Clin Infect Dis. 2006 Glaser 1565 77

Encephalitis: Diagnosis and Management • CID 2006:43 (15 December) • 1565

M A J O R A R T I C L E

Beyond Viruses: Clinical Profiles and EtiologiesAssociated with Encephalitis

C. A. Glaser,1 S. Honarmand,1 L. J. Anderson,3 D. P. Schnurr,1 B. Forghani,1 C. K. Cossen,1 F. L. Schuster,1

L. J. Christie,1 and J. H. Tureen2

1Viral and Rickettsial Disease Laboratory, California Department of Health Services, Richmond, and 2Department of Pediatrics, University ofCalifornia, San Francisco, California; and 3Respiratory and Enteric Viruses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia

Background. Encephalitis is a complex syndrome, and its etiology is often not identified. The CaliforniaEncephalitis Project was initiated in 1998 to identify the causes and further describe the clinical and epidemiologiccharacteristics of encephalitis.

Methods. A standardized report form was used to collect demographic and clinical data. Serum, cerebrospinalfluid, and respiratory specimens were obtained prospectively and were tested for the presence of herpesviruses,arboviruses, enteroviruses, measles, respiratory viruses, Chlamydia species, and Mycoplasma pneumoniae. Theassociation between an identified infection and encephalitis was defined using predetermined, organism-specificcriteria for confirmed, probable, or possible causes.

Results. From 1998 through 2005, a total of 1570 patients were enrolled. Given the large number of patients,subgroups of patients with similar clinical characteristics and laboratory findings were identified. Ten clinicalprofiles were described. A confirmed or probable etiologic agent was identified for 16% of cases of encephalitis:69% of these agents were viral; 20%, bacterial; 7%, prion; 3%, parasitic; and 1%, fungal. An additional 13% ofcases had a possible etiology identified. Many of the agents classified as possible causes are suspected but havenot yet been definitively demonstrated to cause encephalitis; these agents include M. pneumoniae ( ), influenzan p 96virus ( ), adenovirus ( ), Chlamydia species ( ), and human metapneumovirus ( ). An p 22 n p 14 n p 10 n p 4noninfectious etiology was identified for 8% of cases, and no etiology was found for 63% of cases.

Conclusions. Although the etiology of encephalitis remains unknown in most cases, the recognition of discreteclinical profiles among patients with encephalitis should help focus our efforts toward understanding the etiology,pathogenesis, course, and management of this complex syndrome.

Encephalitis is a complex, severe, neurological syn-

drome that is associated with significant morbidity and

mortality, and the etiology of the syndrome often is

not identified [1]. The California Encephalitis Project

(CEP) was initiated to identify the etiologic agents and

define the clinical and epidemiologic characteristics as-

sociated with encephalitis. A previously published re-

port summarized data for the first 334 patients with

encephalitis enrolled in the CEP [2]. In addition, in-

dividual agent-specific case series have also been re-

ported [3–8]. The present article provides an updated

Received 20 June 2006; accepted 11 September 2006; electronically published8 November 2006.

Reprints or correspondence: Dr. Carol A. Glaser, Dept. of Health Services, Viraland Rickettsial Disease Laboratory, 850 Marina Bay Pkwy., Richmond, CA 94804([email protected]).

Clinical Infectious Diseases 2006; 43:1565–77� 2006 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2006/4312-0007$15.00

summary and overview. Based on 11500 cases of en-

cephalitis, the study has identified (1) patient profiles

with similar clinical characteristics and laboratory find-

ings, (2) etiologies that might otherwise have been

missed, and (3) potential novel etiologic agents of en-

cephalitis. These data provide new insights into the

features of this devastating syndrome, and they provide

new ways to consider possible causes and patient

management.

PATIENTS, MATERIALS, AND METHODS

Case finding and enrollment. Patients were referred

to the study by treating physicians and were enrolled

if they were immunocompetent, were �6 months of

age, and met the CEP case definition of encephalitis.

A “case patient” was defined as a patient hospitalized

with encephalopathy (defined by a depressed or altered

level of consciousness lasting �24 h, lethargy, or a per

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Table 1. California Encephalitis Project core testing, 1998–2005.

Specimen type, etiologic agent Test type Comment

CSFHerpes consensusa Conventional PCR Discontinued in 2003b

HSV-1 Real-time PCR [9] Initiated in 2003HSV-2 Real-time PCR [9] Initiated in 2003VZV Real-time PCR [9] Initiated in 2003Mycoplasma pneumoniae Real-time PCR [10] Initiated in 1999Enterovirus Real-time PCR [11] …Measles Serological testing [12] IgG EIAc

General viral isolation Culture Discontinued in 2000d

SerumAcute phase

SLE virus Serological testing [12] IgG EIAc

WEE virus Serological testing [12] IgG EIAc

West Nile virus Serological testing Initiated in 2001; IgM capture EIA (Focus)Epstein-Barr virus Serological testing IgG IFA, IgM IFA, EBNA (Pan Bio)Enterovirus Serological testing Discontinued in 2002e

M. pneumoniae Serological testing IgM EIA (Meridian)Measles Serological testing [12] IgG EIAc

Bartonella species Serological testing Discontinued in 2003f

Convalescent phaseSLE virus Serological testing [12] IgG EIAc

WEE virus Serological testing [12] IgG EIAc

West Nile virus Serological testing Initiated in 2001; IgM capture EIA (Focus)M. pneumoniae Serological testing IgM EIA (Meridian), IgG EIAc [12]Measles Serological testing [12] IgG EIAc

HSV Serological testing [12] IgG EIAc

VZV Serological testing [12] IgG EIAc

Adenovirus Serological testing [12] IgG EIAc

Chlamydia species Serological testing [12] IgG EIAc

Influenza A and B viruses Serological testing [12] IgG EIAc

Bartonella species Serological testing Discontinued in 2003f

RespiratoryEnterovirus Real-time PCR [11] …M. pneumoniae Real-time PCR [10] Initiated in 2001Influenza A and B viruses Real-time PCR Initiated in 2003; discontinued in 2004g

Respiratory panelh Real-time PCR [10] Initiated in 2004General viral isolation Culture Primary monkey kidney and human fetal

diploid cells

NOTE. EBNA, Epstein-Barr virus nuclear antigen; HSV, herpes simplex virus; IFA, indirect fluorescent antibody test;SLE, St. Louis encephalitis; VZV, varicella-zoster virus; WEE, Western equine encephalitis.

a Herpes consensus includes HSV-1 and -2, VZV, Epstein Barr virus, cytomegalovirus, and human herpesvirus 6.b Changed to individual herpes PCR (HSV-1, HSV-2, VZV). Cytomegalovirus testing is no longer conducted because

of low yield in normal host, Epstein-Barr virus testing is done primarily by serologic methods, and human herpesvirus6 testing is currently not part of core testing but is being further evaluated.

c In house.d Due to low yield.e No longer part of core testing; testing was performed if PCR results for CSF and/or respiratory specimens were

positive and/or for clinically compatible cases.f No longer part of core testing; testing now performed for clinically compatible cases.g Changed to a full respiratory panel.h Influenza A and B viruses, adenovirus, human metapneumovirus, and respiratory syncytial virus type A.


