5 ?C at the time of visit during the study period were eligible for validation. The Japanese Ministry of Health, Labour and Welfare sets the criterion for fever at 37.5 ?C [7], and we adopted this criterion in this study. The following patients were excluded from the study: those whose seizures were not witnessed and an occurrence could not be confirmed; those with suspected psychogenic non-Epileptic seizures, and post- traumatic seizures; those discharged from the ED; and those with miss- ing data. The following data were collected from the electronic medical records: age, sex, body temperature (BT), Glasgow Coma Scale score, comorbidities (seizures/epilepsy, CNS diseases, human immuno- deficiency virus [HIV] infection, diabetes mellitus, Cirrhosis, renal dysfunction, cancer, use of immunosuppressive drugs or steroids, alco- holism, and psychiatric disorders), acute findings on head computed tomography (findings of stroke, brain tumor, and Brain edema). Further, administration of LP, white blood cell count in the cere- brospinal fluid (CSF), blood test results (WBC and C-reactive protein [CRP] level), and clinical course after hospitalization were also collected. At our institution, CRP is routinely ordered in blood tests as a parameter of inflammation. Moreover, we performed LP, neuroimaging, electroen- cephalography (EEG), and Polymerase chain reaction testing for Herpes species as standardized tests for patients with suspected menin- gitis or encephalitis. However, other tests (such as oligoclonal bands and paraneoplastic antibodies) are not standardized and are ordered as needed for each patient. CNS diseases as comorbidities were defined as medical histories of internal CNS diseases, except for seizures, epi- lepsy, and Traumatic brain injuries. BT and GCS scores were evaluated at the time of the ED visit; LP and blood tests were performed in the ED. Head CT.was performed on all the patients. There were no specific criteria for performing LP, which was performed at the discretion of the emergency physician. Admission or discharge from the ED was determined by an emergency physician and a neurologist.

• 1. Data analysis

We examined the prevalence of meningitis and encephalitis among eligible patients and compared patients with and without meningitis and encephalitis. Furthermore, we compared and validated the results between patients with and without CSF pleocytosis in patients who underwent LP. CSF pleocytosis was defined as a WBC count of

>=5 cells/mm³ in the CSF [8-10]. In the case of red blood cells in the CSF, WBC count was calculated using the following formula: WBC count in CSF - (Red blood cell count in CSF / 700) [11]. The diagnosis of meningitis was based on CSF findings, including CSF Bacterial culture and viral polymerase chain reaction results. The diagnosis of encephali- tis was made according to the diagnostic criteria proposed in the 2013 Consensus Statement of the International Encephalitis Consortium: altered mental status lasting >=24 h with no alternative cause identified and at least three of the following suggestive findings: fever, seizures, focal neurological signs, WBC count >=5 /mm³ in the CSF, and abnormal- ities in neuroimaging or EEG [8].

The ?² test, Fisher’s exact test, and Mann-Whitney U test were used as statistical methods, and P < 0.05 was considered a significant differ- ence. Statistical analyses were performed using the Bell Curve for Excel (Social Survey research Information Co., Ltd.).

1. Results

During the study period, 1140 patients aged >=16 years visited the ED for seizures (including suspected seizures), of whom 243 (21.3%) had fever >=37.5 ?C. After excluding 37 patients who met the exclusion criteria and 58 discharged from the ED, 148 patients were included in the final cohort (Fig. 1). Patient characteristics are shown in Table 1. Ninety- seven patients (65.5%) were male, and the median age was 60 years (in- terquartile range [IQR]: 41.8-75). Seizures and epilepsy were the most common comorbidities in 71 patients (47.9%), and acute findings on head CT were observed in 9 (6.1%). None of the patients had HIV infec- tion. LP was performed in 105 patients (70.9%), of whom 14 (13.4%) showed CSF pleocytosis. All patients with pleocytosis received Empiric antibiotics/antivirals in the ED. Of the 91 patients who did not have CSF pleocytosis and the 43 who did not undergo LP, most of these patients were diagnosed with seizures of unclear causes or seizures triggered by infections in the ED. Eight patients (4 without LP and 4 without pleocytosis on LP) underwent LP after admission. No patients were diag- nosed with meningitis or encephalitis by a neurologist after admission.

