G Model
YSEIZ-2316; No. of Pages 3 Seizure xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Short communication
Pediatric status epilepticus: How common is cerebrospinal fluid pleocytosis in the absence of infection? Kara B. Johnson a, Kenneth A. Michelson a, Todd W. Lyons a, Lise E. Nigrovic a, Assaf Landschaft a, Tobias Loddenkemper b, Amir A. Kimia a,* a b
Boston Children’s Hospital Medicine, Division of Emergency Medicine, Boston, MA 02446, United States Boston Children’s Hospital Medicine, Department of Neurology, Boston, MA 02446, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 February 2014 Received in revised form 25 March 2014 Accepted 26 March 2014
Purpose: To determine the rate of cerebrospinal fluid (CSF) pleocytosis among children presenting with status epilepticus (SE) without proven central nervous system infection. Method: We performed a retrospective cross-sectional study of all patients aged one month to 21 years of age who were evaluated in a single pediatric emergency department (ED) for SE between 1995 and 2012. We limited our study to those children who had a CSF culture obtained and excluded those children with proven viral or bacterial infection. We defined SE in a patient who had a single seizure or a cluster of seizures without regaining consciousness which lasted 30 min or longer. We defined CSF pleocytosis as a CSF white blood cells (WBC) > 10 cells/mm3 and a peripheral leukocytosis as WBC 15,000 cells/mm3. We compared the rate of CSF pleocytosis between children with and without peripheral leukocytosis using the Fisher’s exact test. Results: We identified 289 ED visits for SE, of which 178 (62%) met study inclusion criteria. Seven children (4%, 95% confidence interval 1.7–8.2%) had CSF pleocytosis. More children with peripheral leukocytosis had CSF pleocytosis: (8.6% with peripheral leukocytosis vs. 0.9% without leukocytosis, p = 0.01). Conclusion: CSF pleocytosis is relatively uncommon among children with prolonged seizures, even in the presence of peripheral leukocytosis. Therefore, all children with CSF pleocytosis after status epilepticus need comprehensive evaluation for central nervous system infection. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Status epilepticus (SE) Emergency department (ED) White blood cell (WBC) Cerebrospinal fluid (CSF)
1. Introduction Children presenting to the emergency department (ED) with status epilepticus (SE) pose a clinical challenge: some are intubated, others are postictal or heavily sedated from the use of anti-epileptic medication. Laboratory evaluation of these children may be equally challenging given the presence of seizure mediated leukocytosis and possibly cerebrospinal fluid (CSF) pleocytosis. Seizure mediated CSF pleocytosis, a phenomenon referred to as ictal pleocytosis1,2 is the result of a transient disruption to the brain barrier and possibly due to the induced peripheral leukocytosis. The rate and clinical importance of ictal pleocytosis is unknown, since it is indistinguishable from other cases of culture-negative CSF pleocytosis. Yet, some inferences are made attributing mild CSF pleocytosis to ictal
pleocytosis3 offering ‘corrections’ to CSF pleocytosis cut-off values among these patients. Clinicians therefore use the overall rate of pleocytosis reported in patients evaluated for seizures as a surrogate for the upper range of potential ictal pleocytosis rates. Existing data on SE related CSF pleocytosis is limited to subgroups of SE, such as children with febrile seizures SE (showing rates of 1%),4 or patients with different definitions of SE and CSF pleocytosis (describing rates of 18%),3 but these results cannot be easily generalized. We sought to determine the rate of CSF pleocytosis among all children presenting with SE (without central nervous system infection) and among the subset of children with peripheral leukocytosis. 2. Methods 2.1. Study design
* Corresponding author. Tel.: +1 617 355 6624. E-mail address: [email protected] (A.A. Kimia).
