MAJOR ARTICLE

Beyond Viruses: Clinical Proles and Etiologies Associated 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
1 Viral and Rickettsial Disease Laboratory, California Department of Health Services, Richmond, and 2Department of Pediatrics, University of California, 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 identied. The California Encephalitis Project was initiated in 1998 to identify the causes and further describe the clinical and epidemiologic characteristics of encephalitis. Methods. A standardized report form was used to collect demographic and clinical data. Serum, cerebrospinal uid, and respiratory specimens were obtained prospectively and were tested for the presence of herpesviruses, arboviruses, enteroviruses, measles, respiratory viruses, Chlamydia species, and Mycoplasma pneumoniae. The association between an identied infection and encephalitis was dened using predetermined, organism-specic criteria for conrmed, 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 ndings were identied. Ten clinical proles were described. A conrmed or probable etiologic agent was identied for 16% of cases of encephalitis: 69% of these agents were viral; 20%, bacterial; 7%, prion; 3%, parasitic; and 1%, fungal. An additional 13% of cases had a possible etiology identied. Many of the agents classied as possible causes are suspected but have not yet been denitively demonstrated to cause encephalitis; these agents include M. pneumoniae (n p 96 ), inuenza virus (n p 22), adenovirus (n p 14), Chlamydia species (n p 10 ), and human metapneumovirus (n p 4 ). A noninfectious etiology was identied 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 discrete clinical proles 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 syndrome that is associated with signicant morbidity and mortality, and the etiology of the syndrome often is not identied [1]. The California Encephalitis Project (CEP) was initiated to identify the etiologic agents and dene the clinical and epidemiologic characteristics associated with encephalitis. A previously published report summarized data for the rst 334 patients with encephalitis enrolled in the CEP [2]. In addition, individual agent-specic case series have also been reported [38]. The present article provides an updated summary and overview. Based on 11500 cases of encephalitis, the study has identied (1) patient proles with similar clinical characteristics and laboratory ndings, (2) etiologies that might otherwise have been missed, and (3) potential novel etiologic agents of encephalitis. These data provide new insights into the features of this devastating syndrome, and they provide new ways to consider possible causes and patient management.

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PATIENTS, MATERIALS, AND METHODS Case nding 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 denition of encephalitis. A case patient was dened as a patient hospitalized with encephalopathy (dened by a depressed or altered level of consciousness lasting 24 h, lethargy, or a per
Encephalitis: Diagnosis and Management CID 2006:43 (15 December) 1565

Received 20 June 2006; accepted 11 September 2006; electronically published 8 November 2006. Reprints or correspondence: Dr. Carol A. Glaser, Dept. of Health Services, Viral and Rickettsial Disease Laboratory, 850 Marina Bay Pkwy., Richmond, CA 94804 (cglaser@dhs.ca.gov). Clinical Infectious Diseases 2006; 43:156577 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4312-0007$15.00

Table 1. California Encephalitis Project core testing, 19982005.

Specimen type, etiologic agent CSF Herpes consensusa HSV-1 HSV-2 VZV Mycoplasma pneumoniae Enterovirus Measles General viral isolation Serum Acute phase SLE virus WEE virus West Nile virus Epstein-Barr virus Enterovirus M. pneumoniae Measles Bartonella species Convalescent phase SLE virus WEE virus West Nile virus M. pneumoniae Measles HSV VZV Adenovirus Chlamydia species Inuenza A and B viruses Bartonella species Respiratory Enterovirus M. pneumoniae Inuenza A and B viruses Respiratory panel General viral isolation
h

Test type Conventional PCR Real-time PCR [9] Real-time PCR [9] Real-time PCR [9] Real-time PCR [10] Real-time PCR [11] Serological testing [12] Culture

Comment Discontinued in 2003b Initiated in 2003 Initiated in 2003 Initiated in 2003 Initiated in 1999 IgG EIAc Discontinued in 2000d

Serological testing [12] Serological testing [12] Serological testing Serological testing Serological testing Serological testing Serological testing [12] Serological testing Serological testing [12] Serological testing [12] Serological testing Serological testing Serological testing [12] Serological testing [12] Serological testing [12] Serological testing [12] Serological testing [12] Serological testing [12] Serological testing Real-time PCR [11] Real-time PCR [10] Real-time PCR Real-time PCR [10] Culture

IgG EIAc IgG EIAc Initiated in 2001; IgM capture EIA (Focus) IgG IFA, IgM IFA, EBNA (Pan Bio) Discontinued in 2002e IgM EIA (Meridian) c IgG EIA Discontinued in 2003 IgG EIAc IgG EIAc Initiated in 2001; IgM capture EIA (Focus) IgM EIA (Meridian), IgG EIA [12] IgG EIA
c c c f
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IgG EIA IgG EIAc IgG EIAc IgG EIA

c c f

IgG EIA

Discontinued in 2003

Initiated in 2001 Initiated in 2003; discontinued in 2004g Initiated in 2004 Primary monkey kidney and human fetal diploid cells

NOTE. EBNA, Epstein-Barr virus nuclear antigen; HSV, herpes simplex virus; IFA, indirect uorescent antibody test; SLE, St. Louis encephalitis; VZV, varicella-zoster virus; WEE, Western equine encephalitis. Herpes consensus includes HSV-1 and -2, VZV, Epstein Barr virus, cytomegalovirus, and human herpesvirus 6. 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 herpesvirus 6 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 Inuenza A and B viruses, adenovirus, human metapneumovirus, and respiratory syncytial virus type A.
b a

Table 2. Details of California Encephalitis Project (CEP) selective testing, 19982005.