Of the 14 patients with CSF pleocytosis, nine (6.1%) were diagnosed with meningitis or encephalitis (Table 2). Bacterial meningitis and her- pes encephalitis were found in 2 cases (1.4%), respectively, and non- infectious encephalitis was found in 5 cases (3.4%). One patient with bac- terial meningitis underwent ventriculoperitoneal shunt placement for subarachnoid hemorrhage. Five patients without CSF pleocytosis but not diagnosed with CNS infections were concluded to have pleocytosis associated with seizures because the fever quickly resolved and their consciousness improved, and there were no findings suggestive of en- cephalitis on EEG or brain magnetic resonance imaging (MRI). The re- sults of the comparative verification between the 9 patients diagnosed with meningitis or encephalitis and the other 134 are shown in Table 3. There were no significant differences in sex, age, BT, or GCS scores. Patients diagnosed with meningitis or encephalitis were signifi- cantly more likely to have GCS <13 (P = 0.03) and less likely to have sei- zures and epilepsy as comorbidities (P = 0.04). In addition, blood tests showed that CRP levels were significantly higher in patients diagnosed with meningitis or encephalitis (P = 0.02). None of the patients diag- nosed with meningitis or encephalitis showed acute findings on head CT. Of the 105 patients who underwent LP, we also performed compar- ative verification between 14 with CSF pleocytosis and 91 without CSF pleocytosis (Table 4). Similar to the validation in patients with meningi- tis or encephalitis, those with CSF pleocytosis were significantly less likely to have seizures or epilepsy as comorbidities and had significantly

higher CRP levels on blood tests (P = 0.04 and 0.01, respectively).

1. Discussion

We examined the prevalence of meningitis or encephalitis in adult patients with fever-associated seizures and evaluated the necessity of routine LP. In this study, 2.7% of patients with fever-associated seizures

Fig. 1. Flowchart of patient inclusion.

had CNS infection, and 3.4% had non-infectious CNS inflammation, sug- gesting that the prevalence of CNS infection is relatively low among adult patients with fever-associated seizures. Keeping in mind that these are Serious diseases that should not be missed, with reference to the clinical course and history of the patient, it may be possible to choose not to routinely perform LP in all patients with fever- associated seizures and choose a hospitalization and follow-up strategy. The indications for LP in adult patients with seizures remain unclear.

The most common use for LP is to confirm CNS infections; however, only 5%-6% of seizures are caused by CNS infections, and LP is rarely per- formed in patients with seizures in the ED [12-15]. Since there are fre- quent complications such as post-LP headache, indications for LP

should be carefully considered. The American College of Emergency Physicians clinical policy states that LP is unnecessary in patients with normal consciousness and those without fever and immunodeficiency [16]. Jagoda and Gupta reported that there were no cases of bacterial meningitis among patients who presented with seizures but had no other symptoms. Thus, LP should be considered in the presence of fever, Severe headache, immunocompromised status, and prolonged impaired consciousness [17]. The course of fever and consciousness of patients in the ED is also important in the decision to perform a LP. In this study, patients with CNS infection were also more likely to have moderate or severe impaired consciousness (GCS <13). Although phys- ical examination and symptoms are not sensitive enough to exclude