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Table 2. Details of California Encephalitis Project (CEP) selective testing, 1998–2005.

Disease or selective pathogena,b

No. ofcasestested Criterion or criteria for testing

Additional arboviruses 195 Travel outside of California and/or extensive mosquito exposureBalamuthia mandrillaris 273 Space-occupying lesion on MRI and/or suggestive laboratory findingsBartonella species 269 Potential exposure to cats or other animals and/or suggestive clinical and

laboratory findingsBaylisascaris procyonis 12 Potential exposure to raccoon feces and/or eosinophiliaBorrelia burgdorferi 15 Cranial nerve involvement and/or tick exposureBrucella species 24 Potential exposure to unpasteurized dairy productsColorado tick fever 7 Potential tick or geographic exposure and/or suggestive laboratory valuesCreutzfeldt-Jakob diseasec 10 Insidious onset and/or compatible clinical findingsEhrlichia species 59 Potential tick or geographic exposure and/or suggestive laboratory valuesHepatitis C 9 Known hepatitis C virus seropositivityLeptospira species 36 Potential exposure to fresh water or hepatitisLymphocytic choriomeningitis 114 Potential exposure to rodentsMumps 36 Cerebellar or brain stem findings and/or unclear vaccine historyMycobacterium tuberculosis 103 Exposure to pathogen and/or suggestive laboratory valuesParvovirus B19 21 Rash illness or anemiaCoxiella burnetii 50 Potential exposure and/or suggestive laboratory valuesRabies 140 Potential exposure and/or rapid deteriorationRickettsia rickettsii 64 Potential tick exposure and/or suggestive laboratory valuesRotavirus 14 Young age, diarrhea, and/or rotavirus antigen–positive stoolRubella 23 Illness consistent with SSPE, but results of tests for measles are

negativeToxocara species 4 Potential exposure to cat/dog feces and/or eosinophilia and results of

tests for B. procyonis are negativeTrichinella species 3 Eosinophilia and negative results of tests for B. procyonisFrancisella tularensis 17 Rural exposure and/or suggestive clinical featuresRickettsia typhi 67 Rural exposure and/or suggestive laboratory values

NOTE. SSPE, subacute sclerosing panencephalitis.a Fungal testing (e.g., for Coccidioides immitis, Cryptococcus neoformans, and Histoplasma capsulatum) was usually performed at the

referring institution. During the early phase of the study, the CEP facilitated fungal testing for several patients.b For many CEP patients, other testing (e.g., for M. tuberculosis, Borrelia burgdorferi, and Creutzfeldt-Jakob prion disease) on the basis

of exposure, clinical presentation, and/or laboratory findings was performed by the referring institution (sometimes in parallel with CEPtesting).

c 14-3-3 protein.

sonality change) with �1 of the following characteristics:

fever, seizure, focal neurological findings, pleocytosis, or

electroencephalography or neuroimaging findings consistent

with encephalitis.

The referring physician completed a case history form that

included information on exposures (e.g., animal or arthropod

contact, recent immunization, medications, etc.), travel, labo-

ratory findings, and clinical and demographic characteristics.

CSF, respiratory, and acute- and convalescent-phase serum

specimens were requested for diagnostic testing. When a brain

biopsy or autopsy was performed, brain tissue specimens were

also requested by the CEP.

CEP testing. A core battery of tests was performed on the

specimens obtained from each patient (table 1). Testing for 16

potential infectious agents of encephalitis, including herpes-

viruses (herpes simplex virus [HSV] 1 and HSV-2), varicella-

zoster virus (VZV), enteroviruses (EVs), measles, St. Louis en-

cephalitis virus, Western equine encephalitis virus, West Nile

virus (WNV), Epstein-Barr virus (EBV), respiratory viruses,

and bacteria (Mycoplasma pneumoniae and Chlamydia species).

Details about CEP testing are described in table 1. Specialized

testing for serum antibodies was done using EIA or indirect

fluorescent antibody testing performed using standard methods

[12]. Agent-specific PCR analyses were performed at the Viral

and Rickettsial Disease Laboratory (California Department of

Health Services; Richmond, CA) [9–11] and other reference

laboratories (e.g., the Centers for Disease Control and Preven-

tion; Atlanta, GA). Testing for additional agents was performed

on the basis of exposure or travel history, time of year, clinical

symptoms, the request of physicians, and the availability of


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1568 • CID 2006:43 (15 December) • Glaser et al.

Table 3. Diagnosis category definitions.

Category Definition Examples from study

Confirmed1a Agent is a well-established cause of encephalitis, Infection due to Baylisascaris procyonis,a enterovirus,

HSV-1, VZV, and WNV; measles causing SSPE; rabies1b agent is detected in CSF or brain specimens OR results of

antibody testing are positive in instances in which PCR isnot the diagnostic test of choice, AND

…

1c clinical presentation and epidemiological profile are consis-tent with infection.

…

Probable1a Agent is a well-established cause of encephalitis, Infection due to Bartonella species, EBV, and HSV-11b agent is not detected in CSF or brain specimens, but there

is strong serological or culture-based evidence of infec-tion, AND

…

1c clinical presentation and epidemiological profile are consis-tent with infection; OR

…

2a agent is not a well-established cause of encephalitis, AND Infection due to hepatitis C virus, HHV-6, Mycoplasmapneumoniae, and rotavirus

2b agent is detected in CSF or brain specimens by PCR. …Possible

1a Agent is a well-established agent of encephalitis, Infection due to Brucella species, enteroviruses, HSV-1,influenza A and B viruses, and VZV

1b clinical presentation and epidemiological profile are consis-tent with infection, AND

…

1c serologic evidence of infection was suggestive but not con-clusive or a positive culture result was noted for a speci-men obtained from a site other than the CNS site; OR

…

2a agent is not well-established or the diagnostic method hasnot been developed,

Infection due to adenovirus, Chlamydia species,M. pneumoniae, and RSV

2b clinical presentation and epidemiological profile are consis-tent with infection, AND

…

2c there is strong serologic or culture-based evidence of infec-tion at a site other than the CNS site.