No. of cases tested 195 273 269 12 15 24 7 10 59 9 36 114 36 103 21 50 140 64 14 23 4 3 17 67

Disease or selective pathogen Additional arboviruses Balamuthia mandrillaris Bartonella species Baylisascaris procyonis Borrelia burgdorferi Brucella species Colorado tick fever Creutzfeldt-Jakob diseasec Ehrlichia species Hepatitis C Leptospira species Lymphocytic choriomeningitis Mumps Mycobacterium tuberculosis Parvovirus B19 Coxiella burnetii Rabies Rickettsia rickettsii Rotavirus Rubella Toxocara species Trichinella species Francisella tularensis Rickettsia typhi
a

a, b

Criterion or criteria for testing Travel outside of California and/or extensive mosquito exposure Space-occupying lesion on MRI and/or suggestive laboratory ndings Potential exposure to cats or other animals and/or suggestive clinical and laboratory ndings Potential exposure to raccoon feces and/or eosinophilia Cranial nerve involvement and/or tick exposure Potential exposure to unpasteurized dairy products Potential tick or geographic exposure and/or suggestive laboratory values Insidious onset and/or compatible clinical ndings Potential tick or geographic exposure and/or suggestive laboratory values Known hepatitis C virus seropositivity Potential exposure to fresh water or hepatitis Potential exposure to rodents Cerebellar or brain stem ndings and/or unclear vaccine history Exposure to pathogen and/or suggestive laboratory values Rash illness or anemia Potential exposure and/or suggestive laboratory values Potential exposure and/or rapid deterioration Potential tick exposure and/or suggestive laboratory values Young age, diarrhea, and/or rotavirus antigenpositive stool Illness consistent with SSPE, but results of tests for measles are negative Potential exposure to cat/dog feces and/or eosinophilia and results of tests for B. procyonis are negative Eosinophilia and negative results of tests for B. procyonis Rural exposure and/or suggestive clinical features Rural exposure and/or suggestive laboratory values
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NOTE. SSPE, subacute sclerosing panencephalitis. 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 ndings was performed by the referring institution (sometimes in parallel with CEP testing). c 14-3-3 protein.

sonality change) with 1 of the following characteristics: fever, seizure, focal neurological ndings, pleocytosis, or electroencephalography or neuroimaging ndings 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, laboratory ndings, 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), varicellazoster virus (VZV), enteroviruses (EVs), measles, St. Louis encephalitis 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 uorescent antibody testing performed using standard methods [12]. Agent-specic PCR analyses were performed at the Viral and Rickettsial Disease Laboratory (California Department of Health Services; Richmond, CA) [911] and other reference laboratories (e.g., the Centers for Disease Control and Prevention; 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

Encephalitis: Diagnosis and Management CID 2006:43 (15 December) 1567

Table 3. Diagnosis category denitions.

Category Conrmed 1a 1b Agent is a well-established cause of encephalitis, agent is detected in CSF or brain specimens OR results of antibody testing are positive in instances in which PCR is not the diagnostic test of choice, AND clinical presentation and epidemiological prole are consistent with infection. Agent is a well-established cause of encephalitis, agent is not detected in CSF or brain specimens, but there is strong serological or culture-based evidence of infection, AND clinical presentation and epidemiological prole are consistent with infection; OR agent is not a well-established cause of encephalitis, AND agent is detected in CSF or brain specimens by PCR. Agent is a well-established agent of encephalitis, clinical presentation and epidemiological prole are consistent with infection, AND serologic evidence of infection was suggestive but not conclusive or a positive culture result was noted for a specimen obtained from a site other than the CNS site; OR agent is not well-established or the diagnostic method has not been developed, clinical presentation and epidemiological prole are consistent with infection, AND there is strong serologic or culture-based evidence of infection at a site other than the CNS site. Infection due to Baylisascaris procyonis,a enterovirus, HSV-1, VZV, and WNV; measles causing SSPE; rabies Denition Examples from study

1c Probable 1a 1b

Infection due to Bartonella species, EBV, and HSV-1

1c 2a 2b Possible 1a 1b 1c

Infection due to hepatitis C virus, HHV-6, Mycoplasma pneumoniae, and rotavirus Infection due to Brucella species, enteroviruses, HSV-1, inuenza A and B viruses, and VZV

