PEDIATRICS Vol. 119 No. 2 February 2007, pp. e399-e407 (doi:10.1542/peds.2006-1494)
ARTICLE |
A 12-Year Prospective Study of Childhood Herpes Simplex Encephalitis: Is There a Broader Spectrum of Disease?
a Divisions of Neurology
b Infectious Diseases, Department of Paediatrics
c Department of Paediatric Laboratory Medicine, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
d Division of Neurology, Department of Paediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
OBJECTIVE. The purpose of this study was to review the experience with herpes simplex encephalitis at the Hospital for Sick Children over the past 12 years.
METHODS. All patients who were admitted to our institution with acute encephalitis between January 1994 and December 2005 were enrolled prospectively in an encephalitis registry. Children from the registry with herpes simplex encephalitis were included in this study; we detailed the clinical presentations, laboratory findings, electroencephalographic findings, diagnostic imaging findings, treatments, and outcomes for all cases.
RESULTS. Of 322 cases of acute encephalitis, 5% were caused by herpes simplex virus. Initially negative herpes simplex virus cerebrospinal fluid polymerase chain reaction results were found in 2 cases (13%), but results became positive in repeat cerebrospinal fluid analyses. Classic clinical presentations were seen in 75% of cases, cerebrospinal fluid pleocytosis was found in 94%, elevated cerebrospinal fluid protein levels were found in 50%, electroencephalographic changes were observed in 94%, and diagnostic imaging abnormalities were noted in 88%. All patients were treated with intravenous acyclovir. Neurologic sequelae occurred in 63% of cases, including seizures in 44% and developmental delays in 25%. There were no deaths in this study group.
CONCLUSIONS. Herpes simplex encephalitis continues to be associated with poor long-term neurologic outcomes despite appropriate therapy. Cerebrospinal fluid polymerase chain reaction results may be negative early in the course of herpes simplex encephalitis; therefore, repeat cerebrospinal fluid analysis should be considered if herpes simplex encephalitis is suspected. Atypical forms of herpes simplex virus central nervous system disease may occur in children.
Key Words: herpes simplex virus • encephalitis • children
Abbreviations: HSV—herpes simplex virus • HSE—herpes simplex encephalitis • CSF—cerebrospinal fluid • PCR—polymerase chain reaction • EEG—electroencephalographic • CT—computed tomography • CNS—central nervous system • RBC—red blood cell • PLEDS—periodic lateralizing epileptiform discharges • ADEM—acute demyelinating encephalomyelitis
Herpes simplex encephalitis (HSE) is regarded as the most common cause of sporadic fatal encephalitis in patients >6 months of age in the Western world. The incidence of HSE is 
1 case per 250000 to 500000 persons per year, with one third of cases occurring in children.1 Untreated HSE has a mortality rate of 70% in adults, with <3% of patients returning to normal function. With treatment, neurologic sequelae occur in 28% of adult cases; survival rates are improved if treatment is initiated within 4 days after the onset of the illness.2 Therefore, early diagnosis and treatment with acyclovir are critical for preventing death and minimizing long-term disability.
Improved laboratory technology and improved neuroimaging accessibility have enhanced our ability to diagnose this condition. Detection of herpes simplex virus (HSV) in the cerebrospinal fluid (CSF) through polymerase chain reaction (PCR) is the diagnostic modality of choice for HSE. According to the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, PCR has sensitivity and specificity of 94% and 98%, respectively, compared with HSV culture from brain biopsy.3 However, PCR detection of microbial nucleic acid can be associated with false-positive and false-negative results and requires the use of a laboratory with a demonstrated record of diagnostic accuracy. Previous studies suggested that failure to detect HSV in the CSF through PCR can occur in the first 24 to 48 hours of the illness and that the sensitivity of PCR in the diagnosis of HSE is lower for children than for adults.4,5 The purpose of this study was to detail the clinical, laboratory, electroencephalographic (EEG), and diagnostic imaging used to establish a diagnosis of HSE, to evaluate PCR as a diagnostic tool, and to assess the impact of HSE on children at our institution over the past 12 years.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
All patients who presented with acute encephalitis at the Hospital for Sick Children (Toronto, Canada) between January 1994 and December 2005 were enrolled prospectively in an encephalitis registry. Inclusion criteria for this registry are documented encephalopathy, defined as depressed or altered level of consciousness persisting for >24 hours, plus
2 of the following: fever (>38°C), seizure, focal central nervous system (CNS) findings, CSF pleocytosis (>5 x 106 cells per L), EEG abnormalities, or diagnostic imaging abnormalities (on brain computed tomography [CT]/MRI scans). Patients were excluded if they had underlying neurologic disease or were known to have immunosuppression. This study did not include cases of neonatal encephalitis and focused on children between 4 weeks and 18 years of age.
