Neurocritical Care

, Volume 9, Issue 1, pp 74–82

Refractory Status Epilepticus in Suspect Encephalitis


    • Viral and Rickettsial Disease BranchCalifornia Department of Public Health
  • Sabrina Gilliam
    • Viral and Rickettsial Disease BranchCalifornia Department of Public Health
  • Somayeh Honarmand
    • Viral and Rickettsial Disease BranchCalifornia Department of Public Health
  • Jay H. Tureen
    • Department of PediatricsUniversity of California, San Francisco
  • Daniel H. Lowenstein
    • Department of NeurologyUniversity of California, San Francisco
  • Larry J. Anderson
    • Respiratory and Enteric Viruses BranchCenters for Disease Control and Prevention
  • Andrew W. Bollen
    • Department of PathologyUniversity of California, San Francisco
  • Marylou V. Solbrig
    • Department of NeurologyUniversity of California
Original Article

DOI: 10.1007/s12028-007-9042-y

Cite this article as:
Glaser, C.A., Gilliam, S., Honarmand, S. et al. Neurocrit Care (2008) 9: 74. doi:10.1007/s12028-007-9042-y



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.


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) 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.


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.


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.


EncephalitisStatus epilepticusRefractory seizuresAnesthetic comaPentobarbitalPhenobarbitalMalignant status epilepticusCalifornia Encephalitis Project


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 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.


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 ≥24 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.

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 summaries were requested on all Group I patients. Additional clinical information was received for 35 of these patients.


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 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.
Table 1

Comparison of demographic, clinical and laboratory characteristics between Group I versus Group II versus Group III


Group I (%)a

Group II (%)a

Group III (%)a







27 (63)

237 (52)

367 (57)

Age, median in years (range)

10.0 (8 months–53)

15.0 (7 months–89)c

30.0 (6 months–92)d



14 (33)

152 (33)

265 (41)


15 (35)

147 (32)

151 (23)


3 (7)

40 (9)

61 (9)


7 (16)

70 (15)

62 (10)


4 (9)

50 (11)

110 (17)


Interval from CNS onset to admit, median in days (range)

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



40 (93)

326 (72)c

423 (67)d

    Personality change

26 (65)

278 (64)

374 (60)

    Extreme irritability

21 (53)

209 (48)

235 (38)


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

    Focal neurologic

17 (42)

197 (46)

263 (42)



    <4.5 per ml

5 (12)

26 (6)c

32 (5)

    4.5–13.0 per ml

31 (74)

253 (59)

435 (71)

    >13.0 per ml

6 (14)

150 (35)

147 (24)

CSF pleocytosis (>5 WBC/ml)

20 (47)

286 (67)c

467 (77)d

CSF elevated protein (>45 mg/dl)

20 (47)

207 (50)

396 (67)d

CSF decreased glucose (<40 mg/dl)

0 (0)

17 (4)

44 (7)

MRI/CT (abnormal, initial study)

7 (16)

254 (57)c

311 (53)d

Mortality (at time of discharge)

9 (21)

69 (15)

56 (9)d

Abbreviations: CBC, complete blood count; WBC, white blood cell; CNS, central nervous system; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; CT, computerized tomography

aDenominators may vary slightly depending on available data

bAssessed 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

cGroup I versus Group II differ significantly (P-value < 0.05)

dGroup I versus Group III differ significantly (P-value < 0.05)

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 respiratory and gastrointestinal symptoms (P = 0.01 and P < 0.001, respectively), and rash (P = 0.05), but less likely to have an abnormal initial neuroimaging scan (P < 0.001) or CSF pleocytosis (P = 0.01) (Table 1).