…

NOTE. EBV, Epstein-Barr virus; HHV-6, human herpesvirus 6; HSV-1, herpes simplex virus 1; RSV, respiratory syncytial virus, SSPE, subacute sclerosingpanencephalitis; VZV, varicella-zoster virus; WNV, West Nile virus.

a PCR is not available or is not the diagnostic test of choice.

appropriate specimens (table 2). Fungal and prion testing were

performed by the referring institution. Methods are further

described elsewhere [2].

Input from the referring institution. Staff from the CEP

were in telephone contact with the referring institution for �2

weeks, depending on the severity of the case. The follow-up calls

provided information on additional laboratory and neuroim-

aging findings, as well as updates on each patient’s condition.

Classification of the association between a pathogen and

encephalitis. We defined the association between an identified

agent and the encephalitis case as confirmed, probable, or possible,

on the basis of the type of specimen in which the potential etiologic

agent was detected, the strength of the previously established as-

sociations between the agent and encephalitis, and the clinical and

epidemiologic characteristics of the disease (table 3).

Statistical analysis. The data were analyzed using Fisher’s ex-

act test or the Kruskal-Wallis test, as appropriate, with statistical

significance denoted by .P � .05

RESULTS

Characteristics of Study Patients

From 1998 through 2005, a total of 2494 patients were referred

to the CEP from 195 institutions throughout California. Of

these patients, 924 were excluded for �1 of the following rea-

sons: insufficient samples or data were provided or patients had

severe immunosuppression, had not been hospitalized, had a

history of prior severe neurological impairment, or were !6

months old. A total of 1570 patients were eligible for evaluation.

Of the 1570 study patients, 1533 (98%) provided CSF speci-

mens, 1540 (98%) provided acute-phase serum specimens, and

696 (44%) provided convalescent-phase serum specimens. De-

mographic and clinical characteristics and laboratory data are


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Table 4. Summary of characteristics of and findings for 1570California Encephalitis Project patients, 1998–2005.

Characteristic or finding Value

DemographicMale 878 (56)Age, median years (range) 23.0 (0–92)Race

White 580 (37)Hispanic 428 (27)Black 138 (9)Asian 191 (12)Other/unknown 223 (14)

ClinicalInterval from onset to hospital admission,a

median days (range) 2.0 (�6 to 712)ICU admission 807 (58)Prodrome or concurrent symptom

Fever 1032 (67)Respiratory symptom 495 (33)Gastrointestinal symptom 501 (34)Rash 194 (13)

Seizure 640 (42)Coma 267 (18)Death

All 162 (11)Within 3 weeks of hospitalization 102 (7)

LOHS, median days (range) 11.0 (0–1124)Laboratory

CSF WBC count, median cells/mm3 (range) 23.0 (0–13,000)CSF protein level, median mg/dL (range) 57.0 (7–11,723)CSF glucose level, median mg/dL (range) 64.0 (6–533)

Initial abnormal neuroimaging 770 (54)

NOTE. Data are no. (%) of patients, unless otherwise indicated. De-nominators used in the calculation of percentages may vary slightly, de-pending on the available data. ICU, intensive care unit; LOHS, length ofhospital stay.

a Interval from onset of CNS symptoms to hospital admission. For 3patients, CNS symptoms developed after admission to the hospital for anonspecific illness.

summarized in table 4. The demographic characteristics of CEP

patients differed from those of the California population in

that pediatric patients (45% vs. 27%) and male patients (56%

vs. 50%) were slightly overrepresented in the CEP. In addition,

blacks (10% vs. 6%) were overrepresented in the CEP popu-

lation, whereas whites (41% vs. 45%) and Hispanics (30% vs.

35%) were slightly underrepresented.

Infectious and Noninfectious Etiologies

A confirmed or probable infectious cause of encephalitis was

determined for 248 CEP patients, and a noninfectious cause

was determined for 122 patients. For cases of encephalitis with

an infectious cause, viral pathogens were most commonly de-

tected, followed by bacterial, parasitic, prion, and fungal eti-

ologies (table 5). Some patients were found to have infectious

meningitis rather than encephalitis. A possible infectious cause

was identified for an additional 208 patients (13%).

Confirmed and Probable Viral Agents

A total of 170 patients had encephalitis with a confirmed or

probable viral etiology, and the most commonly identified viral

agents were EV (for 25% of cases) and HSV-1 (for 24% of

cases). The demographic, clinical, and laboratory data for pa-

tients with encephalitis due to viral and other etiologic agents,

which were identified in association with �5 cases, are sum-

marized in table 6. The median age of individuals with HSV-

1 (54.0 years), VZV (44.0 years), and WNV (66.0 years) en-

cephalitis was greater than that of individuals with EV (12.0

years) and EBV (11.0 years) encephalitis and measles causing

subacute sclerosing panencephalitis (12.0 years). WNV and EV

encephalitis occurred more commonly in the summer, but no

other seasonal association was observed.

As expected, many (75%) of the patients with viral ence-

phalitides presented with fever. Important exceptions included

individuals with measles causing subacute sclerosing panen-

cephalitis, VZV infection, and hepatitis C. No consistent pro-

dromes were seen in association with any specific virus except

influenza virus (respiratory prodromes) and rotavirus (gastro-

intestinal prodrome). Seizures were noted in 38% of patients

with viral encephalitis, most commonly among patients with

measles causing subacute sclerosing panencephalitis (83%), hu-

man herpesvirus 6 infection (75%), and HSV-1 infection

(59%). The initial MRI findings were abnormal for 87 patients

(60%) and were most frequently abnormal for patients with

HSV-1 (93%).

Nonviral Infectious Agents

A confirmed or probable nonviral agent was identified for 78

cases (5%), including cases of meningitis. The bacterial agents

identified were diverse, including Mycobacterium tuberculosis

( ), Bartonella species ( ), M. pneumoniae (n p 19 n p 13 n p

), and Tropheryma whippelii ( ); in addition, 14 cases of2 n p 1

pyogenic bacteria were identified (table 6).

Seven parasitic infections were identified (4 due to Bala-

muthia mandrillaris and 3 due to Baylisascaris procyonis). Of

the patients with infection due to B. mandrillaris, 75% were

male, all were Hispanic [13], and their age range was 3–64

years. Pleocytosis (median CSF WBC count, 126 cells/mm3),

an elevated protein level (median, 945 mg/dL), and abnormal

neuroimaging findings were noted for all patients. The infec-

tions due to B. procyonis occurred in children whose age ranged

from 11 months to 17 years, and all of these children had CSF

and peripheral eosinophilia.

Fungal testing for Cryptococcus neoformans and Coccidioides

immitis was performed by the referring hospital at the discretion


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Table 5. Aggregate data for California Encephalitis Project patients with encephalitis with a confirmed or probable etiology, byetiologic agent.