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2a 2b 2c

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

NOTE. EBV, Epstein-Barr virus; HHV-6, human herpesvirus 6; HSV-1, herpes simplex virus 1; RSV, respiratory syncytial virus, SSPE, subacute sclerosing panencephalitis; 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 neuroimaging ndings, as well as updates on each patients condition. Classication of the association between a pathogen and encephalitis. We dened the association between an identied agent and the encephalitis case as conrmed, 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 associations between the agent and encephalitis, and the clinical and epidemiologic characteristics of the disease (table 3). Statistical analysis. The data were analyzed using Fishers ex1568 CID 2006:43 (15 December) Glaser et al.

act test or the Kruskal-Wallis test, as appropriate, with statistical signicance 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 reasons: insufcient 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 specimens, 1540 (98%) provided acute-phase serum specimens, and 696 (44%) provided convalescent-phase serum specimens. Demographic and clinical characteristics and laboratory data are

Table 4. Summary of characteristics of and ndings for 1570 California Encephalitis Project patients, 19982005.
Characteristic or nding Demographic Male Age, median years (range) Race White Hispanic Black Asian Other/unknown Clinical Interval from onset to hospital admission,a median days (range) ICU admission Prodrome or concurrent symptom Fever Respiratory symptom Gastrointestinal symptom Rash Seizure Coma Death All Within 3 weeks of hospitalization LOHS, median days (range) Laboratory CSF WBC count, median cells/mm3 (range) CSF protein level, median mg/dL (range) CSF glucose level, median mg/dL (range) Initial abnormal neuroimaging 23.0 (013,000) 57.0 (711,723) 64.0 (6533) 770 (54) 878 (56) 23.0 (092) 580 (37) 428 (27) 138 (9) 191 (12) 223 (14) Value

ologies (table 5). Some patients were found to have infectious meningitis rather than encephalitis. A possible infectious cause was identied for an additional 208 patients (13%).
Conrmed and Probable Viral Agents

2.0 ( 6 to 712) 807 (58) 1032 495 501 194 640 267 (67) (33) (34) (13) (42) (18)

162 (11) 102 (7) 11.0 (01124)

NOTE. Data are no. (%) of patients, unless otherwise indicated. Denominators used in the calculation of percentages may vary slightly, depending on the available data. ICU, intensive care unit; LOHS, length of hospital stay. Interval from onset of CNS symptoms to hospital admission. For 3 patients, CNS symptoms developed after admission to the hospital for a nonspecic illness.
a

A total of 170 patients had encephalitis with a conrmed or probable viral etiology, and the most commonly identied viral agents were EV (for 25% of cases) and HSV-1 (for 24% of cases). The demographic, clinical, and laboratory data for patients with encephalitis due to viral and other etiologic agents, which were identied in association with 5 cases, are summarized in table 6. The median age of individuals with HSV1 (54.0 years), VZV (44.0 years), and WNV (66.0 years) encephalitis 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 encephalitides presented with fever. Important exceptions included individuals with measles causing subacute sclerosing panencephalitis, VZV infection, and hepatitis C. No consistent prodromes were seen in association with any specic virus except inuenza virus (respiratory prodromes) and rotavirus (gastrointestinal prodrome). Seizures were noted in 38% of patients with viral encephalitis, most commonly among patients with measles causing subacute sclerosing panencephalitis (83%), human herpesvirus 6 infection (75%), and HSV-1 infection (59%). The initial MRI ndings were abnormal for 87 patients (60%) and were most frequently abnormal for patients with HSV-1 (93%).
Nonviral Infectious Agents

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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 population, whereas whites (41% vs. 45%) and Hispanics (30% vs. 35%) were slightly underrepresented.
Infectious and Noninfectious Etiologies

A conrmed 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 detected, followed by bacterial, parasitic, prion, and fungal eti-

A conrmed or probable nonviral agent was identied for 78 cases (5%), including cases of meningitis. The bacterial agents identied were diverse, including Mycobacterium tuberculosis (n p 19), Bartonella species (n p 13), M. pneumoniae (n p 2), and Tropheryma whippelii (n p 1 ); in addition, 14 cases of pyogenic bacteria were identied (table 6). Seven parasitic infections were identied (4 due to Balamuthia 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 364 years. Pleocytosis (median CSF WBC count, 126 cells/mm3), an elevated protein level (median, 945 mg/dL), and abnormal neuroimaging ndings were noted for all patients. The infections 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

Encephalitis: Diagnosis and Management CID 2006:43 (15 December) 1569

Table 5. Aggregate data for California Encephalitis Project patients with encephalitis with a conrmed or probable etiology, by etiologic agent.
Viral (n p 170) 94 (55) 33.0 (089) 73 (44) 38 (23) 11 (7) 15 (9) 30 (18) Bacterial (n p 50) 32 (64) 19.5 (077) 24 (48) 16 (32) 2 (4) 7 (14) 1 (2) Prion (n p 18) 10 (56) 66.0 (4484) 12 (67) 1 (6) 0 (0) 1 (6) 4 (22) Parasitic (n p 7) 6 (86) 7.0 (064) 2 (29) 5 (71) 0 (0) 0 (0) 0 (0) Fungal (n p 3) 3 (100) 15.0 (122) 0 (0) 1 (33) 1 (33) 1 (33) 0 (0)