We performed a cross-sectional study of all children aged one month to 21 years of age who were evaluated for SE in a
http://dx.doi.org/10.1016/j.seizure.2014.03.015 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Johnson KB, et al. Pediatric status epilepticus: How common is cerebrospinal fluid pleocytosis in the absence of infection? Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.015
G Model
YSEIZ-2316; No. of Pages 3 K.B. Johnson et al. / Seizure xxx (2014) xxx–xxx
2
single urban, tertiary care pediatric ED between 1995 and 2012. The ED serves approximately 55,000 patients per year. The study protocol was approved by the institutional review board. 2.2. Patient identification
they were documented either by the resident or attending physician and missing if not documented by any treating clinician. Data elements missing from ED documentation were abstracted from Neurology consult and discharge summary notes in that order.
Case identification was conducted in two phases. First, for the initial screening, we created a computer-assisted key word screening tool called regular-expression matching.5,6 This technique provides a more comprehensive and inclusive search than keyword searching by including misspelled and mistyped variations. The output of the search tool was further refined by manual medical chart review.
Our primary outcome was rate of CSF pleocytosis defined as a CSF WBC 10 cells/mm3.10 For cases in which red blood cells ‘contaminated’ the sample we used a corrected CSF WBC count defined as a WBC[corrected] = WBC[observed] RBC[observed]/500.
2.3. Patient population
2.6. Statistical analysis
We included children with SE, defined as a single seizure or a cluster of seizures without return to consciousness lasting 30 min or longer.7–9 We limited this investigation to children who also had a CSF culture obtained. We excluded children with a proven central nervous system infection leading to CSF pleocytosis defined by a positive CSF bacterial cultures, CSF pleocytosis with a positive blood culture, positive enterovirus CSF polymerase chain reaction (PCR) test or herpes simplex virus PCR. We also excluded children with significant head trauma or neurosurgical intervention within seven days before ED presentation, known malignancy, known ingestion, ventricular shunt, immunocompromised state, nonconvulsive status epilepticus, or a traumatic lumbar puncture (defined as CSF red blood cells 10,000 cells/mm3).4
We limited our primary analysis to those children who had both CSF cell count and cultures sent (in order to reliably exclude patients with acute bacterial meningitis). We performed univariate analysis using Fishers exact test for categorical data and Mann–Whitney U test for continuous data. Descriptive statistics were used to describe rates. Our secondary analysis involved only the subgroup of patients who had peripheral leukocytosis – defined as peripheral WBC count >15,000/mm3. We used the Statistical Program for the Social Sciences (IBM SPSS Statistic Version 21, IBM Inc., Chicago, IL).
2.4. Data collection The complete hospital medical records from the index visit and the following week of all study patients were reviewed by one of three study investigators (KJ, KM and TL). The following factors were abstracted: patient demographics, clinical features, laboratory and microbiology results and clinical outcome. We defined fever as temperature greater than 38 8C measured at home or in the ED. We defined antibiotics pretreatment if any antibiotics were given within the 48 h preceding the performance of the LP. When attending and trainee medical records differed, study data was abstracted from the attending documentation. Findings were considered present if
2.5. Outcome measure
3. Results During the 17-year study period, there were 937,566 ED visits for patients younger than 21 years of age (eFig. 1). We identified a cohort of 594 visits for SE, of which 220 (37%) were acute symptomatic or had fever and 178 met our inclusion criteria. The median patient age was 2.7 years [interquartile range (IQR) 1.3– 5.5 years] and 46% were female. All 178 children were admitted to the hospital from the ED. Seven patients (3.9%) had CSF pleocytosis [95% CI 1.7–8.2%]. We compared the clinical and laboratory characteristics of the 171 patients without CSF pleocytosis to the seven with CSF pleocytosis. (Table 1) We also examined the peripheral WBC count in children with and without CSF pleocytosis (Fig. 1). More children with peripheral leukocytosis had CSF pleocytosis: (8.6% with peripheral leukocytosis vs. 0.9% without leukocytosis, p = 0.01).
