A 12-Year Prospective Study of Childhood Herpes Simplex Encephalitis: Is There a
Broader Spectrum of Disease?
Jorina M. Elbers, MDa, Ari Bitnun, MD, MScb, Susan E. Richardson, MDc, Elizabeth
L. Ford-Jones, MDb, Raymond Tellier, MD, MScc, Rachel M. Wald, MDb, Martin Petric,
PhDc, Hanna Kolski, MDa,d, Helen Heurter, BScNb and Daune MacGregor, MDa
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.
PEDIATRICS Vol. 119 No. 2 February 2007, pp. e399-e407
Childhood encephalopathy: viruses, immune response, and outcome
Michael Clarke a1, Richard W Newton a2 c1, Paul E Klapper a3, H Sutcliffe a4, I Laing
a5 and Geoff Wallace a6
Abstract
This study examined children with an acute encephalopathy illness for evidence of
viral infection, disordered blood–brain barrier function, intrathecal immunoglobulin
synthesis, and interferon (IFN) production, and related their temporal occurrence
to outcome. A prospective study of 22 children (13 males, 9 females; age range 1mo
to 13y, median 2y 4mo), recorded clinical details, with serum and cerebrospinal
fluid (CSF) analysis near presentation and then on convalescent specimens taken
up to day 39 of the neurological illness. Outcome was assessed with standard scales
between 18 months and 3 years after presentation. A history consistent with viral
infection was given in 17 children but laboratory evidence of viral infection was
found in only 7 (7/17). In 18 out of 21 children, an elevated CSF:serum albumin
ratio indicative of impairment of the blood–CSF and blood–brain barriers
was detected at some stage of the illness. In 14 of the 15 children with a raised
immunoglobulin G index, and in 12 of the 14 children where the CSF was positive
for oligoclonal bands, this was preceded by, or was observed at the same time as,
an abnormal albumin ratio. Sixteen children (16/18) had elevated IFN-α levels
in serum, or CSF, or in both. We conclude that these findings indicate an initial
disruption of the blood–brain barrier followed by intrathecal antibody production
by activated lymphocytes, clonally restricted to a few antigens. This is the first
in vivo study to show this as an important pathogenetic mechanism of encephalitis
in children. Poor outcome was associated with young age, a deteriorating electroencephalogram
pattern from grade 1 to grade 2, and the degree of blood–brain barrier impairment,
particularly when prolonged, but not with Glasgow Coma Scale score. The persistence
of IFN-α was associated with a good prognosis.
Development Medicine & Child Neurology 2006,48: 294-300
Cambridge Journals
Herpes simplex encephalitis: diagnostic problems and late relapse
Xavier Ed Tiège MD, Flore Rozenberg MD PhD, Karine Burlot MD, Joël
Gaudelus MD, Gérard Ponsot MD, Bénédicte Héron MD
A 5-year-old presented with prolonged afebrile reight-sided focal seizures, right
brachio-facial paralysis, and dysartharia; conciousness was not altered. Fever appeared
20 hours after onst of neurological symptoms. At admission (day 1) cerebal computerized
tomography and cerebrospinal fluid (CSF) analyses were normal including undetectable
alpha-interferon (α-IFN) and negative herpes simplex virus (HSV) polymerase
chain reaction (PCR). Acyclovir was started at a dosage of 60mg/kg/day for 21 days
and neurological symptoms improved. Cerebral magnetic resonance imaging (MRI) showed
legions in the left thalamus and left parietal lobe. On day 8, CSF contained as
elevated leukocyte count with a predominance of lymohocytes, but α-IFN and
HSV DNA were still undetectable. Delayed intrathecal synthesis of specific
anti-HSV antibodies was found on day 26 and confirmed herpes simplex encephalitis
(HSE) diagnisis. Twenty months after this episode, the patient persented with
a febrile meningeal syndrome. PCR detected HSV DNA in CSF and cerebral
imaging showed a new left temporal lesion. At relapse onset, intrathecal synthesis
of specific anti-HSV antibodies had disappeared. Acyclovir was started at a
dosage of 60 mg/kg/day for 21 days and neurological status improved. At discharge,
neurological examination showed right hemiparesis and bucco-facial dyspraxia. Diagnostic
problems of HSE diagnosis in children are highlighted. It is suggested that the
premature disappearance of intrathecal synthesis of a specific anti-HSV antibody
might play a permissive role in the resurgence of cerebral viral replication.
Development Medicine & Child Neurology 2006,48: 60-63
Cambridge Journals
Subacute sclerosing panencephalitis in the differential diagnosis of encephalitis
S. Honarmand, MS, C. A. Glaser, DVM MD, E. Chow, MD, J. J. Sejvar, MD, C. P. Preas,
BA, G. C. Cosentino, BS, H. T. Hutchison, MD PhD and W. J. Bellini, PhD
From the Viral and Rickettsial Disease Laboratory (Dr. Glaser, S. Honarmand, C.P.
Preas, and G.C. Cosentino), Division of Communicable Disease Control, California
Department of Health Services, Richmond, CA; Division of Infectious Diseases (Dr.
Chow), Department of Pediatrics, Mattel Children’s Hospital at UCLA Medical
Center, Los Angeles, CA; Division of Viral and Rickettsial Diseases (Drs. Sejvar
and Bellini), Centers for Disease Control and Prevention, Atlanta, GA; and Department
of Neurology (Dr. Hutchison), Children’s Hospital Central California, Madera,
CA.
Abstract – The authors describe five cases of subacute sclerosing panencephalitis
(SSPE) identified through the California Encephalitis Project that emphasize the
importance of considering SSPE in the differential diagnosis of encephalitis, particularly
among pediatric patients. SSPE was not suspected in the differential diagnosis of
three of the cases until results of measles testing were known. The diagnosis of
SSPE is often not considered by clinicians because of its rarity in the United States
and the nonspecific clinical manifestations at onset.
Received March 18, 2004. Accepted in final form July 8, 2004.
Neurology Journal