Characteristic or findingViral

(n p 170)Bacterial(n p 50)

Prion(n p 18)

Parasitic(n p 7)

Fungal(n p 3)

DemographicMale 94 (55) 32 (64) 10 (56) 6 (86) 3 (100)Age, median years (range) 33.0 (0–89) 19.5 (0–77) 66.0 (44–84) 7.0 (0–64) 15.0 (1–22)Race

White 73 (44) 24 (48) 12 (67) 2 (29) 0 (0)Hispanic 38 (23) 16 (32) 1 (6) 5 (71) 1 (33)Black 11 (7) 2 (4) 0 (0) 0 (0) 1 (33)Asian 15 (9) 7 (14) 1 (6) 0 (0) 1 (33)Other/unknown 30 (18) 1 (2) 4 (22) 0 (0) 0 (0)

ClinicalInterval from onset to hospital admission,a

median days (range) 3.0 (0–65) 1.0 (0–107) 36.0 (0–476) 4.0 (1–12) 81.0 (6–208)ICU admission 81 (55) 37 (82) 2 (13) 6 (86) 3 (100)Prodrome or concurrent symptom

Fever 125 (75) 37 (74) 6 (35) 5 (71) 3 (100)Respiratory symptom 38 (24) 14 (30) 4 (25) 1 (14) 2 (67)Gastrointestinal symptom 69 (42) 19 (41) 1 (6) 3 (43) 3 (100)Rash 30 (18) 9 (19) 2 (12) 0 (0) 2 (67)

Seizure 63 (38) 24 (48) 3 (19) 2 (29) 0 (0)Coma 23 (14) 15 (30) 4 (22) 3 (43) 0 (0)Deathb 22 (13) 5 (11) 12 (67) 4 (58) 0 (0)LOHS, median days (range) 10.0 (0–1124) 12.0 (2–66) 16.5 (5–40) 16.0 (8–63) 39.5 (11–68)

LaboratoryCSF WBC count, median cells/mm3 (range) 70.0 (0–2250) 54.0 (0–13,000) 0.0 (0–115) 49.0 (5–354) 117.0 (20–737)CSF protein level, median mg/dL (range) 71.0 (15–881) 92.0 (12–961) 47.0 (20–114) 70.0 (26–1247) 176.0 (51–319)CSF glucose level, median mg/dL (range) 67.0 (28–284) 62 (9–157) 66.0 (58–94) 59.0 (6–74) 25.0 (9–44)

Initial abnormal neuroimaging 87 (60) 30 (62) 15 (88) 7 (100) 3 (100)

NOTE. Data are no. (%) of patients, unless otherwise indicated. Denominators used in the calculation of data may vary slightly, depending on the availabledata. ICU, intensive care unit; LOHS, length of hospital stay.

a Interval from the onset of CNS symptoms to admission to the hospital.b Deaths reported to the California Encephalitis Project.

of the clinician. Three individuals in the CEP were identified

as having fungal infections (2 due to C. immitis and 1 due to

C. neoformans). All 3 patients had an elevated CSF WBC count

(median, 117 cells/mm3), an elevated CSF protein level (me-

dian, 176 mg/dL), and a depressed CSF glucose level (median,

25 mg/dL).

Possible Agents and/or Causes

A total of 204 patients who had a possible etiologic agent iden-

tified were classified as belonging to 1 of 2 categories, as out-

lined in table 3. Acute infection with M. pneumoniae was iden-

tified in 96 patients, a higher frequency than was noted for any

other agent. However, most of these cases were classified as

“possible” because, although there was serological evidence (in

88 cases) and/or PCR evidence (in 18 cases) of an acute in-

fection, the organism was not detected from a CNS site. Other

possible etiologies included influenza A and B viruses (22 cases),

adenovirus (14), HSV-1 (13), Chlamydia species (10), human

metapneumovirus (4), VZV (4), human herpesvirus 6 (2), re-

spiratory syncytial virus (2), Brucella species (2), rotavirus (2),

parainfluenza virus (1), Bartonella species (1), EBV (1), Creutz-

feldt-Jakob prion disease (1), and mixed respiratory infections

(5). Twenty-eight cases of possible EV infection were identified;

15 were identified by detection of EV in respiratory samples,

whereas the remainder were identified by serum EV IgM assay.

Noninfectious Etiologies

For ∼8% of cases, a noninfectious etiology was identified by

the referring institution. These noninfectious causes were as-

sociated with 52 cases of autoimmune disease and/or vasculitis

(43%), 33 neoplastic cases (27%), 7 metabolic cases (6%), and

30 cases due to other disorders (25%).


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Tabl

e6.

Char

acte

rist

ics

ofan

dfin

ding

sfo

rpa

tient

sw

ithen

ceph

aliti

s,ac

cord

ing

tovi

ral

orba

cter

ial

etio

logy

.

Cha

ract

eris

ticor

findi

ng

Vira

letio

logy

Bac

teria

letio

logy

Ent

erov

irus

(np

43)

HS

V-1

(np

40)

VZV

(np

23)

WN

V(n

p19

)E

BV

(np

17)

Mea

sles

caus

ing

SS

PE

(np

6)H

SV-

2(n

p5)

MTB

(np

19)

Pyo

geni

cba

cter

ia(n

p14

)

Bar

tone

llasp

ecie

s(n

p13

)

Dem

ogra

phic

Mal

e24

(56)

15(3

8)17

(74)

15(7

9)8

(47)

4(6

7)2

(40)

12(6

3)10

(71)

7(5

4)

Age

,m

edia

nye

ars

(ran

ge)

12.0

(0–7

4)54

.0(0

–89)

44.0

(4–8

5)66

.0(1

3–84

)11

.0(1

–34)

12.0

(9–1

5)46

.0(3

5–77

)45

.0(0

–77)

17.5

(0–6

7)7.

0(4

–40)

Rac

e

Whi

te13

(30)

22(5

5)12

(55)

12(6

3)6

(35)

0(0

)1

(25)

3(1

6)11

(79)

9(6

9)

His

pani

c14

(33)

7(1

8)1

(5)

5(2

6)5

(29)

4(6

7)1

(25)

8(4

2)2

(14)

4(3

1)

Bla

ck3

(7)

0(0

)1

(5)

1(5

)2

(12)

0(0

)1

(25)

1(5

)0

(0)

0(0

)

Asi

an6

(14)

2(5

)2

(9)

0(0

)1

(6)

2(3

3)0

(0)

7(3

7)0

(0)

0(0

)

Oth

er/u

nkno

wn

7(1

6)9

(22)

6(2

7)1

(5)

3(1

8)0

(0)

1(2

5)0

(0)

1(7

)0

(0)

Clin

ical

Inte

rval

from

onse

tto

hosp

itala

dmis

sion

,a

med

ian

days

(ran

ge)

2.0

(0–7

4)2.