Table 1 Patient characteristics. Characteristic
With CSF pleocytosis (n = 7)
Demographics Median age (years) (IQR) Female gender
4.2 (3.1–9.1) 4 (57%)
History No prior seizures On AED at home History of fever Localization
4 2 5 6
Physical examination Ongoing seizure activity in ED
7 (100%)
Management Antibiotics prior to LP Intubated in the ED Died (n) Laboratory studies Peripheral WBC > 15,000 cell/mm3 Enteroviral PCR obtained (n) HSV PCR obtained (n)
(57%) (29%) (71%) (86%)
Without CSF pleocytosis (n = 171) 2.1 (1.2–5.4) 78 (46%)
94 45 110 93
p-value 0.07 0.7
(55%) (26%) (64%) (54%)
1.00 1.00 1.00 0.14
112 (65%)
0.10
3 (43%) 4 (57%) 0
59 (35%) 79 (46%) 5
0.70 0.71 ***
6 (86%) 3 6
64 (37%) 9 46
0.01 *** ***
*** stand for non-applicable.
Please cite this article in press as: Johnson KB, et al. Pediatric status epilepticus: How common is cerebrospinal fluid pleocytosis in the absence of infection? Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.015
G Model
YSEIZ-2316; No. of Pages 3 K.B. Johnson et al. / Seizure xxx (2014) xxx–xxx
Fig. 1. Distribution of CSF WBC counts for patients with and without peripheral leukocytosis.
Supplementary Fig. I related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.seizure.2014.03.015. Since viral studies become available during later years of our study, only 6 children with CSF pleocytosis (85.7%) and 46 children without CSF pleocytosis (26.9%) had Herpes simplex virus polymerase chain reaction studies (HSV PCR) sent. Fewer children had enterovirus polymerase chain reaction studies (EV PCR) sent [3 children with CSF pleocytosis (42.9%) and 9 children (5.2%) without CSF pleocytosis]. 4. Discussion We assembled a large retrospective cohort of children who had an LP done for the evaluation for SE. Among these children, CSF pleocytosis rate in the absence of proven infection was very low, with a slightly higher rate among children with peripheral leukocytosis. We therefore conclude that in assessment of CSF WBC obtained from a child with SE, an infection should be considered, as seizure driven pleocytosis is relatively uncommon. Ictal pleocytosis, first described in the 1920s1 involves a transient disruption the blood brain barrier2 and induction of peripheral leukocytosis. The average number of CSF WBCs resulting from ictal pleocytosis is not well described, but some authors will describe pleocytosis as CSF WBC count >12 cells/mm3 after ‘adjusting’ for ictal pleocytosis.3 Rates of overall CSF pleocytosis were described in selected subcategories of SE. As part of the FEBSTAT study Frank et al.4 reported a rate of 1% (1/136) among children who had non-traumatic LPs done for evaluation of prolonged febrile seizures. A rate corresponding with reported rate among non-SE febrile seizure cases.11–13 Singh et al. reported a rate of 18% (16/89) in a prospective of children with SE, mirroring the patient population to our cohort. However, the results are hard to compare due to different criteria used for defining SE (seizure lasting more than 20 min) and CSF pleocytosis (CSF WBC count >5 cells/mm3). Our study findings need to be interpreted in the setting of data acquisition. Ictal pleocytosis is a transient phenomenon, yet our ability to analyze the temporal association between seizure activity and CSF pleocytosis was limited by the retrospective design of our study. Not all children with SE had LP done, introducing a selection bias into our findings, choosing the sicker patients. This bias, however, suggests that the true rate of ictal pleocytosis could be even lower than our reported rate. The latter is true for our limited viral testing, which leads to underestimation of viral meningitis cases, accounting for some of the pleocytosis cases and is particularly true for encephalopathic patients in whom infectious and immune-mediated cases are likely to account for up
