A systematic review of acute encephalitis in non-outbreak situations
A systematic review of acute encephalitis in non-outbreak situations
Abstract
Background: The threat of emerging infections and recognition of novel immune-mediated
formsof encephalitis has raised the profile of this condition in recent years. Incidence
is poorly defined and most cases have an unknown cause. There is currently much
interest in identification of new microbial agents of encephalitis, but no work
has investigated systematically reasons for lack of pathogen identification in studies.
Methods: We systematically reviewed published literature on incidence and
etiology of encephalitis in non-outbreak settings and explored possible explanations
for the large number of cases of unknown etiology
Results:Annual incidence ranged from 0.07 to 12.6 cases per 100,000 population
with an evident decrease over time (p ! 0.01). The proportion of cases with unknown
etiology was high across studies ("50% in 26 of 41 studies), with strong evidence
of heterogeneity in study findings (p#0.001). Our meta-regression identified study
period, setting, and subsyndrome to be the main contributors to between-study variation,
rather than methodologic factors such as study design, case definitions, sample
types, and testing strategies.
Conclusions: Our findings support the hypothesis that new and emerging infectious
agents, or new forms of immune-mediated encephalitis, may be responsible for cases
currently of unknown cause and encourage the ongoing global effort to identify these.
Our review highlights research areas that might lead to a better understanding of
the causes of encephalitis and ultimately reduce the morbidity and mortality associated
with this devastating condition.
NEUROLOGY® 2010;75:924–932
Causality in acute encephalitis
Granerod J, Cunningham R, Zuckerman M, Mutton K, Davies NW, Walsh AL, Ward KN, Hilton
DA, Ambrose HE, Clewley JP, Morgan D, Lunn MP, Solomon T, Brown DW,Crowcroft NS.
Summary
Defining the causal relationship between a microbe and encephalitis is complex.
Over 100 different infectious agents may cause encephalitis, often as one of the
rarer manifestations of infection. The gold-standard techniques to detect causative
infectious agents in encephalitis in life depend on the study of brain biopsy material;
however, in most cases this is not possible. We present the UK perspective on aetiological
case definitions for acute encephalitis and extend them to include immune-mediated
causes. Expert opinion was primarily used and was supplemented by literature-based
methods. Wide usage of these definitions will facilitate comparison between studies
and result in a better understanding of the causes of this devastating condition.
They provide a framework for regular review and updating as the knowledge base increases
both clinically and through improvements in diagnostic methods. The importance of
new and emerging pathogens as causes of encephalitis can be assessed against the
principles laid out here.
EPIDEMIOL INFECT. (2010) 138(6):783-800.
Beyond Viruses: Clinical Profiles and Etiologies Associated with Encephalitis
Beyond Viruses: Clinical Profiles 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 Paediatrics, University of California, San
Francisco, California; and 3Respiratory and Enteric Virus Branch, Centers for Disease
Control And prevention, Atlanta, Georgia
Background. Encephalitis is a complex syndrome, and its etiology is
often not identified. The California Encephalitis Project was initialised in 1998
to identify the cause 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 fluid, and respiratory specimens were obtained
prospectively and were tested for the presence of herpesviruses, arboviruses, enteroviruses,
measles, respiratory viruses, Chlamydia, and Mycoplasma pneumoniae. The association
between an identified infection and encephalitis was defined using predetermined,
organism-specific criteria 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 clinical profiles 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%of cases had a possible etiology identified.
Many of the agents classified as possible causes are suspected but have not yet
been defiantly demonstrated to cause encephalitis: these agents include M.pneumoniae
(n=96), influenza virus (n = 22), adenovirus (n = 14), Chlamydia species (n=10),
and human metapneumovirus (n = 4). A non-infectious 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 recognisation of discrete clinical profiles among patients with
encephalitis should help focus our efforts towards understanding the etiology,
pathogenesis, course, and management of this complex syndrome.
Clinical Infectious Diseases CID 2006:43 (15 December)
Oxford Journals
The epidemiology of acute encephalitis
Julia Granerod and Natasha S. Crowcroft
Health protection agency, Centre for Infection, London, UK
Encephalitis means inflammation of the brain matter. Despite being a rare condition,
encephalitis is of public health importance worldwide because it has high morbidity
and mortality. Yet, many details about its epidemiology have yet to be elucidated.
This review attempts to summarise what is known about the epidemiology of the infective
cause of encephalitis and is based on a literature search of the Medline archives.
Infection is the most common cause identified, with viruses being the most important
known aetiological agents. Incidence varies between studies but is generally between
3.5 and 7.4 per 100,000 patient- years. Encephalitis affects people of all ages;
however, incidence is higher in the paediatric population. Although both sexes are
affected, most studies have shown a slight predominance in males. Encephalitis occurs
worldwide; some aetiologies have global distribution (herpesviruses) while others
are geographically restricted (arboviruses). Although definite epidemiological trends
are evident, it is difficult to make generalisations as few population- based studies
exist, most cases are not reported to health authorities, and many possible pathogens
are implicated but in most cases a cause is never found. A better understanding
of the epidemiology of this devastating disease will pave the way for better prevention
and control strategies.
NEUROPSYCHOLOGICAL REHABILITATION 2007,17 (4/5), 406-428
Burden of Encephalitis-Associated Hospitalizations in the United States
1988-1997 N.Khetsuriani et al CID 2002:35 (15 July) 175
www.interscience.wiley.com/
Encephalitis and Aseptic Meningitis, Olstead County, Minnesota
1950 – 1981:1.Epidemiology E. Beghi et al Ann Neurol 16:283-294, 1984
Epidemiology and Outcome studies:
The Epidemiology of Encephalitis in England and Wales.