For identification of a cohort of children with clinically and diagnostically definite HSE, patients in our study fulfilled stringent inclusion criteria: the aforementioned criteria of the encephalitis registry, CSF PCR and/or serologic evidence of HSV infection, and 1 of the following: CSF abnormalities, including the presence of pleocytosis, >50 x 106 red blood cells (RBCs) per L, and/or elevated protein levels (>0.4 g/L), EEG readings consistent with HSE, or CT and MRI findings suggesting HSE, such as focal signal abnormalities or hemorrhage. Patients were excluded if an alternative diagnosis accounted for their symptoms. Eligible patient charts were reviewed for clinical features at admission, medical history, laboratory findings at presentation, EEG results, CNS imaging studies, hospital course, treatments, and outcome.
Detection of HSV in the CSF specimens by PCR was performed by using the method described by Rozenberg and Lebon6 before 1998 and by using a PCR assay detecting all known human herpes viruses, as described by Johnson et al,7 thereafter. Our laboratory monitors for the presence of PCR inhibition in the DNA extracted from specimens, as described.7 Acute HSV infection was defined on the basis of detection of HSV in the CSF by PCR and/or at least a fourfold increase in complement fixation test titer between acute serum and convalescent serum or detection of anti-HSV IgM antibodies in acute or convalescent serum. The complement fixation test was used between 1994 and 1998; subsequently, this was replaced with an enzyme-linked immunosorbent assay (EIAgen HSV IgG; Adaltis, Montreal, Canada). Because detection of acute HSV infection through changes in antibody titers is known to have low sensitivity,8,9 the absence of detectable antibody to HSV in the acute or convalescent serum did not exclude a patient from our study if the CSF was positive for HSV in PCR assays. As part of the encephalitis registry, each patient was also tested for evidence of acute infection with Epstein-Barr virus, cytomegalovirus, varicella zoster virus, human herpesvirus-6, human herpesvirus-7, influenza A and B viruses, parainfluenza viruses,1–3 adenovirus, enteroviruses, measles virus, parvovirus, arboviruses including West Nile virus, Mycoplasma pneumoniae, Bartonella henselae, and syphilis. The microbiologic methods used for the detection of these potential pathogens were described previously.10,11
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Sixteen of 322 patients with acute encephalitis fulfilled our criteria for HSE (Table 1), including 8 male patients and 8 female patients, with a median age of 4 years (range: 2 months to 14 years). Of these, 1 patient was <3 months of age, 3 patients (19%) were between 3 and 12 months of age, 4 patients (25%) were between 1 and 4 years of age, 4 patients (25%) were between 5 and 10 years of age, and 4 patients (25%) were between 10 and 14 years of age. Eight patients (50%) had a known history of, or exposure to, HSV before admission. All 16 patients presented with fever, 11 (69%) presented with focal seizures, 5 (31%) presented with hemiparesis, and 2 (13%) presented with dysphasia. Fifteen (94%) of the 16 patients presented with CSF pleocytosis, and 3 (19%) had 50 to 100 x 106 RBCs per L. CSF protein levels were elevated in 8 cases (50%).