Comparison of Group I versus Group III

In univariate analysis comparing Group I patients to Group III patients, the Group I patients were younger (median age = 10.0 years versus 30.0 years, P < 0.001) and had a shorter interval from onset of CNS symptoms to hospital admission (median number of days = 1.0 day versus 3.0 days, P < 0.001). They were also more likely to present with fevers (P < 0.001), have a prodrome of respiratory and gastrointestinal symptoms (P = 0.001 and P < 0.001, respectively), rash (P = 0.04), and somnolence (P = 0.03), but less likely to have an abnormal initial neuroimaging scan (P < 0.001), stiff neck (P = 0.05), ataxia (P = 0.01), CSF pleocytosis (P < 0.001), or elevated CSF protein (P = 0.001) (Table 1).

Multivariate Analysis

Using multivariate analysis, the development of refractory status epilepticus was associated with younger age (adjusted OR = 1.04, 95% CI: 1.01–1.06, P = 0.01), prodrome of gastrointestinal symptoms (adjusted OR = 2.4, 95% CI: 1.1–5.2, P = 0.03), fever (adjusted OR = 5.5, 95% CI: 1.2–24.3, P = 0.03), normal CBC WBC (adjusted OR = 0.4, 95% CI: 0.2–0.9, P = 0.03), and an initial normal neuroimaging scan (adjusted OR = 0.1, 95% CI: 0.1–0.3, P < 0.001) (Table 2).
Table 2

Risk analysis for the development of Refractory Status Epilepticus (Group I): Group I (n = 43) versus Group II (n = 459)

Risk factor

Adjusted OR from multivariate analysis (95% CI)



1.04 (1.01–1.06)


Respiratory illness

Not retained in model

Gastrointestinal illness

2.4 (1.1–5.2)



Not retained in model


5.5 (1.2–24.3)


CBC WBC (abnormal)

0.4 (0.2–0.9)


CSF pleocytosis

not retained in model

MRI/CT (abnormal, initial study)

0.1 (0.1–0.3)


Abbreviations: OR, odds ratio; CI, confidence interval; CBC, complete blood count; WBC, white blood cell; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; CT, computerized tomography

Supplementary Data on Group I Patients

The additional information about the Group I patients (admission laboratory, H&P, and discharge summaries) were received in 35 of 43 (81%) patients. Laboratory testing, including serum electrolytes, complete blood count, and liver function tests, was generally unremarkable. Results of serum or urine toxicology were negative in 18 of 19 patients; the one patient tested positive for tetra-hydrocannabinol. Clinically, the onset of status epilepticus was early in the course of the illness and the duration of illness was protracted. The median days from initial symptoms to onset of status epilepticus was 4 days (range 0–41). The median length of stay in the hospital for these patients was 47 days (range 9–222), and the median length of time they were in an anesthesia-induced coma was 15 days (range 2–76). Twenty-eight percent of these patients died within 2 years of onset (median days from onset to death = 64.0 days, range 9–652). Almost all surviving patients in Group I had major cognitive or motor impairment (see Table 3).
Table 3

Supplementary data for Group I


Group I (%)


Total (n)



Hospital course

Interval from onset of status to induced coma, median in days (range)

4.0 (0–41)


Number of days induced coma, median in days (range)

15.0 (2–76)


Length of hospital stay, median in days (range)

47.0 (9–222)

Includes patients who died during hospitalization

Classification of agents


3 (7)

Enterovirus (3)


2 (5)

Rotavirus (1), Epstein Barr virus (1)


7 (16)

Mycoplasma pneumoniae (5), Adenovirus (1), HHV6/metabolic myopathy (1)


31 (72)



Significant neurological impairment

24 (56)

18 (42%) entered rehabilitation after hospital discharge for continued management; most patients described by physician as having severe cognitive impairment

Home, baseline

1 (2)



6 (14)



12 (28)


Interval from onset to death, median in days (range)

64.0 (9–652)


Abbreviations: WBC, white blood cell; CSF, cerebral spinal fluid; MRI, magnetic resonance imaging; CT, computed tomography; CNS, central nervous system

aDenominators may vary slightly depending on available data; calculations of median/range based on available data