0(0

–28)

4.0

(0–2

3)3.

0(0

–14)

2.0

(0–1

5)9.

5(1

–912

)1.

5(0

–2)

5.0

(0–6

1)0.

0(0

–5)

0.0

(0–2

)

ICU

adm

issi

on18

(49)

20(5

7)11

(58)

10(5

9)11

(69)

3(5

0)1

(20)

13(7

7)12

(86)

10(7

7)

Pro

drom

eor

conc

urre

ntsy

mpt

om

Feve

r31

(72)

35(9

0)12

(52)

19(1

00)

14(8

2)2

(33)

4(8

0)14

(74)

9(6

4)12

(92)

Res

pira

tory

sym

ptom

s12

(29)

8(2

1)6

(26)

2(1

1)8

(47)

0(0

)0

(0)

3(1

6)6

(46)

4(3

6)

Gas

troi

ntes

tinal

sym

ptom

s17

(41)

18(4

6)7

(30)

9(5

0)9

(53)

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Figure 1. Number of patients with confirmed or probable etiologic agents of encephalitis identified, by CSF WBC count and type of etiologic agent.The etiologic agent(s) and the number of patients with the etiologic agent(s) identified are listed according to diagnosis category definition. 1a comprises6 patients with Epstein-Barr virus (EBV) infection, 5 with enterovirus (EV) infection, 5 with herpes simplex virus 1 (HSV-1) infection, 3 with varicella-zoster virus (VZV) infection, 2 with West Nile virus (WNV) infection, 2 with measles causing subacute sclerosing panencephalitis (SSPE), 2 with rabies,and 1 with rotavirus infection. 1b comprises 15 patients with HSV-1 infection, 7 with EV infection, 6 with WNV infection, 4 with VZV infection, 4with EBV infection, 3 with measles causing SSPE, 1 with acute HIV infection, 1 with hepatitis C, 1 with human herpesvirus-6 (HHV-6) infection, 1with rabies, and 1 with rotavirus infection. 1c comprises 13 patients with EV infection, 9 with WNV infection, 9 with HSV-1 infection, 7 with VZVinfection, 3 with EBV infection, 2 with HHV-6, 2 with hepatitis C, 1 with measles causing SSPE, and 1 with acute HIV infection. 1d comprises 8patients with HSV-1 infection, 7 with VZV infection, 6 with EV infection, 1 with WNV infection, 1 with HSV-2 infection, 1 with acute HIV infection,and 1 with EBV infection. 1e comprises 4 patients with EV infection, 3 with HSV-2 infection, 2 with HSV-1 infection, 1 with EBV infection, 1 withHHV-6 infection, and 1 with rotavirus infection. 2a comprises 11 patients with infection due to Bartonella species, 1 with infection due to Mycoplasmapneumoniae, 1 with Rocky Mountain spotted fever, 1 with poststreptococcal glomerulonephritis, 1 with infection due to Streptococcus agalactiae, 1with urosepsis and infection due to Klebsiella species, and 1 with Sydenham chorea. 2b comprises 2 patients with infection due to Mycobacteriumtuberculosis, 2 with infection due to Streptococcus pneumoniae, 1 with infection due to M. pneumoniae, 1 with infection due to Tropheryma whippelii,1 with infection due to Staphylococcus aureus, and 1 with endocarditis. 2c comprises 9 patients with infection due to M. tuberculosis, 1 with infectiondue to Bartonella species, 1 with infection due to Neisseria meningitidis, and 1 with infection due to Streptococcus viridans. 2d comprises 4 patientswith infection due to M. tuberculosis and 1 with group C b-hemolytic Streptococcus infection. 2e comprises 4 patients with infection due to M.tuberculosis, 2 with infection due to N. meningitides, 1 with infection due to methicillin-resistant S. aureus, and 1 with infection due to S. aureus.3a comprises 1 patient with infection due to Baylisascaris procyonis. 3b comprises 2 patients with infection due to B. procyonis. 3c comprises 2patients with infection due to Balamuthia mandrillaris. 3d comprises 1 patient with infection due to B. mandrillaris. 4a comprises 1 patient withinfection due to Cryptococcus neoformans. 4b comprises 1 patient with infection due to Coccidioides immitis. 4c comprises 1 patient with infectiondue to C. immitis.

Comparative CSF Values

As shown in figure 1 and figure 2, patients with cases due to

viral and bacterial agents had a wide range of CSF WBC counts

and protein levels, as did patients with cases due to noninfec-

tious etiologies. Not surprisingly, comparison of the CSF lab-

oratory values indicates that patients who had an infectious

agent diagnosed had a higher CSF WBC count than did patients

who had a noninfectious agent diagnosed (median CSF WBC

count, 53.5 vs. 9.5 cells/mm3; ). However, the differenceP ! .001

in CSF protein levels was not significant (median level, 71.0

vs. 67.0 mg/dL).

Clinical Profiles

Ten distinct constellations of clinical characteristics—4 focal

and 6 generalized clinical profiles—were recognized in ap-

proximately one-half of the patients. For the remaining pa-

tients, we could not identify groups with common, distinct

characteristics. Patients within a profile were analyzed to de-

termine whether they had other characteristics in common,

such as prodromal symptoms, course of illness, demographic

characteristics, infectious or noninfectious causes of illness,

and/or outcomes (table 7).