|
Twelve (75%) of the 16 patients had HSV detected in the CSF by PCR (Table 2). Four patients with negative CSF PCR results demonstrated at least a fourfold increase in complement fixation titers between acute serum and convalescent serum. Four patients (25%) with positive CSF PCR had no increase in HSV antibody titers. Two of the 12 patients who had HSV detected in the CSF by PCR had negative CSF PCR on day 1 but positive CSF PCR on day 3 or 7. The virus detected by PCR was HSV-1 for 10 (83%) of the 12 patients and was HSV-2 for 2 (17%). Evidence of coinfection with
1 other potential pathogen was observed in 10 of 16 cases (Table 2).
|
EEG assessment was completed in all 16 cases. Generalized background slowing was found in 13 cases (81%), and periodic lateralizing epileptiform discharges (PLEDS) were found in 2 cases (13%). Of the 16 patients with HSE in our study, 15 (94%) underwent cranial CT and 13 (81%) were evaluated with MRI. Neuroimaging abnormalities consistent with HSE (ie, localized edema, mass effect, high/low-density lesions, or hemorrhage on either CT or MRI scans) were noted in 14 cases (88%). Seven cases (44%) showed localization to the limbic system, 2 cases (13%) showed localization to parietal, frontal, or occipital lobes or thalami, 5 cases (31%) showed a larger area involving >2 regions, and 6 cases (38%) showed bilateral disease. Four cases (25%) involved infarction and subsequent hemorrhage, all of which had positive CSF PCR results for HSV-1. Six (40%) of 15 CT scans were read as normal, whereas only 1 of 13 MRI scans showed no evidence of HSV infection. Four (67%) of the 6 cases with negative CT results revealed abnormalities consistent with HSE on MRI scans.
All patients were treated with acyclovir, 7 with a 14-day course before 1999, and 8 with a 21-day course after 1999, according to the treatment protocols in place during each time period. One patient received a 6-week course of acyclovir after infarction and hemorrhage requiring craniotomy. For all patients, therapy was initiated within the first 3 days of illness. One child who was treated with a 14-day course of acyclovir was readmitted 11 days after discharge, with a presumed relapse of HSE presenting with fever, encephalopathy, seizures, and CSF pleocytosis. His initial CSF was positive for HSV by PCR at the time of initial presentation but negative at the time of relapse.
Follow-up data were available in all 16 cases. The minimal follow-up period was 3 months after discharge, with a median of 4 years. Ten (63%) of the 16 patients had adverse neurologic outcomes; 7 children (44%) had seizure disorders, 4 children (25%) had global developmental delays, and 2 children (13%) had residual hemiplegia (Table 1). There was no demonstrable association of adverse outcomes with younger age, gender, clinical features, pleocytosis, elevated CSF protein levels, focal EEG abnormalities, or neuroimaging abnormalities (all P > .2). There were no deaths in this study group.
Five children with acute encephalitis for whom HSV was detected in the CSF by PCR were excluded from our study (Table 3). Three of the children did not fulfill our stringent HSE criteria. For the remaining 2 children, the clinical presentation and course were attributed to an alternative diagnosis (ie, CNS vasculitis and acute demyelinating encephalomyelitis [ADEM]). Four of the 5 patients had serologic results that were negative for HSV.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Our experience with HSE in children over the past 12 years is congruent with much of the documented literature but updates knowledge on the incidence, clinical presentation, diagnosis, and outcome of childhood HSE. HSE accounted for 5% of all acute nonneonatal encephalitis cases seen in this large, pediatric, single-center cohort, which is consistent with the rate found for 175 children with acute encephalitis in Finland.12 Our estimate of HSE prevalence, although perhaps somewhat conservative because of our stringent inclusion criteria, is clearly lower than rates of adult acute encephalitis, for which incidence rates between 10% and 20% have been reported.13,14 There was no gender or age predilection in our study population. The classic clinical presentation of HSE (consisting of fever, altered level of consciousness, focal motor seizures, dysphasia, and hemiparesis), which was found in 90% of cases of adult HSE,15 was present in 12 (75%) of 16 cases in our childhood population. Other presentations consisted of ataxia, decreased visual acuity, tremor, or generalized tonic-clonic seizures.