Characteristic or nding Demographic Male Age, median years (range) Race White Hispanic Black Asian Other/unknown Clinical Interval from onset to hospital admission,a median days (range) ICU admission Prodrome or concurrent symptom Fever Respiratory symptom Gastrointestinal symptom Rash Seizure Coma Deathb LOHS, median days (range) Laboratory CSF WBC count, median cells/mm3 (range) CSF protein level, median mg/dL (range) CSF glucose level, median mg/dL (range) Initial abnormal neuroimaging

3.0 (065) 81 (55) 125 38 69 30 63 23 (75) (24) (42) (18) (38) (14)

1.0 (0107) 37 (82) 37 14 19 9 24 15 (74) (30) (41) (19) (48) (30)

36.0 (0476) 2 (13) 6 4 1 2 3 4 (35) (25) (6) (12) (19) (22)

4.0 (112) 6 (86) 5 1 3 0 2 3 (71) (14) (43) (0) (29) (43)

81.0 (6208) 3 (100) 3 2 3 2 0 0 (100) (67) (100) (67) (0) (0)

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22 (13) 10.0 (01124) 70.0 (02250) 71.0 (15881) 67.0 (28284) 87 (60)

5 (11) 12.0 (266) 54.0 (013,000) 92.0 (12961) 62 (9157) 30 (62)

12 (67) 16.5 (540) 0.0 (0115) 47.0 (20114) 66.0 (5894) 15 (88)

4 (58) 16.0 (863) 49.0 (5354) 70.0 (261247) 59.0 (674) 7 (100)

0 (0) 39.5 (1168) 117.0 (20737) 176.0 (51319) 25.0 (944) 3 (100)

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

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

of the clinician. Three individuals in the CEP were identied 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 (median, 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 identied were classied as belonging to 1 of 2 categories, as outlined in table 3. Acute infection with M. pneumoniae was identied in 96 patients, a higher frequency than was noted for any other agent. However, most of these cases were classied as possible because, although there was serological evidence (in 88 cases) and/or PCR evidence (in 18 cases) of an acute infection, the organism was not detected from a CNS site. Other

possible etiologies included inuenza A and B viruses (22 cases), adenovirus (14), HSV-1 (13), Chlamydia species (10), human metapneumovirus (4), VZV (4), human herpesvirus 6 (2), respiratory syncytial virus (2), Brucella species (2), rotavirus (2), parainuenza virus (1), Bartonella species (1), EBV (1), Creutzfeldt-Jakob prion disease (1), and mixed respiratory infections (5). Twenty-eight cases of possible EV infection were identied; 15 were identied by detection of EV in respiratory samples, whereas the remainder were identied by serum EV IgM assay.
Noninfectious Etiologies

For 8% of cases, a noninfectious etiology was identied by the referring institution. These noninfectious causes were associated 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%).

1570 CID 2006:43 (15 December) Glaser et al.

Table 6. Characteristics of and ndings for patients with encephalitis, according to viral or bacterial etiology.
Viral etiology Bacterial etiology

Characteristic or nding

Enterovirus (n p 43) HSV-2 (n p 5) MTB (n p 19)

HSV-1 (n p 40)

VZV (n p 23)

WNV (n p 19)

EBV (n p 17)

Measles causing SSPE (n p 6)

Pyogenic bacteria (n p 14)

Bartonella species (n p 13)

Demographic 24 (56) 12.0 (074) 13 (30) 14 (33) 3 (7) 6 (14) 7 (16)

a

Male 54.0 (089) 22 (55) 7 (18) 0 (0) 2 (5) 9 (22) 6 (27) 1 (5) 3 (18) 0 (0) 2 (9) 0 (0) 1 (6) 2 (33) 0 (0) 1 (25) 1 (5) 1 (5) 2 (12) 0 (0) 1 (25) 1 (5) 5 (26) 5 (29) 4 (67) 1 (25) 12 (55) 12 (63) 6 (35) 0 (0) 1 (25) 44.0 (485) 66.0 (1384) 11.0 (134) 12.0 (915) 46.0 (3577)

15 (38)

17 (74)

15(79)

8 (47)

4 (67)

2 (40)

12 (63) 45.0 (077) 3 (16) 8 (42) 1 (5) 7 (37) 0 (0)

10 (71) 17.5 (067) 11 (79) 2 (14) 0 (0) 0 (0) 1 (7)

7 (54) 7.0 (440) 9 (69) 4 (31) 0 (0) 0 (0) 0 (0)

Age, median years (range)