3
to 80% of the cases.14 Although all children in this study had a CSF culture obtained, some children were pretreated with antibiotics prior to diagnostic lumbar puncture that may have rendered cultures falsely negative.15 Finally, the low incidence of CSF pleocytosis prevented a detailed analysis of patient characteristics associated with this phenomenon. Future directions could include better characterizing the relationship between peripheral leukocytosis and CSF pleocytosis. This would require larger numbers of patients who had CSF pleocytosis, but could result in clinically useful prediction models to guide the workup of pediatric patients with CSF pleocytosis. We conclude that children with CSF pleocytosis after SE need comprehensive evaluation for central nervous system infections, echoing recommendations for the interpretation of CSF results in children after a seizure.11,16 Maintaining clinical suspicion for CNS infection in children with CSF pleocytosis will increase the likelihood that these acutely ill children receive appropriate care. Conflict of interest statement We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References 1. Patterson H, Levi P. The spinal fluid in epilepsy: a study of 50 cases. Arch Neurol Psychiatry 1926;(15):353–64. 2. Petito CK, Schaefer JA, Plum F. Ultrastructural characteristics of the brain and blood–brain barrier in experimental seizures. Brain Res 1977;127(May (2)):251–67. 3. Singh RK, Stephens S, Berl MM, Chang T, Brown K, Brown K, et al. Prospective study of new-onset seizures presenting as status epilepticus in childhood. Neurology 2010;74(February (8)):636–42. 4. Frank LM, Shinnar S, Hesdorffer DC, Shinnar RC, Pellock JM, Gallentine W, et al. Cerebrospinal fluid findings in children with fever-associated status epilepticus: results of the consequences of prolonged febrile seizures (FEBSTAT) study. JPediatr 2012;161(December (6)):1169–71. 5. Friedl JEF. Mastering regular expressions. 3rd ed. Sebastopol, CA: O’Reilly; 2006. 6. Goyvaerts J, Levithan S. Safari tech books online. Regular expressions cookbook., 1st ed. Beijing/Cambridge: Oreilly; 2009http://proquest.safaribooksonline.com/?uiCode=yaleu&xmlId=9780596802837. 7. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30(July–August (4)):389–99. 8. Riviello Jr JJ, Ashwal S, Hirtz D, Glauser T, Ballaban-Gil K, Kelley K, et al. Practice parameter: diagnostic assessment of the child with status epilepticus (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2006;67(November (9)):1542–50. 9. Shinnar S, Hesdorffer DC. Pediatric status epilepticus: should the diagnostic evaluation change? Neurology 2010;74(February (8)):624–5. 10. Nigrovic LE, Kuppermann N, Macias CG, Cannavino CR, Moro-Sutherland DM, Schremmer RD, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA 2007;297(January (1)):52–60. 11. Haeusler GM, Tebruegge M, Curtis N. Question 1. Do febrile convulsions cause CSF pleocytosis? Arch Dis Child 2012;97(February (2)):172–5. 12. Kimia A, Ben-Joseph EP, Rudloe T, Capraro A, Sarco D, Hummel D, et al. Yield of lumbar puncture among children who present with their first complex febrile seizure. Pediatrics 2010;126(July (1)):62–9. 13. Kimia AA, Capraro AJ, Hummel D, Johnston P, Harper MB. Utility of lumbar puncture for first simple febrile seizure among children 6 to 18 months of age. Pediatrics 2009;123(January (1)):6–12. 14. Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 2010;10(December (12)):835–44. 15. Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 2001;108(November (5)):1169–74. 16. Rider LG, Thapa PB, Del Beccaro MA, Gale JL, Foy HM, Farwell JR, et al. Cerebrospinal fluid analysis in children with seizures. Pediatr Emerg Care 1995;11(August (4)):226–9.