HSV PCR was performed in all 16 cases, and results were positive in 12 (75%). Four cases (25%) had negative CSF PCR, despite serologic evidence of acute HSV infection, which suggests that a single negative CSF PCR does not exclude HSV as a cause of acute encephalitis. Two (17%) of the 12 cases in which HSV was detected by PCR in the CSF showed negative results on day 1 but positive results in repeat testing on days 3 or 7. This information helps to consolidate previous evidence reported by Weil et al,4 who described 3 cases of HSE (1 child and 2 adults) in which CSF PCR for HSV was negative on the first day but positive in repeat testing on days 4 to 7. Our data suggest that the rate of early negative CSF PCR for children is higher than the rates of 3% to 5% reported for adults16,17 and that negative HSV PCR results obtained within the first 3 days of illness do not exclude HSV as a cause of encephalitis. Therefore, we recommend that a second lumbar puncture be performed after this time period for children with initial negative HSV PCR results who are suspected of having HSE on the basis of clinical presentation and imaging studies.
CSF analysis, EEG testing, and diagnostic imaging are all used to aid in the diagnosis of HSE. Although typical laboratory results are highly suggestive of HSV (CSF pleocytosis, elevated protein levels, and elevated RBC counts), the absence of these features does not rule out a diagnosis of HSE. In our cohort, 1 patient (6%) did not demonstrate CSF pleocytosis, 50% had normal CSF protein levels, and only 3 (19%) showed elevated RBC counts. The latter observation contrasts with previous reports that suggested that elevated CSF RBC counts occur in 50% of cases.18 EEG records showing PLEDS had sensitivity of 81% and specificity of 59% for adult HSE.15 In our study, only 2 (13%) of 16 patients displayed PLEDS on EEG tracings, which suggests that this abnormality has a lower incidence in childhood HSE. MRI is considered the most sensitive method for detecting lesions of HSE.19 This was borne out in our cohort of children; 67% of MRI studies performed after normal CT studies detected significant abnormalities. Cranial MRI may show a variety of abnormalities, including areas of hyperintensity on T2-weighted scans, localized edema, and petechial or larger hemorrhage. In our study, 44% of cases showed localization to the limbic system, 31% showed more-diffuse involvement, and 38% showed bilateral disease.
There were no deaths in our cohort, but 10 patients (63%) experienced significant neurologic sequelae, including seizures, developmental delays, and hemiplegia. Neither the clinical features nor diagnostic test abnormalities were predictive of adverse outcomes. Previous studies reported mortality rates of 7% to 17% despite appropriate acyclovir therapy.20,21 Others suggested that adverse neurologic outcomes and the risk of recurrence are associated with delayed initiation and shorter courses of acyclovir therapy.19 The standard of care in the past decade has seen an increase in the duration of treatment from 14 days to 21 days.22 In our study, patients who received a 21-day course of acyclovir, compared with a 14-day course, tended to have a lower incidence of adverse neurologic outcomes (55% [5 of 9 cases] and 71% [5 of 7 cases], respectively). In addition, the patient who experienced a relapse of HSE was treated initially with a 14-day course of acyclovir. These observations may represent additional evidence that a 21-day course of acyclovir is more effective in reducing the incidence of adverse neurologic outcomes and the risk of recurrence associated with HSE.
Our case definition was designed to include cases that are generally accepted as representing typical cases of HSE. Three children for whom HSV was detected in the CSF by PCR were excluded because they did not fulfill the case definition; they had normal CSF analysis results, normal EEG results, and no detectable abnormalities on neuroimaging. Two of those patients presented with fever, generalized seizures, and ataxia, and another presented with headache and lethargy. Previous studies suggested that mild or atypical presentations of HSE do occur among adults.23–28 The clinical spectrum of these atypical cases included focal or generalized seizures and minimal reductions in the level of consciousness. The 3 mild cases in our cohort, which were excluded from our series, suggest that mild forms of HSE may also occur among children. Such cases might have been missed previously because the degree of severity did not warrant brain biopsy.