EEG abnormalities, based on general descriptions in the chart or original EEG reports, were identified in 42 of 43 patients. The formal EEG reports documented a range of abnormalities: generalized spike discharges, generalized spike and sharp wave activity, independent bi-hemispheric spike discharges, multi-focal sharp activity, repetitive sharp waves, focal epileptiform (spike or sharp wave) discharges, left or right temporal spike and sharp activity preceding generalized spread of activity; continuous spike and spike and wave activity; rhythmic 2–4 Hz spike wave discharges; electrographic seizures; or focal or generalized epileptiform activity. All patients were receiving anticonvulsants at the time EEGs were performed. In general, treatment with a range of different anticonvulsant agents was ineffective, necessitating anesthetic anticonvulsants at dosages to cause suppression of electrographic seizures or attainment of a burst-suppression pattern on the EEG.

All patients had at least one MRI performed, and the initial brain MRI or CT was unremarkable in 84% of patients. In those patients who had more than one study (n = 41), the subsequent neuroimaging showed focal or multifocal signal abnormalities in the temporal lobe and other cortices, subcortical gray matter, or cerebellar regions. Hyperintense T2 signal in mesial temporal regions, when found, was reported as consistent with herpes encephalitis. Other signal abnormalities overlapped findings typical of acute ischemic or postictal changes. No patients had imaging findings reported as acute disseminated encephalomyelitis (ADEM).

Three patients had brain biopsies and another three patients had autopsies. Biopsies in two patients showed mild astrogliosis with no inflammatory infiltrate present and no histopathology indicative of neuronal viral infection. Biopsy in the third patient demonstrated a meningoencephalitis with marked lymphocyte infiltrates in both the cortex and overlying leptomeninges and microglial nodules. No inclusions suggestive of a viral infection were noted and no pathogen was identified. The three autopsy brain specimens showed anoxic-ischemic damage, including cerebral edema and neuronal necrosis, but no parenchymal infiltration or other features suggestive of encephalitis. One patient had a meningeal infiltrate consistent with a lymphocytic meningitis.

Etiologic Studies

Of the 43 Group I patients, an etiology was identified in 12 (28%), all of whom were children. This rate of identification is similar to other patients in the CEP [6]. Based on previously designated criteria [7], three patients had a confirmed etiology (enteroviruses) and two patients had a probable etiology (rotavirus and EBV). Seven patients had a possible etiology [M. pneumoniae (five patients), HHV6 (one patient), and adenovirus (one patient)] (Table 3) based on serologic evidence of acute infection. The patient with positive rotavirus has been previously reported [8]. The patient with a HHV6 infection was also noted to have a possible mitochondrial disorder. In one additional patient, the hospital obtained a positive test for RSV on a respiratory swab, but follow-up testing at our laboratory was negative.


In this study, we sought to determine what features, if any, might distinguish patients with suspected encephalitis who developed refractory status epilepticus from those who did not. Our multivariate analysis determined that patients who are younger, have a prodrome of fever and gastrointestinal symptoms, or, interestingly, have a normal neuroimaging study initially, were significantly more likely to develop severe refractory status epilepticus than other encephalitis patients presenting with seizures. The microbiologic studies identified enterovirus in CSF in three, rotavirus in CSF in one and raised the possibility of CNS infection with EBV, HHV6, adenovirus and Mycoplasma pneumoniae in additional patients.

The younger age for the Group I patients could suggest an age-associated risk for exposure to some of the etiologic agents of the encephalitis (e.g., RSV, enterovirus, HHV6) or possibly an age-associated risk for a more severe outcome. The higher frequency of a prodromal illness suggestive of infection raises the possibility that a catabolic state was induced and unmasked a previously unsuspected inborn error of metabolism. However, the normal electrolyte, serum glucose, and liver function tests do not support this hypothesis. Another notable clinical feature was that two out of three patients with brain biopsy showed minimal histologic abnormalities. These modest pathologic findings, along with the non-inflammatory CSF findings and lack of abnormal neuroimaging findings, raise the possibility that a non-infectious process (such as an autoimmune disorder) was responsible for the disease in many of the patients. Non-infectious entities include drug and heavy metal toxicities, Hashimoto’s encephalopathy and other autoimmune disorders [9].