Table 1 Patient characteristics.
	All (n = 148)	LP (n = 105)		No LP (n = 43)
		Pleocytosis in CSF*	No pleocytosis in CSF
N	148	14 (13.3)	91 (86.7)	43
Male, n (%)	97 (65.5)	8 (57.1)	59 (64.8)	30 (69.8)
Age, median (IQR)	60 (41.8-75)	52 (37.5-73.8)	65 (46-78)	49 (35-66)
BT, median (IQR)	38.2 (37.8-39.0)	38.7 (37.9-39.1)	38.5 (38.0-39.3)	37.8 (37.6-38.4)
GCS, n (%) 3-8	65 (43.9)	8 (57.1)	49 (53.8)	8 (18.6)
9-12	32 (21.6)	6 (42.9)	21 (23.1)	5 (11.6)
13-15	51 (34.4)	0 (0)	21 (23.1)	30 (69.8)
Comorbidities, n (%) ** Seizure/epilepsy	71 (47.9)	2 (14.3)	39 (42.9)	30 (69.8.)
Intracranial disease	61 (41.2)	3 (21.4)	34 (37.4)	24 (55.8)
Diabetes mellitus	15 (10.1)	1 (7.1)	12 (13.2)	2 (4.7)
Cirrhosis	8 (5.4)	0 (0)	5 (5.5)	3 (7.0)
Renal dysfunction	8 (5.4)	0 (0)	6 (6.6)	2 (4.7)
Cancer	15 (10.1)	0 (0)	10 (11.0)	5 (11.6)
Use of immunosuppressive drugs or steroids	2 (1.4)	0 (0)	2 (2.2)	0 (0)
Alcoholism	13 (8.8)	2 (14.3)	7 (7.7)	4 (9.3)
Psychiatric	33 (22.3)	0 (0)	20 (22.0)	13 (30.2)
Acute findings of head CT, n (%)	9 (6.1)	1 (7.1)	4 (4.4)	4 (9.3)
Cerebral hemorrhage	2 (1.4)	0 (0)	0 (0)	2 (4.7)
Cerebral infarction	2 (1.4)	1 (7.1)	1 (1.1)	0 (0)
CSDH	2 (1.4)	0 (0)	1 (1.1)	1 (2.3)
Brain tumor	3 (2.0)	0 (0)	2 (2.2)	1 (2.3)

LP: lumbar puncture; IQR: interquartile range; BT: body temperature; GCS: Glasgow Coma Scale; CT: computed tomography; CSDH: chronic subdural hematoma

*Pleocytosis in CSF: WBC > 5 mm³, ** There are duplicates.

Table 2

Characteristics of patients diagnosed with meningitis or encephalitis.

No	Age	Sex	GCS	BT (?C)	CSF Leucocyte count (/mm3)	Diagnosis
1	61	Male	6	38.9	2149	Listeria meningitis
2	40	Female	10	39.1	86	Herpes encephalitis
3	70	Male	3	39.4	10	Herpes encephalitis
4	76	Female	4	38.4	2308	Meningitis due to ventriculoperitoneal shunt infection
5	37	Male	6	37.9	33	Non-infectious CNS inflammation
6	16	Female	3	37.8	66	Non-infectious CNS inflammation
7	31	Female	12	38	14	Non-infectious CNS inflammation
8	75	Female	5	39	36	Non-infectious CNS inflammation
9	39	Male	10	40	8	Non-infectious CNS inflammation

GCS: Glasgow Coma Scale; BT: body temperature; CSF: cerebrospinal fluid; CNS: central nervous system

meningitis [18], if fever subsides and the patient’s consciousness tends to improve over time during ED observation, we consider that observa- tion is very important strategy.

Seizures occur in 5%-24% of patients with meningitis or encephalitis [19-22]. Meningitis and encephalitis should not be missed in the ED as 95% of patients with meningitis have at least two of the following three signs: fever, neck stiffness, and impaired consciousness [23]. In pa- tients with seizures associated with fever, the signs of fever and im- paired consciousness are more likely to be fulfilled, and clinicians should consider the need for LP. In addition, Abnormal head CT findings and immunocompromised conditions are risk factors for seizures in pa- tients with meningitis; therefore, these comorbidities should be consid- ered as additional indications for LP [19,24]. However, in practice, not all patients with fever-associated seizures undergo LP. In this study, 29% of patients were hospitalized for follow-up without LP. Moreover, 6.1% of patients with fever-associated had CNS infection and inflammation (CNS infection was observed in 2.7% of patients), indicating that while the possibility of CNS infection and inflammation cannot be ignored, the prevalence of CNS infection is relatively low. Furthermore, the result of this study revealed that patients with mild impaired consciousness (GCS >=13), seizures or epilepsy, and no elevated CRP levels were even less likely to have meningitis or encephalitis as the cause of seizures as- sociated with fever. Of course, delays in treatment for bacterial menin- gitis and encephalitis can lead to serious outcomes, so Empiric therapy is necessary if these diseases cannot be ruled out. With this in mind, by considering the patient’s course of consciousness, clinical history,

and laboratory findings, hospitalization and follow-up may be one of the treatment strategies rather than performing LP for all patients with fever-associated seizures.