An additional 2 patients were excluded from our study, despite having positive PCR for HSV in the CSF, because of alternate diagnoses. The detection of HSV in the CSF in these cases could be attributed to true false-positive PCR results or to the presence of HSV in the CSF as a result of neuronal injury through a non–HSV-related pathologic process. The first of these cases, which may illustrate this process, involved a 15-year-old female patient who presented with a 10-day history of decreased level of consciousness, right-sided hemiparesis, dysphasia, dysarthria, and a generalized tonic-clonic seizure. Her CSF was positive for HSV DNA by PCR; although there was no pleocytosis, the CSF did show a high level of protein. A repeat lumbar puncture sample obtained 1 week later was again positive for HSV DNA by PCR, but a 14-day treatment with acyclovir failed to yield improvement of the patient's symptoms. Elevation of the erythrocyte sedimentation rate was found during her admission, and an antinuclear antibody test yielded strongly positive results. Results of a conventional angiogram were negative; however, this is not uncommon for primary vasculitis in children.29 The patient began treatment with methylprednisolone and showed dramatic clinical improvement within 2 days. Her discharge diagnosis was CNS vasculitis. The positive HSV CSF PCR in this case could be attributable to secondary reactivation of HSV as a result of tissue damage from primary vasculitis. Alternatively, the vasculitic process could have been precipitated by HSV, although this does not explain the positive antinuclear antibody results. The occurrence of 2 positive PCR tests on different days of illness makes the possibility of laboratory error very unlikely.
The final case that was excluded despite the finding of HSV in the CSF by PCR had a diagnosis of ADEM. The patient presented with fever, headache, vomiting, and ataxia 3 weeks after receiving the influenza vaccine. His CSF showed mild pleocytosis and elevated protein levels, and MRI demonstrated diffuse gray and white matter lesions involving the cerebrum, cerebellum, and brainstem. His CSF was positive for HSV-1 by PCR, and IgG antibodies to HSV were detected in both acute and convalescent sera. IgM antibodies to M pneumoniae were also detected in serum. The patient was treated with a 3-week course of acyclovir and high-dose corticosteroids, with good clinical response. Four years later, the MRI findings remained abnormal but no additional episodes of demyelination had occurred. There are a few case reports describing possible HSV-related ADEM,30,31 one of which described a 3-year-old boy who developed ADEM after acute herpetic gingivostomatitis.30 Anti-HSV IgM and IgG antibodies were demonstrated in both blood and CSF samples, but HSV-DNA was not detected in the CSF by PCR.30 We speculate that our patient's ADEM might have been attributable to primary HSV infection; alternatively, this could represent another case in which a primary CNS disease process causes release of HSV DNA from latently infected cells.
Although the preceding 2 cases from our cohort were excluded from our series on the basis of a likely alternate diagnosis, it must be emphasized that both received full courses of intravenous acyclovir therapy. Given the high mortality and morbidity rates associated with HSE, prudence dictates that any patient with a neurologic disease and positive CSF PCR for HSV should receive a course of acyclovir therapy, even if the clinical presentation is atypical.
The 2 cases described above lead to consideration of the reactivation of latent HSV, residing in cells in the CNS, after an unrelated primary CNS process. Other authors6,27,32 postulated that the presence of HSV DNA in the CNS might be attributable to reactivation of latent HSV or transport of HSV to the CNS after reactivation of a latent infection in peripheral sensory or autonomic ganglia.6,27,32 Although PCR is useful for detecting the presence of viral DNA, it cannot distinguish between infectious virions, damaged virions, and cell-associated DNA. This may illustrate that, although the addition of PCR to our diagnostic repertoire has resulted in the diagnosis of HSE in many more cases, perhaps it has also identified cases in which, although HSV DNA is present, it may not be involved in the pathogenesis of the presenting disease.