Race

White

Hispanic

Black

Asian

Other/unknown

Clinical 2.0 (074) 18 (49) 31 (72) 12 (29) 17 (41) 6 (14) 12 (28) 2 (5) 3 (7) 5.0 (01124) 13.5 (0738) 14.0 (1749) 7 (18) 0 (0) 2 (11) 7.0 (0108) 7 (18) 0 (0) 3 (17) 23 (59) 3 (13) 2 (12) 2 (5) 12 (52) 3 (17) 18 (46) 7 (30) 9 (50) 8 (21) 6 (26) 2 (11) 8 (47) 9 (53) 4 (24) 10 (63) 4 (24) 1 (6) 8.0 (279) 35 (90) 12 (52) 19 (100) 14 (82) 20 (57) 11 (58) 10 (59) 11 (69) 2.0 (028) 4.0 (023) 3.0 (014) 2.0 (015) 9.5 (1912) 3 (50) 2 (33) 0 (0) 2 (33) 1 (17) 5 (83) 3 (50) 3 (50) 20.0 (662) 1.5 (02) 1 (20) 4 (80) 0 (0) 1 (20) 0 (0) 0 (0) 0 (0) 0 (0) 3.5 (214) 5.0 (061) 13(77) 14 (74) 3 (16) 7 (37) 1 (5) 6 (32) 7 (37) 4 (21) 28.0 (866) 0.0 (05) 12 (86) 9 (64) 6 (46) 8 (57) 2 (14) 6 (43) 4 (29) 1 (8) 11.0 (241) 0.0 (02) 10 (77) 12 (92) 4 (36) 2 (20) 5 (46) 11 (85) 2 (17) 0 (0) 5.5 (321)

Interval from onset to hospital admission, median days (range)

ICU admission

Prodrome or concurrent symptom

Fever

Respiratory symptoms

Gastrointestinal symptoms

Rash

Seizure

Coma

Death

LOHS, median days (range)

Laboratory 100.0 (01080) 54.0 (16881) 67.0 (38159) 13 (48) 37 (93) 42.0 (0975) 100.5 (0608) 67.5 (0468) 7.0 (02250) 9.0 (058) 726.0 (3891250) 165.0 (202845) 63.0 (013,000) 182.5 (116250) 60.5 (5083) 13 (68) 5 (29) 8 (47) 69.0 (6275) 3(60) 50.5 (48284) 2 (67) 174.0 (66357) 36.0 (9132) 14 (82) 79.0 (24961) 63.5 (25157) 13 (93) 1.5 (054) 37.0 (19398) 83.5 (60129) 0 (0)

CSF WBC count, median cells/mm3 (range)

CSF protein level, median mg/dL (range)

70.0 (15297) 98.0 (45316) 86.0 (71300) 37.0 (21139) 38.5 (2056) 69.0 (39112) 59.0 (28118) 83.0 (47192)

CSF glucose level, median mg/dL (range)

Initial abnormal neuroimaging ndings

NOTE. Data are no. (%) of patients, unless otherwise indicated. Only those etiologic agents associated with 5 cases are included in the table. Denominators used in the calculation of data may vary slightly, depending on the available data. EBV, Epstein-Barr virus; HSV, herpes simplex virus; ICU, intensive care unit; LOHS, length of hospital stay; MTB, Mycobacterium tuberculosis; SSPE, subacute sclerosing panencephalitis; VZV, varicella-zoster virus; WNV, West Nile virus.

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

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Figure 1. Number of patients with conrmed or probable etiologic agents of encephalitis identied, by CSF WBC count and type of etiologic agent. The etiologic agent(s) and the number of patients with the etiologic agent(s) identied are listed according to diagnosis category denition. 1a comprises 6 patients with Epstein-Barr virus (EBV) infection, 5 with enterovirus (EV) infection, 5 with herpes simplex virus 1 (HSV-1) infection, 3 with varicellazoster 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, 4 with EBV infection, 3 with measles causing SSPE, 1 with acute HIV infection, 1 with hepatitis C, 1 with human herpesvirus-6 (HHV-6) infection, 1 with rabies, and 1 with rotavirus infection. 1c comprises 13 patients with EV infection, 9 with WNV infection, 9 with HSV-1 infection, 7 with VZV infection, 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 8 patients 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 with HHV-6 infection, and 1 with rotavirus infection. 2a comprises 11 patients with infection due to Bartonella species, 1 with infection due to Mycoplasma pneumoniae, 1 with Rocky Mountain spotted fever, 1 with poststreptococcal glomerulonephritis, 1 with infection due to Streptococcus agalactiae, 1 with urosepsis and infection due to Klebsiella species, and 1 with Sydenham chorea. 2b comprises 2 patients with infection due to Mycobacterium tuberculosis, 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 infection due to Bartonella species, 1 with infection due to Neisseria meningitidis, and 1 with infection due to Streptococcus viridans. 2d comprises 4 patients with 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 2 patients with infection due to Balamuthia mandrillaris. 3d comprises 1 patient with infection due to B. mandrillaris. 4a comprises 1 patient with infection due to Cryptococcus neoformans. 4b comprises 1 patient with infection due to Coccidioides immitis. 4c comprises 1 patient with infection due to C. immitis. Comparative CSF Values

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As shown in gure 1 and gure 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 noninfectious etiologies. Not surprisingly, comparison of the CSF laboratory 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; P ! .001 ). However, the difference in CSF protein levels was not signicant (median level, 71.0 vs. 67.0 mg/dL).
Clinical Proles

proximately one-half of the patients. For the remaining patients, we could not identify groups with common, distinct characteristics. Patients within a prole were analyzed to determine 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

Ten distinct constellations of clinical characteristics4 focal and 6 generalized clinical proleswere recognized in ap1572 CID 2006:43 (15 December) Glaser et al.

