Neurocrit Care (2008) 9:74–82 DOI 10.1007/s12028-007-9042-y
ORIGINAL ARTICLE
Refractory Status Epilepticus in Suspect Encephalitis Carol A. Glaser Æ Sabrina Gilliam Æ Somayeh Honarmand Æ Jay H. Tureen Æ Daniel H. Lowenstein Æ Larry J. Anderson Æ Andrew W. Bollen Æ Marylou V. Solbrig
Published online: 21 December 2007 Ó Humana Press Inc. 2007
Abstract Background The California Encephalitis Project (CEP) is a program designed to determine causes of encephalitis. We sought to determine whether there are any distinguishing characteristics of patients with encephalitis who develop refractory status epilepticus from those who do not. Methods Data from all patients in the CEP were retrospectively reviewed and analyzed. Diagnostic testing was performed for a panel of infectious agents and medical information collected using a standardized form. Encephalitis patients were subdivided into three categories: (i)
C. A. Glaser (&) S. Gilliam S. Honarmand Viral and Rickettsial Disease Branch, California Department of Public Health, 850 Marina Bay Parkway, Richmond, CA 94804, USA e-mail:
[email protected] S. Honarmand e-mail:
[email protected] J. H. Tureen Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA D. H. Lowenstein Department of Neurology, University of California, San Francisco, San Francisco, CA, USA L. J. Anderson Respiratory and Enteric Viruses Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA A. W. Bollen Department of Pathology, University of California, San Francisco, San Francisco, CA, USA M. V. Solbrig Department of Neurology, University of California, Irvine, CA, USA
patients with status epilepticus unresponsive to standard antiepileptic therapy who required general anesthetic coma for management (Group I), (ii) patients with seizures or status epilepticus responsive to standard antiepileptic therapy (Group II), and (iii) patients without seizures (Group III). Supplementary information was requested on Group I patients. Results Of 1,151 patients; 43 (4%) were classified as Group I, 459 (40%) as Group II, and 649 (56%) as Group III. Compared to Groups II and III, Group I patients were younger (median age = 10.0 years), more likely to have fever (93%), prodromal respiratory (57%) or gastrointestinal illness (64%), and less likely to have CSF pleocytosis (47%) or abnormal neuroimaging (16%). A causative infectious agent was verified in three of the Group I patients; and a putative agent in nine others. Supplementary information on Group I revealed that 28% died within 2 years and 56% were neurologically impaired or undergoing rehabilitation. Conclusions Encephalitis and refractory status epilepticus occur most commonly in the pediatric age group, an infectious etiology is usually not established, and outcomes are generally poor. Keywords Encephalitis Status epilepticus Refractory seizures Anesthetic coma Pentobarbital Phenobarbital Malignant status epilepticus California Encephalitis Project
Purpose Acute viral encephalitis is a frequent cause of seizures, and the incidence of seizures varies by agent. Seizures have been described in 89% of patients with herpes simplex virus encephalitis (HSE) [1], 46% of patients with Japanese
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encephalitis virus (JEV) [2], and 36% of patients with St. Louis encephalitis (SLE) [3]. Status epilepticus is reported in 17% of JEV [4], 9% of SLE [3], and 15% of encephalitis patients overall [5]. Among patients referred to the California Encephalitis Project (CEP) from 1998 to 2004, a subset of patients presented with or developed status epilepticus that was resistant to standard first-line antiepileptic drug (AED) therapy (intravenously administered benzodiazepines, phenytoins and/or phenobarbital) and required general anesthetic coma for management. Since the clinical presentation and course of illness for these patients appeared distinctive from other patients referred to the CEP, we sought to identify common denominators of an epidemiologic, clinical, laboratory, and microbiologic nature that might clarify the etiology, pathophysiology, and management strategies of patients with refractory status epilepticus in the setting of encephalitis.
Methods Background, Entry Criteria, and Core Laboratory Testing Initiated in 1998, the CEP is a collaborative project between the California Department of Public Health’s (CDPH) Viral and Rickettsial Disease Laboratory (VRDL) and the Centers for Disease Control and Prevention. Patients meet the case definition of encephalitis if they are hospitalized with encephalopathy (depressed or altered level of consciousness lasting C24 h, lethargy or change in personality), and have one or more of the following: fever (>100°F), seizure, focal neurological findings, CSF pleocytosis (>5 WBC/ml), or EEG or neuroimaging findings consistent with encephalitis. Patients referred to the CEP are enrolled if they are immunocompetent, 6-months of age or older, their condition meets the CEP’s case definition of encephalitis, and a case report form is completed and appropriate clinical specimens are received by the VRDL. A core battery of tests for at least 14 infectious agents is performed on specimens sent to the CEP [6]. The core testing algorithm is based on agents that are most commonly associated with encephalitis and includes herpes simplex viruses (HSV1 and HSV2), varicella zoster virus (VZV), Epstein Barr virus (EBV), human herpes virus 6 (HHV6), SLE, Western equine encephalitis (WEE), West Nile virus (WNV), measles virus, enteroviruses (EV), adenovirus, influenza A and B (during influenza season), Chlamydia species, and Mycoplasma pneumoniae. Testing for additional agents, including other common respiratory agents, such as parainfluenza and respiratory syncytial virus (RSV), is performed based on exposure, travel history, clinical information, and availability of specimens.
