Brief Research ReportEmpiric Acyclovir Is Infrequently Initiated in the Emergency Department to Patients Ultimately Diagnosed With Encephalitis
Introduction
Encephalitis and meningitis describe inflammatory processes involving the brain (encephalitis) and the meninges (meningitis). The cardinal features of meningitis are headache, fever, and neck stiffness, whereas encephalitis is characterized by headache, fever, and neurologic or psychiatric alteration. Although the most common cause in both cases is infectious, the differentiation between meningitis and encephalitis in the emergency department (ED) is not always clear. Both are acute illnesses with evidence of central nervous system inflammation on analysis of cerebrospinal fluid. Although the 2 conditions may be differentiated with further testing, including magnetic resonance imaging (MRI), specialized cerebrospinal fluid analysis, and electroencephalography (EEG), these modalities are often unavailable in the time required to make decisions about empiric therapy in the ED. Moreover, the 2 conditions may overlap. In this case, the term “acute meningoencephalitis” is preferred because it broadens the differential diagnosis and resultant empiric therapies.
Although therapy for acute encephalitis is supportive in most cases, intravenous acyclovir has been shown to be highly effective in the treatment of herpes simplex encephalitis (HSE). Herpes simplex encephalitis is a hemorrhagic, necrotizing encephalitis caused by herpes simplex virus type 1. It is the most common cause of sporadic encephalitis, with an incidence of more than 2,000 cases annually in the United States.1 An additional 1,500 cases occur as disseminated herpes simplex virus type 2 disease in neonates, bringing the total burden of serious disease to more than 3,500 cases per year.2 Furthermore, newer highly sensitive assays are detecting subacute, atypical, and less severe cases of herpes simplex encephalitis that were previously undiagnosed.3
With treatment, mortality decreases dramatically from approximately 75% to approximately 25%.1, 4, 5 Significant neurologic impairment in survivors is also markedly decreased with treatment, with many patients reporting minor or no neurologic impairment at follow-up.4 Two groups of patients are known to have poorer outcomes: those presenting with severe symptoms and signs and those in whom treatment with acyclovir is delayed for several days.4, 6 For this reason, it is recommended that antiviral therapy be initiated early, before a delay in treatment adversely affects outcome in patients ultimately determined to have herpes simplex encephalitis. Despite multiple articles in the neurologic, pediatric, infectious disease, and psychiatric literature emphasizing the need for prompt empiric acyclovir therapy to patients with encephalitis of unclear cause, we were unable to find mention of such a practice in the emergency medicine literature (PubMed 1965 to 2004).4, 7, 8, 9, 10 In contrast, there are many articles in the emergency medicine literature advocating immediate empiric antibacterial therapy to patients with suspected bacterial meningitis.11, 12, 13
The goal of this study is to determine how frequently empiric therapy with acyclovir is initiated in the ED in patients who are ultimately diagnosed with encephalitis before discharge. We hypothesized that empiric acyclovir is underused in patients presenting to the ED despite findings consistent with encephalitis. We further hypothesized that omissions or delays of empiric antibacterial administration would be less common.
Section snippets
Study Design
We conducted an explicit retrospective medical record review of patients discharged from the Los Angeles County–University of Southern California Medical Center with a diagnosis of herpes simplex encephalitis or viral encephalitis not otherwise specified for the period July 1, 1993, to June 1, 2003. In this case, “discharge” referred to anyone discharged home or to another facility for extended care, as well as to the morgue in fatal cases. The study was approved in advance by the University of
Characteristics of Study Subjects
Ninety-nine (99) medical records were requested, of which 90 were available for review. Of the original 90 reviewed, 24 met the inclusion criteria. Fifty-six (82%) of the cases excluded were because of an absence of fever at or before the decision point. An inability to obtain a cerebrospinal fluid specimen from the ED before admission accounted for 8 excluded cases (12%), and 2 (3%) were excluded because of a normal initial cerebrospinal fluid examination result. Of the 24 included patients,
Limitations
We chose a rather conservative definition of encephalitis that substantially increased the likelihood of a central nervous system source of infection. We did this because we wanted to examine the practice of emergency physicians in situations in which empiric acyclovir was most likely to be considered. Empiric acyclovir may be a consideration in a larger group of patients, such as those that met only 2 of the 3 inclusion criteria used for this study. In fact, of the 66 patients reviewed who
Discussion
Our findings suggest that, although empiric treatment for bacterial pathogens occurred regularly in the ED, empiric treatment of encephalitis with acyclovir did not. Only 29% of patients ultimately diagnosed with encephalitis received acyclovir while in the ED, despite clinical presentations consistent with encephalitis. Moreover, the clinical diagnosis of acute encephalitis or acute meningoencephalitis was made in our ED in only 17% of these cases.