|
CONCLUSIONS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
HSV accounted for 5% of all cases of acute childhood encephalitis over a 12-year period in our institution. Three fourths of all patients diagnosed as having HSE presented with the classic clinical features of fever, decreased level of consciousness, and focal neurologic deficits. Our data support previous findings that a single negative PCR result does not exclude the possibility of HSV as a cause of encephalitis, particularly if the CSF was obtained during the first 72 hours after presentation. PCR detection of HSV in the CSF for patients who do not fit the clinical picture of HSE may represent atypical presentations of HSE, reactivation of HSV by an unrelated primary disease process, or true false-positive results. MRI is a more sensitive diagnostic imaging modality for detecting abnormalities associated with HSE and should be used in preference to CT evaluation. Lastly, although the absence of deaths in our cohort is reassuring, the high prevalence of morbidity despite appropriate therapy is sobering and illustrates that additional therapeutic modalities are needed if we are to improve the outcome of this devastating disease.
|
FOOTNOTES |
|---|
Accepted Aug 15, 2006.
Address correspondence to Ari Bitnun, MD, MSc, FRCPC, Division of Infectious Diseases, Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada. E-mail: ari.bitnun{at}sickkids.ca
The authors have indicated they have no financial relationships relevant to this article to disclose.
This work was presented at the annual conference of the Infectious Disease Society of America; October 6–9, 2005; San Francisco, CA; and the Association of Medical Microbiology and Infectious Disease, Canada; March 15–19, 2006; Victoria, Canada.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
- Whitley RJ, Kimberlin DW. Herpes simplex encephalitis: children and adolescents. Semin Pediatr Infect Dis. 2005;16 :17 –23[CrossRef][Medline]
- Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet. 2002;359 :507 –513[CrossRef][Web of Science][Medline]
- Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease: National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1995;171 :857 –863[Web of Science][Medline]
- Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. 2002;34 :1154 –1157[CrossRef][Web of Science][Medline]
- Troendle-Atkins J, Demmler GJ, Buffone GJ. Rapid diagnosis of herpes simplex virus encephalitis by using the polymerase chain reaction. J Pediatr. 1993;123 :376 –380[CrossRef][Web of Science][Medline]
- Rozenberg F, Lebon P. Amplification and characterization of herpesvirus DNA in cerebrospinal fluid from patients with acute encephalitis.
J Clin Microbiol. 1991;29
:2412
–2417
[Abstract/Free Full Text] - Johnson G, Nelson S, Petric M, Tellier R. Comprehensive PCR-based assay for detection and species identification of human herpesviruses.
J Clin Microbiol. 2000;38
:3274
–3279
[Abstract/Free Full Text] - Moser H, Behrens F, Ziegelmaier R, Hilfenhaus J, Mauler R. Correlation of herpes simplex virus antibody titers and specific lymphocyte stimulation in adult blood donors.
J Clin Microbiol. 1981;13
:36
–41
[Abstract/Free Full Text] - Boos J, Esiri MM. Herpes simplex encephalitis. In: Boos J, Esiri MM, eds. Viral Encephalitis in Humans 1st ed. Washington, DC: ASM Press; 2003:41 –60
- Bitnun A, Ford-Jones EL, Petric M, et al. Acute childhood encephalitis and Mycoplasma pneumoniae. Clin Infect Dis. 2001;32 :1674 –1684[CrossRef][Web of Science][Medline]
- Kolski H, Ford-Jones EL, Richardson S, et al. Etiology of acute childhood encephalitis at the Hospital for Sick Children, Toronto, 1994–1995. Clin Infect Dis. 1998;26 :398 –409[Web of Science][Medline]
- Koskiniemi M, Korppi M, Mustonen K, et al. Epidemiology of encephalitis in children: a prospective multicentre study. Eur J Pediatr. 1997;156 :541 –545[CrossRef][Web of Science][Medline]
- Corey L, Spear PG. Infections with herpes simplex viruses (2). N Engl J Med. 1986;314 :749 –757[Web of Science][Medline]
- Rantalaiho T, Farkkila M, Vaheri A, Koskiniemi M. Acute encephalitis from 1967 to 1991. J Neurol Sci. 2001;184 :169 –177[CrossRef][Web of Science][Medline]
- Whitley RJ, Soong SJ, Linneman C Jr, Liu C, Pazin G, Alford CA. Herpes simplex encephalitis: clinical assessment.