Enterovirus, identified in three patients, was the only agent with a well-established CNS neurotropism. Rotavirus was detected in the spinal fluid of one patient, but its role as a neurotropic agent is not proven [8]. The etiologic significance of EBV, HHV-6, adenovirus, and Mycoplasma pneumonia is unclear since there was serologic evidence of current infection but no direct evidence of CNS infection. These agents may have been present, but below the threshold of detection in CSF by our tests. A number of these pathogens are known to cause seizures and EEG abnormalities. Mycoplasma pneumonia has been associated with extreme spindles [10, 11], EBV can cause encephalitis with PLEDS [12] and HHV6 is associated with febrile seizures [13].

Similar cohort studies have been described in retrospective case series, including both children [14, 15] and adult patients [16]. For example, one report described epileptic encephalopathy of school-aged children in whom the seizures required anesthesia-induced coma for control [15]. As in our case series, many of these patients initially experienced a non-specific febrile prodrome. However, in contrast to our series, causal agents were not found [15]. Fifty percent of patients died in one of the pediatric case series [15]. Similarly, the morbidity was high; both pediatric series described ‘all patients’ with major cognitive difficulty or severe neurologic impairment. In a report of adults with status epilepticus a subgroup of patients were characterized as having a “malignant” variant of status epilepticus [16]. As in our study, the investigators found younger age to be significantly associated with refractory seizures [16].

Until further studies are done, management of these cases will continue to be very difficult. An extensive discussion of both conventional and unconventional therapy was included in a recent case report of an adult patient presenting with a similar syndrome as described in this article. This discussion about therapy may be helpful to clinicians managing these types of cases [17].

There are a number of limitations in the current study. First, our results may not be comparable to the general population because the CEP is not a population-based study but rather a large sampling of patients from throughout California. Second, there were limited pathologic data since few patients in our group underwent autopsy or brain biopsy, and the pathologic material may not truly reflect the initial disease process because, in most patients, it was obtained weeks after onset. Furthermore, given the retrospective nature of this study, data collection was not always complete and we relied primarily on the information given on the case history form. The outcome data for Group I were gathered primarily from discharge summaries that were descriptive in nature and could not be easily quantified or objectively measured.

A further limitation is inherent to the syndrome of encephalitis itself. Encephalitis generally refers to inflammation of the brain parenchyma and clinically presents as fever, headache, alteration in consciousness, impaired cognition, seizures, or focal neurologic signs [18]. Without the identification of a neurotropic agent through laboratory studies or direct analysis of brain tissue, the diagnosis of encephalitis is presumptive and based on clinical features. All the patients in our series met the CEP case definition for encephalitis, which is similar to that used in other studies [19] and is inherently sensitive but not specific. However, for all cases, the physicians generally have a strong suspicion for encephalitis prior to completing the case history form and collecting the appropriate specimens for referral of each case. Despite these limitations, this summary of patients provides important insights into this syndrome, especially since it represents a large study with comprehensive diagnostic testing for infectious agents at a common site and a thorough review of the available epidemiologic, clinical, and laboratory data.


We thank the clinicians who referred patients to the CEP. We thank Fred Schuster, David Schnurr, Karen Bloch, and Lisa Bateman for their careful review of the manuscript. We also gratefully acknowledge the laboratory staff in the CDHS VRDL and Microbial Disease Laboratory for performing the diagnostic testing. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Financial support: Centers for Disease Control and Prevention Emerging Infections Program (U50/CCU915546–10). M. Solbrig is supported by the National Institute of Neurological Disorders and Stroke (NINDS) grant NS042307 and D. Lowenstein by NINDS grants NS053998, NS056975, and U54RR023566.

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© Humana Press Inc. 2007