Please cite this article in press as: Johnson KB, et al. Pediatric status epilepticus: How common is cerebrospinal fluid pleocytosis in the absence of infection? Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.015
YSEIZ-2316; No. of Pages 3 Seizure xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Short communication
Pediatric status epilepticus: How common is cerebrospinal fluid pleocytosis in the absence of infection? Kara B. Johnson a, Kenneth A. Michelson a, Todd W. Lyons a, Lise E. Nigrovic a, Assaf Landschaft a, Tobias Loddenkemper b, Amir A. Kimia a,* a b
Boston Children’s Hospital Medicine, Division of Emergency Medicine, Boston, MA 02446, United States Boston Children’s Hospital Medicine, Department of Neurology, Boston, MA 02446, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 February 2014 Received in revised form 25 March 2014 Accepted 26 March 2014
Purpose: To determine the rate of cerebrospinal fluid (CSF) pleocytosis among children presenting with status epilepticus (SE) without proven central nervous system infection. Method: We performed a retrospective cross-sectional study of all patients aged one month to 21 years of age who were evaluated in a single pediatric emergency department (ED) for SE between 1995 and 2012. We limited our study to those children who had a CSF culture obtained and excluded those children with proven viral or bacterial infection. We defined SE in a patient who had a single seizure or a cluster of seizures without regaining consciousness which lasted 30 min or longer. We defined CSF pleocytosis as a CSF white blood cells (WBC) > 10 cells/mm3 and a peripheral leukocytosis as WBC 15,000 cells/mm3. We compared the rate of CSF pleocytosis between children with and without peripheral leukocytosis using the Fisher’s exact test. Results: We identified 289 ED visits for SE, of which 178 (62%) met study inclusion criteria. Seven children (4%, 95% confidence interval 1.7–8.2%) had CSF pleocytosis. More children with peripheral leukocytosis had CSF pleocytosis: (8.6% with peripheral leukocytosis vs. 0.9% without leukocytosis, p = 0.01). Conclusion: CSF pleocytosis is relatively uncommon among children with prolonged seizures, even in the presence of peripheral leukocytosis. Therefore, all children with CSF pleocytosis after status epilepticus need comprehensive evaluation for central nervous system infection. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Status epilepticus (SE) Emergency department (ED) White blood cell (WBC) Cerebrospinal fluid (CSF)
1. Introduction Children presenting to the emergency department (ED) with status epilepticus (SE) pose a clinical challenge: some are intubated, others are postictal or heavily sedated from the use of anti-epileptic medication. Laboratory evaluation of these children may be equally challenging given the presence of seizure mediated leukocytosis and possibly cerebrospinal fluid (CSF) pleocytosis. Seizure mediated CSF pleocytosis, a phenomenon referred to as ictal pleocytosis1,2 is the result of a transient disruption to the brain barrier and possibly due to the induced peripheral leukocytosis. The rate and clinical importance of ictal pleocytosis is unknown, since it is indistinguishable from other cases of culture-negative CSF pleocytosis. Yet, some inferences are made attributing mild CSF pleocytosis to ictal
pleocytosis3 offering ‘corrections’ to CSF pleocytosis cut-off values among these patients. Clinicians therefore use the overall rate of pleocytosis reported in patients evaluated for seizures as a surrogate for the upper range of potential ictal pleocytosis rates. Existing data on SE related CSF pleocytosis is limited to subgroups of SE, such as children with febrile seizures SE (showing rates of 1%),4 or patients with different definitions of SE and CSF pleocytosis (describing rates of 18%),3 but these results cannot be easily generalized. We sought to determine the rate of CSF pleocytosis among all children presenting with SE (without central nervous system infection) and among the subset of children with peripheral leukocytosis. 2. Methods 2.1. Study design
* Corresponding author. Tel.: +1 617 355 6624. E-mail address: [email protected] (A.A. Kimia).