JAMA. 1982;247
:317
–320
[Abstract/Free Full Text] - Guffond T, Dewilde A, Lobert PE, Caparros-Lefebvre D, Hober D, Wattre P. Significance and clinical relevance of the detection of herpes simplex virus DNA by the polymerase chain reaction in cerebrospinal fluid from patients with presumed encephalitis. Clin Infect Dis. 1994;18 :744 –749[Web of Science][Medline]
- Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis. 2002;35 :254 –260[CrossRef][Web of Science][Medline]
- Koskiniemi M, Vaheri A, Taskinen E. Cerebrospinal fluid alterations in herpes simplex virus encephalitis. Rev Infect Dis. 1984;6 :608 –618[Web of Science][Medline]
- Kennedy PG, Chaudhuri A. Herpes simplex encephalitis.
J Neurol Neurosurg Psychiatry. 2002;73
:237
–238
[Free Full Text] - Lahat E, Barr J, Barkai G, Paret G, Brand N, Barzilai A. Long term neurological outcome of herpes encephalitis.
Arch Dis Child. 1999;80
:69
–71
[Abstract/Free Full Text] - McGrath N, Anderson NE, Croxson MC, Powell KF. Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome.
J Neurol Neurosurg Psychiatry. 1997;63
:321
–326
[Abstract/Free Full Text] - Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet. 2001;357 :1513 –1518[CrossRef][Web of Science][Medline]
- DeVincenzo JP, Thorne G. Mild herpes simplex encephalitis diagnosed by polymerase chain reaction: a case report and review. Pediatr Infect Dis J. 1994;13 :662 –664[Web of Science][Medline]
- Domingues RB, Tsanaclis AM, Pannuti CS, Mayo MS, Lakeman FD. Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis. 1997;25 :86 –91[Web of Science][Medline]
- Fodor PA, Levin MJ, Weinberg A, Sandberg E, Sylman J, Tyler KL. Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF.
Neurology. 1998;51
:554
–559
[Abstract/Free Full Text] - Klapper PE, Cleator GM, Longson M. Mild forms of herpes encephalitis.
J Neurol Neurosurg Psychiatry. 1984;47
:1247
–1250
[Abstract/Free Full Text] - Jeffery KJ, Read SJ, Peto TE, Mayon-White RT, Bangham CR. Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results. Lancet. 1997;349 :313 –317[CrossRef][Web of Science][Medline]
- Vahlne A, Edstrom S, Hanner P, Andersen O, Svennerholm B, Lycke E. Possible association of herpes simplex virus infection with demyelinating disease. Scand J Infect Dis Suppl. 1985;47 :16 –21[Medline]
- Benseler SM, deVeber G, Hawkins C, et al. Angiography-negative primary central nervous system vasculitis in children: a newly recognized inflammatory central nervous system disease. Arthritis Rheum. 2005;52 :2159 –2167[CrossRef][Web of Science][Medline]
- Ito T, Watanabe A, Akabane J. Acute disseminated encephalomyelitis developed after acute herpetic gingivostomatitis. Tohoku J Exp Med. 2000;192 :151 –155[CrossRef][Web of Science][Medline]
- Kaji M, Kusuhara T, Ayabe M, Hino H, Shoji H, Nagao T. Survey of herpes simplex virus infections of the central nervous system, including acute disseminated encephalomyelitis, in the Kyushu and Okinawa regions of Japan. Mult Scler. 1996;2 :83 –87[Medline]
- Davies NW, Brown LJ, Gonde J, et al. Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections.
J Neurol Neurosurg Psychiatry. 2005;76
:82
–87
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  D. D. Sloan and K. R. Jerome Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10 J. Virol., November 15, 2007; 81(22): 12504 - 12514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 CARPHOLOGY BY Rajendra Practical Neurology, August 1, 2007; 7(4): 276 - 276. [Full Text] [PDF]
|
|
|
|
 |
|
 The Spectrum of Herpes Simplex Encephalitis in Children Journal Watch Infectious Diseases, February 21, 2007; 2007(221): 3 - 3. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