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The link between an identified infection and encephalitis was defined using predetermined, organism-specific criteria as (i) confirmed, (ii) probable or, (iii) possible, depending on the type of specimen in which the agent was detected, the strength of the documented association between the age [7]. Classification of Groups I, II, and III Groups I, II, and III were categorized primarily based on the information received on the case history form. The case history form (see Appendix A) gathers information on whether seizures are present, if the seizures are intractable and whether the seizures were managed by anesthesia-induced coma. Using the information obtained from phone follow-up and the supplementary data (described below), CEP staff confirmed the occurrences of seizures and qualified the level of seizure activity to ensure appropriate categorization of patients into Group I. For patients in Group I, the attending physician had diagnosed status epilepticus as continuous generalized seizures, frequent generalized seizures without regaining consciousness between seizures, or non-convulsive status epilepticus. The decision to use anesthesia coma, typically because of the failure of standard AED therapy (intravenous benzodiazepines, phenytoin, or phenobarbital), was also made by the attending physician. Various anesthetic agents were used to induce coma including pentobarbital, midazolam, thiopental, and propofol. Data Analysis Demographic, clinical, and laboratory data from the Group I patients were compared with data from patients in the CEP (both Group II and Group III groups) using two-tailed Fisher’s exact test or Kruskal–Wallis test as appropriate. Statistical significance was set at P < 0.05. Variables with P-value >0.10 on univariate analysis were excluded from further analysis. Stepwise, forward, and backward logistic regression models were applied to data for all patients presenting with seizures. Variables were added or dropped on the basis of the log-likelihood ratio and log-likelihood test results. Results are reported as adjusted odds ratios (OR) with 95% confidence intervals (CI) and P-values.
Supplementary Information Group I While much of the pertinent laboratory and clinical data are captured on the case history form (Appendix A), portions of hospital medical chart including admitting laboratory data, the patient’s history and physical (H&P), infectious disease and neurology consults, progress notes, and discharge
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summaries were requested on all Group I patients. Additional clinical information was received for 35 of these patients.
required general anesthetic coma for management, 459 (40%) patients had seizures not requiring anesthesia coma, and 649 (56%) did not have seizures. Demographic, clinical, and laboratory data are presented in Table 1.
Results From 1998 to 2004, 1,197 patients met the case definition of encephalitis [7]. Of these patients, seizure status was known on 1,151 patients (46 patients were excluded from this analysis because of unknown seizure status). Among the 1,151 patients, 43 (4%) presented with, or developed, status epilepticus that was resistant to standard AED therapy and
Table 1 Comparison of demographic, clinical and laboratory characteristics between Group I versus Group II versus Group III
Comparison of Group I versus Group II In univariate analysis comparing Group I patients to Group II patients, the Group I patients were younger (median age = 10.0 years versus 15.0 years, P = 0.004), were more likely to present with fevers (P = 0.002), have a prodrome of
Group I (%)a Total (n)
43
Group II (%)a 459
Group III (%)a 649
Demographics Male
27 (63)
Age, median in years (range)
237 (52)
367 (57)
10.0 (8 months–53) 15.0 (7 months–89)c 30.0 (6 months–92)d
Race White
14 (33)
152 (33)
265 (41)
Hispanic
15 (35)
147 (32)
151 (23)
Black Asian
3 (7) 7 (16)
40 (9) 70 (15)
61 (9) 62 (10)
Other/unknown
4 (9)
50 (11)
110 (17)
1.0 (0–17)
1.0 (-4–712)
3.0 (-20–368)d
24 (57)
160 (37)c
194 (31)d
27 (64)
147 (35)
c
223 (36)d
10 (25)
57 (14)
c
84 (13)d
Fever
40 (93)
326 (72)c
423 (67)d
Personality change Extreme irritability
26 (65) 21 (53)
278 (64) 209 (48)
374 (60) 235 (38)
Clinical Interval from CNS onset to admit, median in days (range) Prodromeb Respiratory Gastrointestinal Rash Symptoms Abbreviations: CBC, complete blood count; WBC, white blood cell; CNS, central nervous system; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; CT, computerized tomography a Denominators may vary slightly depending on available data b
Assessed by the referring physician using a standard form Categorical data: Chi-square test or Fisher’s exact test as appropriate; Continuous data: Kruskal–Wallis test; significant at P < 0.05
c
Group I versus Group II differ significantly (P-value < 0.05)
d
Group I versus Group III differ significantly (P-value < 0.05)
b
Hallucinations
6 (16)
88 (22)
105 (17)
Stiff neck
9 (22)
102 (24)
236 (37)d
31 (78)
311 (71)
376 (60)d
6 (20)
115 (32)
240 (45)d
17 (42)
197 (46)
263 (42)
5 (12)
26 (6)c
32 (5)
Somnolence Ataxia Focal neurologic Laboratory CBC WBC: 5 WBC/ml)
20 (47)
286 (67)c
467 (77)d
CSF elevated protein (>45 mg/dl)
20 (47)
207 (50)
396 (67)d
>13.0 per ml
CSF decreased glucose (