We performed a cross-sectional study of all children aged one month to 21 years of age who were evaluated for SE in a
http://dx.doi.org/10.1016/j.seizure.2014.03.015 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Johnson KB, et al. Pediatric status epilepticus: How common is cerebrospinal fluid pleocytosis in the absence of infection? Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.015
G Model
YSEIZ-2316; No. of Pages 3 K.B. Johnson et al. / Seizure xxx (2014) xxx–xxx
2
single urban, tertiary care pediatric ED between 1995 and 2012. The ED serves approximately 55,000 patients per year. The study protocol was approved by the institutional review board. 2.2. Patient identification
they were documented either by the resident or attending physician and missing if not documented by any treating clinician. Data elements missing from ED documentation were abstracted from Neurology consult and discharge summary notes in that order.
Case identification was conducted in two phases. First, for the initial screening, we created a computer-assisted key word screening tool called regular-expression matching.5,6 This technique provides a more comprehensive and inclusive search than keyword searching by including misspelled and mistyped variations. The output of the search tool was further refined by manual medical chart review.
Our primary outcome was rate of CSF pleocytosis defined as a CSF WBC 10 cells/mm3.10 For cases in which red blood cells ‘contaminated’ the sample we used a corrected CSF WBC count defined as a WBC[corrected] = WBC[observed] RBC[observed]/500.
2.3. Patient population
2.6. Statistical analysis
We included children with SE, defined as a single seizure or a cluster of seizures without return to consciousness lasting 30 min or longer.7–9 We limited this investigation to children who also had a CSF culture obtained. We excluded children with a proven central nervous system infection leading to CSF pleocytosis defined by a positive CSF bacterial cultures, CSF pleocytosis with a positive blood culture, positive enterovirus CSF polymerase chain reaction (PCR) test or herpes simplex virus PCR. We also excluded children with significant head trauma or neurosurgical intervention within seven days before ED presentation, known malignancy, known ingestion, ventricular shunt, immunocompromised state, nonconvulsive status epilepticus, or a traumatic lumbar puncture (defined as CSF red blood cells 10,000 cells/mm3).4
We limited our primary analysis to those children who had both CSF cell count and cultures sent (in order to reliably exclude patients with acute bacterial meningitis). We performed univariate analysis using Fishers exact test for categorical data and Mann–Whitney U test for continuous data. Descriptive statistics were used to describe rates. Our secondary analysis involved only the subgroup of patients who had peripheral leukocytosis – defined as peripheral WBC count >15,000/mm3. We used the Statistical Program for the Social Sciences (IBM SPSS Statistic Version 21, IBM Inc., Chicago, IL).
2.4. Data collection The complete hospital medical records from the index visit and the following week of all study patients were reviewed by one of three study investigators (KJ, KM and TL). The following factors were abstracted: patient demographics, clinical features, laboratory and microbiology results and clinical outcome. We defined fever as temperature greater than 38 8C measured at home or in the ED. We defined antibiotics pretreatment if any antibiotics were given within the 48 h preceding the performance of the LP. When attending and trainee medical records differed, study data was abstracted from the attending documentation. Findings were considered present if
2.5. Outcome measure
3. Results During the 17-year study period, there were 937,566 ED visits for patients younger than 21 years of age (eFig. 1). We identified a cohort of 594 visits for SE, of which 220 (37%) were acute symptomatic or had fever and 178 met our inclusion criteria. The median patient age was 2.7 years [interquartile range (IQR) 1.3– 5.5 years] and 46% were female. All 178 children were admitted to the hospital from the ED. Seven patients (3.9%) had CSF pleocytosis [95% CI 1.7–8.2%]. We compared the clinical and laboratory characteristics of the 171 patients without CSF pleocytosis to the seven with CSF pleocytosis. (Table 1) We also examined the peripheral WBC count in children with and without CSF pleocytosis (Fig. 1). More children with peripheral leukocytosis had CSF pleocytosis: (8.6% with peripheral leukocytosis vs. 0.9% without leukocytosis, p = 0.01).