Focal Group of Encephalitides

Temporal lobe involvement. The most common profile (in

144 cases) was encephalitis with temporal lobe enhancement

noted on MRI or CT. Not surprisingly, HSV-1 was the most

common agent identified (in 32 [22%] of cases). Other her-

pesviruses identified in this profile group included VZV (5

cases), EBV (2 cases), and human herpesvirus 6 (1 case). An


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Figure 2. Number of patients with confirmed or probable etiologic agents of encephalitis identified, by CSF protein level and type of etiologic agent.The etiologic agent(s) and the number of patients with the etiologic agent(s) identified are listed according to diagnosis category definition. 1a comprises16 patients with enterovirus (EV) infection, 11 with herpes simplex virus 1 (HSV-1) infection, 8 with Epstein-Barr virus (EBV) infection, 4 with measlescausing subacute sclerosing panencephalitis (SSPE), 2 with hepatitis C, 2 with rabies, 2 with rotavirus infection, 1 with human herpesvirus 6 (HHV-6) infection, and 1 with varicella-zoster virus (VZV) infection. 1b comprises 16 patients with HSV-1 infection, 13 with EV infection, 13 with West Nilevirus (WNV) infection, 9 with VZV infection, 5 with EBV infection, 2 with measles causing SSPE, 1 with hepatitis C, and 1 with HHV-6. 1c comprises8 patients with HSV-1 infection, 8 with VZV infection, 5 with EV infection, 4 with WNV infection, 4 with HSV-2 infection, 2 with EBV infection, 2with HHV-6 infection, 2 with acute HIV infection, and 1 with rabies. 1d comprises 1 patient with VZV infection, 1 with EV infection, and 1 with acuteHIV infection. 2a comprises 8 patients with infection due to Bartonella species, 1 with infection due to Mycoplasma pneumoniae, 1 with poststreptococcalglomerulonephritis, 1 with urosepsis and infection due to Klebsiella species, and 1 with Sydenham chorea. 2b comprises 4 patients with infectiondue to M. tuberculosis, 3 with infection due to Bartonella species, 2 with infection due to Streptococcus pneumoniae, 1 with infection due toTropheryma whippelli, 1 with infection due to M. pneumoniae, 1 with infection due to Streptococcus viridans, and 1 with Staphylococcus aureusendocarditis. 2c comprises 13 patients with infection due to M. tuberculosis, 1 with infection due to Neisseria meningitidis, and 1 with infection dueto S. aureus. 2d comprises 2 patients with infection due to M. tuberculosis, 2 with infection due to N. meningitidis, 1 with infection due to Bartonellaspecies, 1 with group C b-hemolytic Streptococcus infection, and 1 with infection due to Streptococcus agalactiae. 3a comprises 2 patients withinfection due to Baylisascaris procyonis. 3b comprises 1 patient with infection due to B. procyonis. 3c comprises 2 patients with infection due toBalamuthia mandrillaris. 4a comprises 1 patient with infection due to Cryptococcus neoformans. 4b comprises 1 patient with infection due to Coccidioidesimmitis. 4c comprises 1 patient with infection due to C. immitis.

additional 42 patients had temporal lobe activity noted on elec-

troencephalography but had no enhancement noted on CT or

MRI. The etiologic agents identified for this group of patients

were similar to those identified for patients with temporal le-

sions visualized on neuroimaging.

Movement and/or extrapyramidal disorders. Movement

disorders were observed in 47 patients. These patients were

younger (median age, 11 years) than other patients in the CEP

(median age, 23 years) ( ). The length of hospitalizationP ! .001

was prolonged for this group of patients (median duration, 39

days), compared with that noted for other patients in the CEP

(median duration, 11 days) ( ), but the mortality rateP ! .001

for this group (9%) was comparable to the overall morality

rate noted in the CEP study (11%).

Cerebellar disorders. Eighty-seven patients presented with

a predominance of cerebellar signs (i.e., ataxia and dysmetria)

and/or focal cerebellar lesions noted on MRI. The median age

of this group was 15 years, compared with a median age of 23

years for other patients in the CEP ( ). The mortalityP p .001

rate for this group (2%) was lower than the overall mortality

rate noted in the CEP (11%) ( ). No single infectiousP p .01

agent was found to be predominant in this group, and a rel-

atively high percentage (16%) of noninfectious etiologies were

identified.

Hydrocephalus. Thirty-two patients who presented with

encephalitis were found to have new-onset hydrocephalus. A

relatively high percentage of nonviral organisms (47%) were

identified in this profile group, and these organisms included

bacterial (11 cases), fungal (2 cases), and parasitic (2 cases)

agents.

Generalized Group of Encephalitides

Diffuse cerebral edema. Forty-seven patients presented with

or developed diffuse generalized cerebral edema within 7 days

of admission, as evidenced by CT, MRI, or autopsy findings.


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Table 7. Clinical profiles of California Encephalitis Project cases, 1998–2005.

Clinical profile Patient description

Age,median

years (range)

Outcome Viral etiologic agenta

Mortalityrate, %

LOHS,median

days (range) Confirmed or probable

Focal

Temporal lobe (n p 186) Patients with temporal lobe enhancement onneuroimaging (n p 142)

32.5 (0–92) 10 18.0 (0–749) n p 45: HSV-1 (32), VZV (5), EV (3), EBV (1),EBV/ADV (1), HHV-6 (1), measles causingSSPE (1), WNV (1)

Patients with temporal lobe activity on EEG on-lyb (n p 44)

32.5 (0–71) 10 12.0 (0–94) n p 2: HSV-1 (2)

Extrapyramidal (move-ment disorder)(n p 47)

Patients presenting with movement disordersc 11.0 (0–74) 9 39.0 (6–303) n p 6: measles causing SSPE (3), EV (2), VZV (1)

Cerebellar (n p 87) Patients presenting with a predominance ofcerebellar signsd and/or focal cerebellarlesions on MRI

15.0 (0–82) 2 11.0 (1–372) n p 3: EBV (2), hepatitis C virus (1)

Hydrocephalus (n p 32) Patients presenting with hydrocephalus on MRI 13.0 (0–66) 21 11.0 (1–66) n p 3: EV (2), EV/M. pneumoniae (1)

Generalized

Diffuse cerebral edema(n p 47)

Patients presenting with diffuse cerebraledemaf

12.0 (0–74) 74 2.0 (0–408) VZV (1)

Intractable seizures(treated with anes-thetic coma) (n p 62)

Patients presenting with or develop intractableseizures requiring anesthesia coma formanagement

10.0 (0–74) 32 46.0 (9–221) n p 5: EV (3), EBV (1), rotavirus (1)

Primarily seizure withrapid recovery(n p 25)

Patients presenting predominantly with sei-zures and recovery within 7 days

9.0 (0–49) 0 5.0 (3–7) n p 4: EBV (3), EV (1)

Psychosis presentation(n p 51)

Patients presenting with psychosis 23.0 (7–81) 9 11.0 (1–226) n p 6: hepatitis C (2), rabies (1), VZV (1), EV (1),WNV/EV (1)

Recurrent or chronic in-flammatory CNS dis-ease (n p 29)

Patients presenting with recurrent or chronicCNS disease

41.0 (1–75) 7 8.0 (4–88) …

Multifocal white matterlesions (n p 120)

Patients presenting with multifocal white mat-ter involvement on neuroimaging

20.0 (0–90) 13 13.0 (1–1105) n p 11: EBV (2), HSV-1 (2), WNV (2), VZV (1), ro-tavirus (1), measles causing SSPE (1), influenzaB virus/M. pneumoniae (1), acute HIV infec-tion/EV (1)

NOTE. ADV, adenovirus; B. mandrillaris, Balamuthia mandrillaris; B. procyonis, Baylisascaris procyonis; CJD, Creutzfeldt-Jakob disease; C. immitis, Coc-cidiodes immitis; C. neoformans, Cryptococcus neoformans; EBV, Epstein-Barr virus; EEG, electroencephalography; EV, enterovirus; GAD, glutamic aciddecarboxylase; GBS, Guillian-Barre syndrome; HHV-6, human herpesvirus 6; HSV-1, herpes simplex virus 1; LOHS, length of hospital stay; M. pneumoniae,Mycoplasma pneumoniae; MS, multiple sclerosis; M. tuberculosis, Mycobacterium tuberculosis; N. meningitidis, Neisseria meningitidis; PNET, primitiveneuroectodermal tumor; S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae; SSPE, subacute sclerosing panencephalitis; VZV,varicella-zoster virus; WNV, West Nile virus.

a Data in parentheses denote the number of patients with the etiology diagnosed.b No temporal lobe enhancement on MRI or CT.c Presumably related to extrapyrimidal system.d Ataxia, dysarthria, and dysmetria.e Miller Fisher variant.f As evidenced by neuroimaging or autopsy.g Same patient as patient with HHV-6 infection.