This study also examined patients with and without CSF pleocytosis; however, caution should be exercised when interpreting CSF pleocytosis results in patients with seizures. There are various possible causes of CSF pleocytosis associated with seizures, including the possi- bility that the seizure itself causes CSF pleocytosis or reflects some brain abnormalities that caused the seizure [15,25,26]. In this study, 5 of 14 patients (36%) had CSF pleocytosis (6-40/uL) without meningitis or encephalitis. These patients were concluded to have pleocytosis asso- ciated with seizures. However, it is difficult to determine the exact etiol- ogy of CSF pleocytosis in the ED setting. In meningitis and encephalitis, delays in treatment can have a significant effect on outcome and se- quelae. Therefore, treatment should be initiated for patients with CSF pleocytosis immediately in the ED.

This study had several limitations. First, meningitis or encepha- litis is uncommon; therefore, many patients need to be evaluated for general assessment. Therefore, it is difficult to draw strong con- clusions from this study, which included only 148 patients. How- ever, despite the relatively small sample size, the prevalence of CNS infections in this study was similar to those reported in previ- ous studies. Second, we have performed brain MRI in only 55% of cases, which is useful for diagnosing CNS disease. In this study, no patient was diagnosed with CNS infection by MRI. However, 3%-38% of patients with first seizures showed abnormalities in

Table 3

Comparison between patients diagnosed with and without meningitis or encephalitis (n = 148).

	With meningitis or encephalitis	Without meningitis or encephalitis	P value
N, (%)	9 (6.1)	139 (93.9)
Male, n (%)	4 (44.4)	93 (66.9)	0.28
Age, median (IQR)	40 (37-70)	60 (43-75)	0.26
BT, median (IQR) GCS, n (%)	38.9 (38.0-39.1)	38.2 (37.7-39.0)	0.27
3-8	6 (66.7)	59 (42.4)	0.18
9-12	3 (33.3)	29 (20.9)	0.41
13-15	0 (0)	51 (36.7)	0.03**
Comorbidities, n (%) * Seizure/epilepsy	1 (11.1)	70 (50.3)	0.04**
Intracranial disease	1 (11.1)	60 (43.2)	0.08
Diabetes mellitus	0 (0)	15 (10.8)	0.60
Cirrhosis	0 (0)	8 (5.8)	1.00
Renal dysfunction	0 (0)	8 (5.8)	1.00
Cancer	0 (0)	15 (10.8)	0.60
Use of immunosuppressive drugs or steroids	0 (0)	2 (1.4)	1.00
Alcoholism	1 (11.1)	12 (8.6)	0.57
Psychiatric	0 (0.0)	33 (23.7)	0.21
Laboratory data WBC (/ul), median (IQR)	13,900 (6300-16,600)	10,700 (7700-13,600)	0.53
CRP (mg/dL), median (IQR)	3.04 (0.94-7.50)	0.62 (0.13-2.16)	0.02**
Acute findings on head CT, n (%)	0 (0)	9 (6.5)	1.00

IQR: interquartile range; BT: body temperature; GCS: Glasgow Coma Scale; WBC: white blood cell; CRP: C-reactive protein; CT: computed tomography

*There are duplicates.; **P < 0.05 is statistically significant

Table 4

Comparison between patients with and without pleocytosis in cerebrospinal fluid (CSF) (n = 105).