Table 1 Patient characteristics. Characteristic
With CSF pleocytosis (n = 7)
Demographics Median age (years) (IQR) Female gender
4.2 (3.1–9.1) 4 (57%)
History No prior seizures On AED at home History of fever Localization
4 2 5 6
Physical examination Ongoing seizure activity in ED
7 (100%)
Management Antibiotics prior to LP Intubated in the ED Died (n) Laboratory studies Peripheral WBC > 15,000 cell/mm3 Enteroviral PCR obtained (n) HSV PCR obtained (n)
(57%) (29%) (71%) (86%)
Without CSF pleocytosis (n = 171) 2.1 (1.2–5.4) 78 (46%)
94 45 110 93
p-value 0.07 0.7
(55%) (26%) (64%) (54%)
1.00 1.00 1.00 0.14
112 (65%)
0.10
3 (43%) 4 (57%) 0
59 (35%) 79 (46%) 5
0.70 0.71 ***
6 (86%) 3 6
64 (37%) 9 46
0.01 *** ***
*** stand for non-applicable.
Please cite this article in press as: Johnson KB, et al. Pediatric status epilepticus: How common is cerebrospinal fluid pleocytosis in the absence of infection? Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.015
G Model
YSEIZ-2316; No. of Pages 3 K.B. Johnson et al. / Seizure xxx (2014) xxx–xxx
Fig. 1. Distribution of CSF WBC counts for patients with and without peripheral leukocytosis.
Supplementary Fig. I related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.seizure.2014.03.015. Since viral studies become available during later years of our study, only 6 children with CSF pleocytosis (85.7%) and 46 children without CSF pleocytosis (26.9%) had Herpes simplex virus polymerase chain reaction studies (HSV PCR) sent. Fewer children had enterovirus polymerase chain reaction studies (EV PCR) sent [3 children with CSF pleocytosis (42.9%) and 9 children (5.2%) without CSF pleocytosis]. 4. Discussion We assembled a large retrospective cohort of children who had an LP done for the evaluation for SE. Among these children, CSF pleocytosis rate in the absence of proven infection was very low, with a slightly higher rate among children with peripheral leukocytosis. We therefore conclude that in assessment of CSF WBC obtained from a child with SE, an infection should be considered, as seizure driven pleocytosis is relatively uncommon. Ictal pleocytosis, first described in the 1920s1 involves a transient disruption the blood brain barrier2 and induction of peripheral leukocytosis. The average number of CSF WBCs resulting from ictal pleocytosis is not well described, but some authors will describe pleocytosis as CSF WBC count >12 cells/mm3 after ‘adjusting’ for ictal pleocytosis.3 Rates of overall CSF pleocytosis were described in selected subcategories of SE. As part of the FEBSTAT study Frank et al.4 reported a rate of 1% (1/136) among children who had non-traumatic LPs done for evaluation of prolonged febrile seizures. A rate corresponding with reported rate among non-SE febrile seizure cases.11–13 Singh et al. reported a rate of 18% (16/89) in a prospective of children with SE, mirroring the patient population to our cohort. However, the results are hard to compare due to different criteria used for defining SE (seizure lasting more than 20 min) and CSF pleocytosis (CSF WBC count >5 cells/mm3). Our study findings need to be interpreted in the setting of data acquisition. Ictal pleocytosis is a transient phenomenon, yet our ability to analyze the temporal association between seizure activity and CSF pleocytosis was limited by the retrospective design of our study. Not all children with SE had LP done, introducing a selection bias into our findings, choosing the sicker patients. This bias, however, suggests that the true rate of ictal pleocytosis could be even lower than our reported rate. The latter is true for our limited viral testing, which leads to underestimation of viral meningitis cases, accounting for some of the pleocytosis cases and is particularly true for encephalopathic patients in whom infectious and immune-mediated cases are likely to account for up
3