Temporal lobe involvement. The most common prole (in 144 cases) was encephalitis with temporal lobe enhancement noted on MRI or CT. Not surprisingly, HSV-1 was the most common agent identied (in 32 [22%] of cases). Other herpesviruses identied in this prole group included VZV (5 cases), EBV (2 cases), and human herpesvirus 6 (1 case). An

Figure 2. Number of patients with conrmed or probable etiologic agents of encephalitis identied, by CSF protein level and type of etiologic agent. The etiologic agent(s) and the number of patients with the etiologic agent(s) identied are listed according to diagnosis category denition. 1a comprises 16 patients with enterovirus (EV) infection, 11 with herpes simplex virus 1 (HSV-1) infection, 8 with Epstein-Barr virus (EBV) infection, 4 with measles causing subacute sclerosing panencephalitis (SSPE), 2 with hepatitis C, 2 with rabies, 2 with rotavirus infection, 1 with human herpesvirus 6 (HHV6) infection, and 1 with varicella-zoster virus (VZV) infection. 1b comprises 16 patients with HSV-1 infection, 13 with EV infection, 13 with West Nile virus (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 comprises 8 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, 2 with 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 acute HIV infection. 2a comprises 8 patients with infection due to Bartonella species, 1 with infection due to Mycoplasma pneumoniae, 1 with poststreptococcal glomerulonephritis, 1 with urosepsis and infection due to Klebsiella species, and 1 with Sydenham chorea. 2b comprises 4 patients with infection due to M. tuberculosis, 3 with infection due to Bartonella species, 2 with infection due to Streptococcus pneumoniae, 1 with infection due to Tropheryma whippelli, 1 with infection due to M. pneumoniae, 1 with infection due to Streptococcus viridans, and 1 with Staphylococcus aureus endocarditis. 2c comprises 13 patients with infection due to M. tuberculosis, 1 with infection due to Neisseria meningitidis, and 1 with infection due to S. aureus. 2d comprises 2 patients with infection due to M. tuberculosis, 2 with infection due to N. meningitidis, 1 with infection due to Bartonella species, 1 with group C b-hemolytic Streptococcus infection, and 1 with infection due to Streptococcus agalactiae. 3a comprises 2 patients with infection due to Baylisascaris procyonis. 3b comprises 1 patient with infection due to B. procyonis. 3c comprises 2 patients with infection due to Balamuthia mandrillaris. 4a comprises 1 patient with infection due to Cryptococcus neoformans. 4b comprises 1 patient with infection due to Coccidioides immitis. 4c comprises 1 patient with infection due to C. immitis.

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additional 42 patients had temporal lobe activity noted on electroencephalography but had no enhancement noted on CT or MRI. The etiologic agents identied for this group of patients were similar to those identied for patients with temporal lesions 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) (P ! .001). The length of hospitalization 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) (P ! .001), but the mortality rate 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 (P p .001). The mortality rate for this group (2%) was lower than the overall mortality rate noted in the CEP (11%) (P p .01). No single infectious agent was found to be predominant in this group, and a relatively high percentage (16%) of noninfectious etiologies were identied. Hydrocephalus. Thirty-two patients who presented with encephalitis were found to have new-onset hydrocephalus. A relatively high percentage of nonviral organisms (47%) were identied in this prole 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 ndings.

Encephalitis: Diagnosis and Management CID 2006:43 (15 December) 1573

Table 7. Clinical proles of California Encephalitis Project cases, 19982005.

Outcome Age, median years (range) LOHS, median days (range) Viral etiologic agenta

Clinical prole Focal Temporal lobe (n p 186)

Patient description

Mortality rate, %

Conrmed or probable

Patients with temporal lobe enhancement on neuroimaging (n p 142)

32.5 (092)

10

18.0 (0749)

n p 45: HSV-1 (32), VZV (5), EV (3), EBV (1), EBV/ADV (1), HHV-6 (1), measles causing SSPE (1), WNV (1) n p 2: HSV-1 (2) n p 6: measles causing SSPE (3), EV (2), VZV (1)

Patients with temporal lobe activity on EEG onlyb (n p 44) Extrapyramidal (movement disorder) (n p 47) Cerebellar (n p 87) Patients presenting with movement disordersc

32.5 (071) 11.0 (074)

10 9

12.0 (094) 39.0 (6303)

Patients presenting with a predominance of cerebellar signsd and/or focal cerebellar lesions on MRI

15.0 (082)

11.0 (1372)

n p 3: EBV (2), hepatitis C virus (1)

Hydrocephalus (n p 32)

Patients presenting with hydrocephalus on MRI

13.0 (066)

21

11.0 (166)

n p 3: EV (2), EV/M. pneumoniae (1)

Generalized Diffuse cerebral edema (n p 47) Patients presenting with diffuse cerebral edemaf 12.0 (074) 74 2.0 (0408) VZV (1)