	Pleocytosis in CSF*	No pleocytosis in CSF	P-value
N, (%)	14 (13.4)	91 (86.7)
Male, n (%)	8 (57.1)	59 (64.8)	0.60
Age, median (IQR)	52 (37.5-73.8)	65 (46-78)	0.24
BT, median (IQR)	38.7 (37.9-39.1)	38.5 (38.0-39.3)	0.99
GCS, n (%) 3-8	8 (57.1)	49 (53.8)	0.82
9-12	6 (42.9)	21 (23.1)	0.19
13-15	0 (0)	21 (23.1)	0.07
Comorbidities, n (%)** Seizure/epilepsy	2 (14.3)	39 (42.9)	0.04***
Intracranial disease	3 (21.4)	34 (37.4)	0.37
Diabetes mellitus	1 (7.1)	12 (13.2)	1.00
Cirrhosis	0 (0)	5 (5.5)	1.00
Renal dysfunction	0 (0)	6 (6.6)	1.00
Cancer	0 (0)	10 (11.0)	0.35
Use of immunosuppressive drugs or steroids	0 (0)	2 (2.2)	1.00
Alcohol	2 (14.3)	7 (7.7)	0.35
Psychiatric	0 (0)	20 (22.0)	0.07
Laboratory data WBC (/uL), median (IQR)	12,050 (9600-12,575)	11,550 (8525-14,900)	0.76
CRP (mg/dL), median (IQR)	2.64 (0.68-7.84)	0.77 (0.18-2.26)	0.01***
Acute findings on head CT, n (%)	1 (7.1)	4 (4.4)	0.52

CSF: cerebrospinal fluid; IQR: interquartile range; BT; body temperature; GCS: Glasgow Coma Scale; WBC: white blood cell; CRP: C-reactive protein; CT: computed tomography

*Pleocytosis in CSF: WBC > 5 mm³; **There are duplicates; ***P < 0.05 is statistically significant.

neuroimaging, and MRI is more sensitive than CT in detecting ab- normalities [27]. If brain MRI had been performed on all patients, It is possible that some patients would have had abnormalities de- tected, including those discharged from the ED. Third, we have per- formed PCR testing for Herpes species in patients with suspected meningitis and encephalitis, but have not performed multiplex PCR for other pathogens. This is because there is no change in man- agement for viral infections other than the Herpes species. There- fore, it cannot be ruled out that some of the patients diagnosed with non-infectious CNS infections had viral CNS infections. Fourth, fever was defined as a temperature of 37.5 ?C or higher in accor- dance with Japanese standards, but it is difficult to generalize be- cause the criteria are limited to specific regions. Finally, patients discharged from the ED were omitted, and discharged patients may have later developed meningitis or encephalitis. Hospitaliza- tion is not always necessary for patients with First-time seizures if they have returned to their baseline mental status and have no ab- normal neurological findings. The decision to hospitalize is not standardized and should be based on an assessment of each pa- tient’s background and risks [16,17]. Although this study included patients with non-first-episode seizures, all discharged patients re- turned to their baseline mental status and had no abnormal neuro- logical findings. Furthermore, all patients were appropriately counseled regarding the need for outpatient follow-up to minimize the risk of missing meningitis or encephalitis.

In conclusion, the prevalence of meningitis and encephalitis is rela- tively low in adult patients with fever-associated seizures. LP is not con- sidered necessary to be performed routinely, but its indication should be carefully considered with reference to the clinical course, comorbid- ities, and blood tests. Further validation studies with larger sample sizes are needed to confirm the findings of this study.

Author contributions

DM contributed to the study concept, design, and data acquisition. YM provided statistical expertise. DM, YM, and JYH contributed to data analysis and interpretation. DM drafted the manuscript. All the au- thors contributed substantially to the critical revision of the manuscript for important intellectual content.

Credit authorship contribution statement

Daisuke Mizu: Conceptualization, Data curation, Formal analysis, In- vestigation, Methodology, Project administration, Visualization, Writing - original draft, Writing - review & editing. Yoshinori Matsuoka: Data curation, Formal analysis, Writing - review & editing. Ji-Young Huh: Formal analysis, Writing - review & editing. Yuka Kamitani: Writing - review & editing. Satoru Fujiwara: Writing - review & editing. Koichi Ariyoshi: Writing - review & editing.

Declaration of Competing Interest

The authors declare no conflict of interest. This research did not re- ceive any specific grants from funding agencies in the public, commer- cial, or not-for-profit sectors.

Acknowledgements

We would like to thank Yukiko Kitamura, Secretary of the Emergency Department, for the data collection. We would also like to thank Editage (www.editage.com) for the English language editing. We obtained permission to acknowledge the individual and the group.

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