to 80% of the cases.14 Although all children in this study had a CSF culture obtained, some children were pretreated with antibiotics prior to diagnostic lumbar puncture that may have rendered cultures falsely negative.15 Finally, the low incidence of CSF pleocytosis prevented a detailed analysis of patient characteristics associated with this phenomenon. Future directions could include better characterizing the relationship between peripheral leukocytosis and CSF pleocytosis. This would require larger numbers of patients who had CSF pleocytosis, but could result in clinically useful prediction models to guide the workup of pediatric patients with CSF pleocytosis. We conclude that children with CSF pleocytosis after SE need comprehensive evaluation for central nervous system infections, echoing recommendations for the interpretation of CSF results in children after a seizure.11,16 Maintaining clinical suspicion for CNS infection in children with CSF pleocytosis will increase the likelihood that these acutely ill children receive appropriate care. Conflict of interest statement We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References 1. Patterson H, Levi P. The spinal fluid in epilepsy: a study of 50 cases. Arch Neurol Psychiatry 1926;(15):353–64. 2. Petito CK, Schaefer JA, Plum F. Ultrastructural characteristics of the brain and blood–brain barrier in experimental seizures. Brain Res 1977;127(May (2)):251–67. 3. Singh RK, Stephens S, Berl MM, Chang T, Brown K, Brown K, et al. Prospective study of new-onset seizures presenting as status epilepticus in childhood. Neurology 2010;74(February (8)):636–42. 4. Frank LM, Shinnar S, Hesdorffer DC, Shinnar RC, Pellock JM, Gallentine W, et al. Cerebrospinal fluid findings in children with fever-associated status epilepticus: results of the consequences of prolonged febrile seizures (FEBSTAT) study. JPediatr 2012;161(December (6)):1169–71. 5. Friedl JEF. Mastering regular expressions. 3rd ed. Sebastopol, CA: O’Reilly; 2006. 6. Goyvaerts J, Levithan S. Safari tech books online. Regular expressions cookbook., 1st ed. Beijing/Cambridge: Oreilly; 2009http://proquest.safaribooksonline.com/?uiCode=yaleu&xmlId=9780596802837. 7. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30(July–August (4)):389–99. 8. Riviello Jr JJ, Ashwal S, Hirtz D, Glauser T, Ballaban-Gil K, Kelley K, et al. Practice parameter: diagnostic assessment of the child with status epilepticus (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2006;67(November (9)):1542–50. 9. Shinnar S, Hesdorffer DC. Pediatric status epilepticus: should the diagnostic evaluation change? Neurology 2010;74(February (8)):624–5. 10. Nigrovic LE, Kuppermann N, Macias CG, Cannavino CR, Moro-Sutherland DM, Schremmer RD, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA 2007;297(January (1)):52–60. 11. Haeusler GM, Tebruegge M, Curtis N. Question 1. Do febrile convulsions cause CSF pleocytosis? Arch Dis Child 2012;97(February (2)):172–5. 12. Kimia A, Ben-Joseph EP, Rudloe T, Capraro A, Sarco D, Hummel D, et al. Yield of lumbar puncture among children who present with their first complex febrile seizure. Pediatrics 2010;126(July (1)):62–9. 13. Kimia AA, Capraro AJ, Hummel D, Johnston P, Harper MB. Utility of lumbar puncture for first simple febrile seizure among children 6 to 18 months of age. Pediatrics 2009;123(January (1)):6–12. 14. Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 2010;10(December (12)):835–44. 15. Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 2001;108(November (5)):1169–74. 16. Rider LG, Thapa PB, Del Beccaro MA, Gale JL, Foy HM, Farwell JR, et al. Cerebrospinal fluid analysis in children with seizures. Pediatr Emerg Care 1995;11(August (4)):226–9.
Please cite this article in press as: Johnson KB, et al. Pediatric status epilepticus: How common is cerebrospinal fluid pleocytosis in the absence of infection? Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.015