Evidence of inflammation was minimal (median CSF WBC

count, 8 cells/mm3). Although the CNS findings were similar

to those associated with Reye syndrome, none of the patients

had significant elevation of transaminase levels, hypoglycemia,

or hyperammonemia. A confirmed or probable infectious cause

was identified for only 2 cases. Of note, 34 patients (72%) died

within 7 days after hospitalization.

Intractable seizures. Sixty-two patients either presented

with or developed intractable seizures requiring general anes-

thesia or a barbiturate-induced coma to interrupt status epi-

lepticus. Most patients (69%) were !18 years of age (median

age, 10 years). These patients had prolonged hospital stays (me-

dian duration, 46 days), compared with other patients who

were referred to the CEP (median duration, 11 days) (P !

). Most cases (73%) in this patient group had no causative.001

agents identified. Twenty percent of these patients died before

discharge from the hospital, and of the patients who survived,

most required extensive rehabilitation.


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Viral etiologic agenta Infectious nonviral etiologic agenta

Not infectiousa

Unknown,no. ofcasesPossible Confirmed or probable Possible

n p 12: HSV-1 (5), EV (2), ADV (1),influenza A virus (1), influenza B vi-rus (1), influenza B virus/M. pneu-moniae (1), VZV (1)

n p 6: M. tuberculosis (4), B. mandrillaris (1), CJDprion disease (1)

n p 8: M. pneumoniae (6),Chlamydia species (2)

n p 4: astrocytoma (1), MS (1), paraneoplasticsyndrome (1), subdural hematoma/hemor-rhagic stroke (1)

69

n p 4: HSV-1 (1), influenza A virus(1), VZV (1), EV (1)

n p 2: M. tuberculosis (1), CJD prion disease (1) n p 3: M. pneumoniae (2),Chlamydia species (1)

n p 3: glioma (1), glioneuronal “hamartias” (1),stroke (1)

28

n p 2: HHV-6 (1), VZV (1) S. pneumoniae/Sydenham chorea (1) M. pneumoniae (2) n p 5: EBV lymphoma (1), small cell cancer(1), tumor (1), ovarian teratoma (1), paraneo-plastic syndrome (1)

31

n p 4: EV (1), rotavirus (2), ADV (1) B. procyonis (1) M. pneumoniae (5) n p 11: paraneoplastic syndrome (2), meta-bolic (2), MS (1), neuroblastoma (1), vasculi-tis (1), anti-GAD antibody–“stiff man syn-drome” (1), autoimmune/vasculitis (1),cardiovascular accident (1), GBSe (1),

60

n p 2: parainfluenza 1 (1), ADV (1) n p 15: M. tuberculosis (9), C. immitis (1), C. neo-formans (1), B. procyonis (1), B. mandrillaris (1),N. meningitidis (1), S. pneumoniae (1)

M. pneumoniae (1) n p 3: left mastoiditis/thrombosis (1), PNET(1), MS (1)

8

n p 9: influenza A virus (4), humanmetapneumovirus (2), influenza Bvirus/M. pneumoniae (1), HSV-1 (1),EV (1)

S. pneumoniae (1) n p 4: M. pneumoniae (3),Chlamydia species (1)

… 32

n p 4: ADV (2), HHV-6/mitochondrialdisease (1), HSV-1 (1)

… M. pneumoniae (6) n p 2: hepatic encephalitis (1), mitochondrialdisease (1)g

45

n p 3: ADV (1), influenza A virus (1),influenza B virus (1)

Bartonella species (5) M. pneumoniae (3) Metabolic thyroiditis (1) 9

n p 2: EV (1), influenza A virus (1) n p 3: Bartonella species (1), CJD prion disease (2) … n p 10: psychosis (3), schizophrenia (3), lupus(1), neuroleptic malignant syndrome (1), tem-poral arteritis (1), Hashimoto encephalopathy(n p 1)

30

n p 2: HSV-1 (1), influenza A virus (1) CJD prion disease (1) M. pneumoniae (2) n p 8: MS (3), vasculitis (2), metabolic disor-der (1), B cell lymphoma (1), Hashimoto en-cephalopathy (1)

16

n p 12: EV (4), ADV (3), influenza Avirus (3), human metapneumovirus(1)

n p 7: B. mandrillaris (2), Bartonella species (1), B.procyonis (1), M. tuberculosis (1), M. pneumon-iae (1), S. aureus (1)

n p 7: M. pneumoniae (6),Chlamydia species (1)

n p 7: B cell lymphoma (1), chronic T cell leu-kemia (1), intracranial hemorrhage (1), EBVlymphoma (1), hypertensive encephalopathy(1), MS (1), psychosis (1)

76

Seizures with rapid recovery. In contrast to the patient

group with intractable seizures, 25 patients presented with sei-

zures but had a rapid recovery and were discharged from the

hospital within 7 days after hospital admission.

Psychosis presentation. Fifty-one patients presented with

new-onset psychosis. Noninfectious causes were noted more

frequently (in 20% of cases) than infectious causes (12%) in

this group. Thirty (59%) of the cases in this group had no

etiology identified.

Recurrent or chronic inflammatory CNS disease. Twenty-

nine patients who were referred to the CEP had experienced

at least 1 previous hospitalization for CNS symptoms. The me-

dian age of the patients in this profile group was 41 years.

Other than a single case of Creutzfeldt-Jakob disease, no con-

firmed or probable infections were identified in this group,

although a number of autoimmune and other noninfectious

entities were identified.

Multifocal white matter disease. A total of 120 patients

had multifocal white-matter lesions noted on neuroimaging.

These patients often reported viral prodromal symptoms (34%

reported upper respiratory tract infection, and 41% reported

gastrointestinal symptoms). A number of possible agents were

identified, including M. pneumoniae and respiratory viruses,

consistent with a postinfectious disease process.