Intractable seizures (treated with anesthetic coma) (n p 62) Primarily seizure with rapid recovery (n p 25) Psychosis presentation (n p 51)

Patients presenting with or develop intractable seizures requiring anesthesia coma for management Patients presenting predominantly with seizures and recovery within 7 days Patients presenting with psychosis

10.0 (074)

32

46.0 (9221)

n p 5: EV (3), EBV (1), rotavirus (1)

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9.0 (049)

5.0 (37)

n p 4: EBV (3), EV (1)

23.0 (781)

11.0 (1226)

n p 6: hepatitis C (2), rabies (1), VZV (1), EV (1), WNV/EV (1)

Recurrent or chronic inammatory CNS disease (n p 29) Multifocal white matter lesions (n p 120)

Patients presenting with recurrent or chronic CNS disease Patients presenting with multifocal white matter involvement on neuroimaging

41.0 (175)

8.0 (488)

20.0 (090)

13

13.0 (11105)

n p 11: EBV (2), HSV-1 (2), WNV (2), VZV (1), rotavirus (1), measles causing SSPE (1), inuenza B virus/M. pneumoniae (1), acute HIV infection/EV (1)

NOTE. ADV, adenovirus; B. mandrillaris, Balamuthia mandrillaris; B. procyonis, Baylisascaris procyonis; CJD, Creutzfeldt-Jakob disease; C. immitis, Coccidiodes immitis; C. neoformans, Cryptococcus neoformans; EBV, Epstein-Barr virus; EEG, electroencephalography; EV, enterovirus; GAD, glutamic acid decarboxylase; 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, primitive neuroectodermal tumor; S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae; SSPE, subacute sclerosing panencephalitis; VZV, varicella-zoster virus; WNV, West Nile virus.
a b c d e f g

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

Evidence of inammation was minimal (median CSF WBC count, 8 cells/mm3). Although the CNS ndings were similar to those associated with Reye syndrome, none of the patients had signicant elevation of transaminase levels, hypoglycemia, or hyperammonemia. A conrmed or probable infectious cause was identied 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 anes1574 CID 2006:43 (15 December) Glaser et al.

thesia or a barbiturate-induced coma to interrupt status epilepticus. Most patients (69%) were !18 years of age (median age, 10 years). These patients had prolonged hospital stays (median duration, 46 days), compared with other patients who were referred to the CEP (median duration, 11 days) (P ! .001). Most cases (73%) in this patient group had no causative agents identied. Twenty percent of these patients died before discharge from the hospital, and of the patients who survived, most required extensive rehabilitation.

Viral etiologic agenta

Infectious nonviral etiologic agenta Unknown, no. of cases

Possible

Conrmed or probable

Possible

Not infectious

n p 12: HSV-1 (5), EV (2), ADV (1), inuenza A virus (1), inuenza B virus (1), inuenza B virus/M. pneumoniae (1), VZV (1) n p 4: HSV-1 (1), inuenza A virus (1), VZV (1), EV (1) n p 2: HHV-6 (1), VZV (1)

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

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

n p 4: astrocytoma (1), MS (1), paraneoplastic syndrome (1), subdural hematoma/hemorrhagic stroke (1) n p 3: glioma (1), glioneuronal hamartias (1), stroke (1) n p 5: EBV lymphoma (1), small cell cancer (1), tumor (1), ovarian teratoma (1), paraneoplastic syndrome (1) n p 11: paraneoplastic syndrome (2), metabolic (2), MS (1), neuroblastoma (1), vasculitis (1), anti-GAD antibodystiff man syndrome (1), autoimmune/vasculitis (1), cardiovascular accident (1), GBSe (1), n p 3: left mastoiditis/thrombosis (1), PNET (1), MS (1)

69

n p 2: M. tuberculosis (1), CJD prion disease (1) S. pneumoniae/Sydenham chorea (1)

n p 3: M. pneumoniae (2), Chlamydia species (1) M. pneumoniae (2)

28 31

n p 4: EV (1), rotavirus (2), ADV (1)

B. procyonis (1)

M. pneumoniae (5)

60

n p 2: parainuenza 1 (1), ADV (1)

n p 15: M. tuberculosis (9), C. immitis (1), C. neoformans (1), B. procyonis (1), B. mandrillaris (1), N. meningitidis (1), S. pneumoniae (1) S. pneumoniae (1)

M. pneumoniae (1)

n p 9: inuenza A virus (4), human metapneumovirus (2), inuenza B virus/M. pneumoniae (1), HSV-1 (1), EV (1) n p 4: ADV (2), HHV-6/mitochondrial disease (1), HSV-1 (1) n p 3: ADV (1), inuenza A virus (1), inuenza B virus (1) n p 2: EV (1), inuenza A virus (1)

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

32

M. pneumoniae (6)

n p 2: hepatic encephalitis (1), mitochondrial disease (1)g Metabolic thyroiditis (1)

45

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Bartonella species (5)