McGrath et al,8 in their study of 42 patients,
References (15)
- et al.
Viral encephalitis: familiar infections and emerging pathogens
Lancet
(2002) - et al.
Time to antiviral treatment as a predictor of cognitive recovery from herpes encephalitis
Arch Clin Neuropsychol
(1999) - et al.
Presentation, time to antibiotics, and mortality of patients with bacterial meningitis at an urban county medical center
J Emerg Med
(2001) - et al.
Analysis of emergency department management of suspected bacterial meningitis
Ann Emerg Med
(1989) - et al.
Relationship of clinical presentation to time to antibiotics for the emergency department management of suspected bacterial meningitis
Ann Emerg Med
(1993) - et al.
Herpes simplex encephalitis
J Neurol Neurosurg Psychiatry
(2002) - et al.
Predictors of morbidity and mortality in neonates with herpes simplex virus infections: the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
N Engl J Med
(1991)
Cited by (35)
Management of adult infectious encephalitis in metropolitan France
2017, Medecine et Maladies InfectieusesCitation Excerpt :Indeed, administering acyclovir after 48 hours is associated with a higher risk of neurological sequelae [4,5,27]. Factors associated with a longer treatment delay were the absence of HSV encephalitis evidence and the presence of confounding factors (alcohol abuse, comorbidities, normal initial CSF), or a longer time before receiving imaging results [5,28,29]. Other factors associated with poor prognosis were altered consciousness (based on GCS) at hospital admission and older age [4].
A hair-raising diagnosis: Goose bumps as sign of herpes simplex encephalitis
2015, American Journal of Emergency MedicineCitation Excerpt :Clinicians can improve patient outcomes with a high index of suspicion and early antiviral treatment. Many studies, however, demonstrate that acyclovir therapy is rarely initiated early in its symptoms in patients ultimately diagnosed with HSV [7]. The patient described in this case report presented with a new onset generalized tonic-clonic seizure before arrival and the subtle physical examination finding of piloerection of the left arm.
Encephalitis
2014, Mandell, Douglas, and Bennett's Principles and Practice of Infectious DiseasesVaricella zoster encephalitis mimicking stroke
2014, American Journal of Emergency MedicineCitation Excerpt :Thus, the rate of a PCR-positive result for VZV DNA in the CSF tends to decline rapidly within 7 to 10 days after the onset of rash, whereas the rate of anti-VZV IgG antibody elevation tends to increase and then be maintained during the clinical course [14-16]. Empiric treatment for HSV-1 infection with acyclovir (10 mg/kg IV Q8h) should always be initiated as soon as possible if the patient has encephalitis without apparent explanation [17]. Early therapy is vital because it is associated with a significant decrease in mortality and morbidity.
Risk stratification and management of the febrile young child
2013, Emergency Medicine Clinics of North AmericaCitation Excerpt :Risk factors include primary maternal HSV infection (especially in those neonates delivered vaginally); prolonged rupture of membranes at delivery; the use of fetal scalp electrodes; skin, eye or mouth lesions; and seizures.78,80,81 Rates of morbidity and mortality are high with neonatal HSV, and delays to treatment are common.82,83 Acyclovir is not recommended routinely for empiric treatment in febrile neonates79 but should be considered in neonates with risk factors for neonatal HSV, especially in neonates less than or equal to 21 days of age84 and with CSF pleocytosis.85
Meningitis, Encephalitis, and Brain Abscess
2012, Emergency Medicine: Clinical Essentials, SECOND EDITION
Supervising editor: Gregory J. Moran, MD
Author contributions: PCB was solely responsible for the medical record reviewing, data analysis, and the literature search. PCB and SPS wrote and revised the manuscript. PCB takes responsibility for the paper as a whole.
Funding and support: The authors report this study did not receive any outside funding or support.
Presented at Society for Academic Emergency Medicine Western Regional Conference, Oakland, CA, April 2004, and American College of Emergency Physicians Scientific Assembly, San Francisco, CA, October 2004.
Reprints not available from the authors.