Bahn, A. (1994)
The incidence and lifetime prevalence of neurological disorders in a prospective
community – based study in the UK.
B.K.MacDonald, O.C.Cockerell, et al Brain (2000)
123, 665-676
www.brain.oupjournals.org/
Viral encephalitis in England, 1989-1998: What did we miss?
Davison, K.L., Crowcroft, N.S., Ramsey, M.E., Brown, D.W.G., Andrews, N.J. (2003)
Emerging Infectious Diseases, Vol 9, No.2, 234-240
www.cdc.gov/ncidod/EID/
Etiology of Encephalitis in
Australia, 1990–2007
Clare Huppatz, David N. Durrheim, Christopher Levi, Craig Dalton, David Williams, Mark S. Clements, and Paul M. Kelly
Encephalitis is a clinical syndrome commonly caused by emerging pathogens, which are not under surveillance in Australia. We reviewed rates of hospitalization for patients with encephalitis in Australia’s most populous state, New South Wales, from January 1990 through December 2007. Encephalitis was the primary discharge diagnosis for 5,926 hospital admissions; average annual hospitalization rate was 5.2/100,000 population. The most commonly identified pathogen was herpes simplex virus (n = 763, 12.9%). Toxoplasma encephalitis and subacute sclerosing panencephalitis showed notable declines. The average annual encephalitis case-fatality rate (4.6%) and the proportion of patients hospitalized with encephalitis with no identified pathogen (69.8%, range 61.5%–78.7%) were stable during the study period. The nonnotifiable status of encephalitis in Australia and the high proportion of this disease with no known etiology may conceal emergence of novel pathogens.
Unexplained encephalitis should be investigated, and encephalitis hospitalizations should be subject to statutory notification in Australia.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 9, September 2009
Etiology of Encephalitis in Australia 1990 - 2007.pdf
Etiology of aseptic meningitis and encephalitis in an adult population
L. Kupila, MD; T. Vuorinen, MD, PHD; R. Vaininonpää, PHD; V. Hukkanen,
MD, PHD; R.J. Marttila, MD, PHD; and P. Kotilainen, MD, PHD
Abstract – objective: to investigate the etiology of aseptic meningitis
and encephalitis in an adult population using modern micro biologic methods. Methods:
Consecutive patients (age’s ≥ 16) with aseptic meningitis or encephalitis
treated in Turku University Hospital, Finland, during 1999 to 2003 were4 included
in the study. Microbiologic tests ere performed, including CSF PCR tests doe enteroviruses,
herpes simple virus (HSV) 1, HSV-2, and varicella zoster virus (VZV), as well as
serum and CSF antibody analysis for these viruses. Antibody testing was also performed
for other pathogens commonly involved in neurologic infections. Virus culture was
performed on CSF, faecal and throat swab specimens. Results: Etiology was defined
in 95 of 144(66%) patients with aseptic meningitis. Enteroviruses were the major
causative agents (26%), followed by HSV-2 (17% of all, 25% of females) and VZV (8%).
Etiology was identified in 15 of 42 (36%) patients with encephalitis, VZV (12%),
HSV_1 (9%), and tick-borne encephalitis virus (9%) being the most commonly involved
Pathogens. Etiology diagnosis was achieved by PCR in 43% of patients with meningitis
and in 17% of those with encephalitis. Conclusion: Enteroviruses and HSV-2 are the
leading cause of adult aseptic meningitis, and PCR is of diagnostic value. However,
in most cases of encephalitis, the etiology remains undefined.
NEUROLOGY 20026; 66:75-80
www.neurology.org
In Search of Encephalitis Etiologies: Diagnostic Challenges in the California Encephalitis
Project, 1998-2000
Carol A. Glaser,1 Sabrina Gilliam,1 David Schnurr,1 Bagher Forghani,1 Somayeh Honarmand,1
Nino Khetsuriani,2 Marc Fischer,3 Cynthia K. Cossen,1 and Larry J. Anderson2
1 Viral and Rickettsial Disease Laboratory, California Department of Health Services,
Richmond, California; and 2 Respiratory and Enteric Viruses Branch and 3 Meningitis
and Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta,
Georgia
The California Encephalitis Project was initiated in June 1998 to identify the causes
and characterize the clinical and epidemiologic features of encephalitis in California.
Testing for 13 agents, including herpesviruses, enteroviruses, arboviruses, Bartonella
species, Chlamydia species, and Mycoplasma pneumoniae, was performed at the Viral
and Rickettsial Disease Laboratory (Richmond, California). Epidemiologic and clinical
information collected for each case guided further testing. From June 1998 through
December 2000, 334 patients who met our case definition of encephalitis were enrolled.
A confirmed or probable viral agent of encephalitis was found in 31 cases (9%),
a bacterial agent was found in 9 cases (3%), and a parasitic agent was found in
2 cases (1%). A possible etiology was identified in 41 cases (12%). A noninfectious
etiology was identified in 32 cases (10%), and a nonencephalitis infection was identified
in 11 (3%). Despite extensive testing and evaluation, the etiology of 208 cases
(62%) remained unexplained.
Received 4 September 2002; accepted 2 December 2002; electronically published 3
March 2003.
Clin Infect Dis 2003: 36:731
Full Text www.ncbi.nlm.nih.gov/pubmed/12627357
Last modified: March 2011