DISCUSSION

Encephalitis is an inflammation of the brain parenchyma and

presents as an alteration in consciousness, fever, headache, sei-

zures, and/or focal neurologic signs [14]. However, without the

identification of a neurotropic agent or confirmation by brain

tissue analysis, the diagnosis of encephalitis is presumptive and

is based on clinical characteristics. The case definition used in

the present study reflects these nonspecific clinical manifesta-

tions of encephalitis and, thus, is inherently sensitive but not

specific. Clinicians refer patients to the CEP on the basis of


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clinical characteristics that are compatible with encephalitis and

may overlap with the clinical characteristics of other disease

entities, including noninfectious conditions, bacterial and fun-

gal infections, and traditional viral causes of encephalitis. Even

after an exhaustive examination has been conducted, the con-

dition of many patients remains undiagnosed, and management

is problematic, demonstrating the need for further study.

The CEP study provided a unique opportunity to system-

atically investigate the cases of a large number of patients who

presented with symptoms of encephalitis. The present report

provides data on 1570 patients over a 7-year period. This large

cohort made it possible to identify clinical profiles on the basis

of the presence of predominant clinical signs and symptoms

(e.g., intractable seizures and movement disorders) or neu-

roimaging findings (e.g., temporal lobe involvement and hy-

drocephalus). Grouping by clinical profile is a new approach

and may clarify some aspects of this syndrome. First, the profiles

have allowed us to estimate prognosis and consider manage-

ment strategies. In the cerebral edema profile group, many

patients experienced tentorial herniation and died within 7

days, suggesting that measures to control elevated intracranial

pressure may improve outcomes [15]. Second, knowledge of

the natural history of a given profile may also be helpful in

counseling families. For example, patients who have seizures

that terminate in a few days seem to have an excellent prognosis,

whereas patients who have movement disorders or intractable

seizures often have a poor prognosis. Additional studies, how-

ever, are needed to determine the precision of these estimates

and the effectiveness of profile-specific management strategies.

Third, the profiles may also provide a better way to consider

etiology. Cases within a profile group may be more likely to

have a single or related etiology, possibly making it easier to

associate an agent with the disease. For example, HSV-1 is

commonly found in patients with temporal lobe involvement,

but our study identifies other etiologies that should be consid-

ered [16]. Finally, the clinical grouping may promote a system-

atic investigation into pathogenesis.

Interestingly, agents that are considered to be important

causes of encephalitis worldwide, such as arboviruses [17], were

infrequently detected in this study. No cases of Western equine

encephalitis or St. Louis encephalitis were identified, and only

19 cases of WNV infection were identified through the CEP in

2004 and 2005 (the initial years of significant WNV activity in

humans in California). There were, however, 111 cases of en-

cephalitis caused by WNV infection in California in 2004 that

were not included in the present study. The cases of WNV

infection not referred to the CEP illustrate an important lim-

itation of this study. The CEP is not a population-based study,

and, thus, cases caused by agents that can be readily diagnosed

with laboratory studies available in the community (e.g., HSV-

1 and WNV) are underrepresented in this study. Indeed, cli-

nicians often refer specimens to the West Nile Surveillance

Project (which is also at the Viral and Rickettsial Disease Lab-

oratory), and, if the test results are negative, the clinicians re-

quest that the patient be enrolled into the CEP. Furthermore,

in the CEP, only 2.5% of cases were due to HSV-1, compared

with other studies in which 8%–20% of all cases were due to

HSV-1 [18, 19].

Bacterial, parasitic, and fungal agents were identified in a

small but significant number of cases. The most frequently

confirmed nonviral infection found in this cohort was caused

by M. tuberculosis. M. tuberculosis infection of the CNS usually

presents as chronic meningitis; however, patients with M. tu-

berculosis infection may appear to have encephalitis [20]. Fur-

thermore, the CSF laboratory values for patients with M. tu-

berculosis infection of the CNS may be atypical and may

resemble those associated with infection caused by viral path-

ogens. Other uncommon but nonetheless important pathogens

that were etiologically confirmed included Bartonella species,

B. mandrillaris, and B. procyonis.

More than 10% of patients had evidence of an acute infection

without evidence sufficient to establish a causal relationship to

the illness. This occurred often with respiratory pathogens when

laboratory studies demonstrated an acute infection, either by

serological tests or molecular testing of respiratory specimens.

Although M. pneumoniae is commonly accepted as a cause of

encephalitis, infections are typically diagnosed on the basis of

an increase in serial serological titers and, rarely, by detection

in CSF by PCR or by isolation from CSF or brain tissue spec-

imens [21]. Chlamydia pneumoniae is a less-commonly de-

scribed neuropathogen and is usually diagnosed by serological

testing (of serum and CSF specimens) rather than by direct

detection within the CNS [22]. Similarly, influenza viruses and

other respiratory viral agents are associated with encephalitis,

but the agents are rarely found in the CNS [23]. The large

number of patients included in this study will provide oppor-

tunities to reconsider ways to determine causal relationships

between these infections and encephalitis.

The failure to identify an etiologic agent for many of these

cases is, in part, because of a referral bias toward diagnostically

challenging cases; other factors may include insufficiently sen-

sitive tests, lack of access to appropriate specimens (especially

convalescent-phase serum specimens), suboptimal specimen

handling, and the possible presence of a novel pathogen. In

addition, some cases may have a noninfectious etiology that

was not identified. Another factor in the low rate of identifi-

cation of a causative agent is the use of stringent criteria for

classification of confirmed or probable agents. With the use of

these criteria, some agents that otherwise might be causally

associated with the disease were considered to be only possible

etiologic agents. The low rate of diagnosis of the etiology of


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encephalitis underscores the need for better tools and new ap-

proaches to identifying the etiology.

The present study demonstrates the diversity of clinical, ep-

idemiologic, and etiologic characteristics of encephalitis. This

diversity no doubt contributes to the difficulty in the diagnosis,

management, and treatment of encephalitis in patients. The

recognition of subgroups of patients with encephalitis as de-

scribed in this report may be useful to clinicians in identifying

the etiology of encephalitis, selecting the treatment strategy, and

anticipating the course of illness and the prognosis for the

patient.

Acknowledgments

We thank the laboratory staff in the Viral and Rickettsial Disease Lab-oratory and Microbial Diseases Laboratory for performing diagnostic test-ing. We also thank the clinicians who referred cases to the CaliforniaEncephalitis Project. We gratefully acknowledge the assistance received fromKaren Bloch, Abbie Collins, Audrey Foster-Barber, Shilpa Gavali, SabrinaGilliam, Cynthia Jean, Nino Khetsuriani, Ashley LaMonte, Janice Louie,Jim Sejvar, and Allan Tunkel.

Financial support. Centers for Disease Control and Prevention Emerg-ing Infections Program (U50/CCU915546-09).

Potential conflicts of interest. All authors: no conflicts.

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