M. pneumoniae (3)

n p 3: Bartonella species (1), CJD prion disease (2)

n p 10: psychosis (3), schizophrenia (3), lupus (1), neuroleptic malignant syndrome (1), temporal arteritis (1), Hashimoto encephalopathy (n p 1) n p 8: MS (3), vasculitis (2), metabolic disorder (1), B cell lymphoma (1), Hashimoto encephalopathy (1) n p 7: B cell lymphoma (1), chronic T cell leukemia (1), intracranial hemorrhage (1), EBV lymphoma (1), hypertensive encephalopathy (1), MS (1), psychosis (1)

30

n p 2: HSV-1 (1), inuenza A virus (1)

CJD prion disease (1)

M. pneumoniae (2)

16

n p 12: EV (4), ADV (3), inuenza A virus (3), human metapneumovirus (1)

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

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

76

Seizures with rapid recovery. In contrast to the patient group with intractable seizures, 25 patients presented with seizures 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 identied. Recurrent or chronic inammatory CNS disease. Twentynine patients who were referred to the CEP had experienced at least 1 previous hospitalization for CNS symptoms. The median age of the patients in this prole group was 41 years. Other than a single case of Creutzfeldt-Jakob disease, no conrmed or probable infections were identied in this group, although a number of autoimmune and other noninfectious entities were identied. 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 identied, including M. pneumoniae and respiratory viruses, consistent with a postinfectious disease process. DISCUSSION Encephalitis is an inammation of the brain parenchyma and presents as an alteration in consciousness, fever, headache, seizures, and/or focal neurologic signs [14]. However, without the identication of a neurotropic agent or conrmation by brain tissue analysis, the diagnosis of encephalitis is presumptive and is based on clinical characteristics. The case denition used in the present study reects these nonspecic clinical manifestations of encephalitis and, thus, is inherently sensitive but not specic. Clinicians refer patients to the CEP on the basis of

Encephalitis: Diagnosis and Management CID 2006:43 (15 December) 1575

clinical characteristics that are compatible with encephalitis and may overlap with the clinical characteristics of other disease entities, including noninfectious conditions, bacterial and fungal infections, and traditional viral causes of encephalitis. Even after an exhaustive examination has been conducted, the condition of many patients remains undiagnosed, and management is problematic, demonstrating the need for further study. The CEP study provided a unique opportunity to systematically 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 proles on the basis of the presence of predominant clinical signs and symptoms (e.g., intractable seizures and movement disorders) or neuroimaging ndings (e.g., temporal lobe involvement and hydrocephalus). Grouping by clinical prole is a new approach and may clarify some aspects of this syndrome. First, the proles have allowed us to estimate prognosis and consider management strategies. In the cerebral edema prole 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 prole 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, however, are needed to determine the precision of these estimates and the effectiveness of prole-specic management strategies. Third, the proles may also provide a better way to consider etiology. Cases within a prole 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 identies other etiologies that should be considered [16]. Finally, the clinical grouping may promote a systematic 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 identied, and only 19 cases of WNV infection were identied through the CEP in 2004 and 2005 (the initial years of signicant WNV activity in humans in California). There were, however, 111 cases of encephalitis 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 limitation 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., HSV1 and WNV) are underrepresented in this study. Indeed, cli1576 CID 2006:43 (15 December) Glaser et al.

nicians often refer specimens to the West Nile Surveillance Project (which is also at the Viral and Rickettsial Disease Laboratory), and, if the test results are negative, the clinicians request 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 identied in a small but signicant number of cases. The most frequently conrmed 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. tuberculosis infection may appear to have encephalitis [20]. Furthermore, the CSF laboratory values for patients with M. tuberculosis infection of the CNS may be atypical and may resemble those associated with infection caused by viral pathogens. Other uncommon but nonetheless important pathogens that were etiologically conrmed included Bartonella species, B. mandrillaris, and B. procyonis. More than 10% of patients had evidence of an acute infection without evidence sufcient 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 specimens [21]. Chlamydia pneumoniae is a less-commonly described neuropathogen and is usually diagnosed by serological testing (of serum and CSF specimens) rather than by direct detection within the CNS [22]. Similarly, inuenza 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 opportunities 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 insufciently sensitive 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 identied. Another factor in the low rate of identication of a causative agent is the use of stringent criteria for classication of conrmed 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 approaches to identifying the etiology. The present study demonstrates the diversity of clinical, epidemiologic, and etiologic characteristics of encephalitis. This diversity no doubt contributes to the difculty in the diagnosis, management, and treatment of encephalitis in patients. The recognition of subgroups of patients with encephalitis as described 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 Laboratory and Microbial Diseases Laboratory for performing diagnostic testing. We also thank the clinicians who referred cases to the California Encephalitis Project. We gratefully acknowledge the assistance received from Karen Bloch, Abbie Collins, Audrey Foster-Barber, Shilpa Gavali, Sabrina Gilliam, Cynthia Jean, Nino Khetsuriani, Ashley LaMonte, Janice Louie, Jim Sejvar, and Allan Tunkel. Financial support. Centers for Disease Control and Prevention Emerging Infections Program (U50/CCU915546-09). Potential conicts of interest. All authors: no conicts.

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