A Toxic Infant with Aseptic Meningitis
Radiology Cases in Pediatric Emergency Medicine
Volume 7, Case 9
Kevin H. Higashigawa, Medical Student
Loren G. Yamamoto, MD, MPH
Kapiolani Medical Center For Women And Children
University of Hawaii John A. Burns School of Medicine
An 8-month-old female is brought into the emergency
department by her mother. The infant was in her usual
state of good health until three days ago, when her
mother noted that she felt warm. She was less active,
but eating well and had no vomiting, diarrhea, or other
complaints. The following day (2 days ago), she
refused to eat. She continued to have fevers and
remained less active than normal. That evening she
was taken to the ED and was found to have a
temperature of 39.5 degrees C. She was described by
her mother as being less active, not eating well, and
having a decreased urine output. CBC showed a white
count of 12.1 (32 segs, 2 bands, 53 lymphs, 9 monos),
hemoglobin 11.1, and hematocrit 32.8. A blood culture
was obtained. A chest radiograph was felt to be
normal. The infant was given antipyretics and
The next day (yesterday), she continued to have
fevers. Her temperature was 38.5 degrees C. She was
less active and was not eating or drinking. She had not
voided according to her mother. There was no
vomiting, diarrhea, or respiratory symptoms. Her
mother also noted on this morning that she had some
skin lesions which resembled insect bites. They were
red and raised. She was taken to see her primary care
physician, who evaluated her and discharged her.
She is brought to the ED today because of
increasing lethargy, very poor oral intake, no urine
output for 24 hours and continued fever.
Past Medical History: She was born via normal
spontaneous vaginal delivery. Prenatal and postnatal
courses were uncomplicated. She is usually on formula
but has taken some solid foods. Her immunizations are
up to date. She had one prior hospitalization at 4
weeks of age for fever during which time a sepsis
workup was negative. Her family history is
Exam: VS T 39 degrees C, P 160, R 35, BP 95/46.
She is very lethargic. She is not cooing, smiling, or
vocalizing. She has a weak cry and is tachypneic. She
does not respond to painful stimuli. She assumes a
position of comfort, in which her lower and upper
extremities are flexed and her head is turned to the
right. Attempts to place her head midline result in a
weak cry. There is slight nuchal rigidity. She is pale
with mottling of her lower extremities. There are
multiple skin lesions across her face and a few on her
arm. They are irregularly crusted (questionably
pustular) centrally, surrounded by some erythema. She
appears to have a facial droop on the right. Her
anterior fontanelle is small but sunken. Her mucus
membranes are sticky and she does not produce any
tears when she cries. She does open her eyes, but will
not follow objects and has a dysconjugate gaze. Breath
sounds are bilaterally coarse. She has some upper
airway rhonchi. She has no wheezes, crackles, or
rales. Heart regular without murmurs. Abdomen flat
and soft. Radial pulses are 2-3+ bilaterally and equal.
Her hands and feet are cool.
An IV is started and IV fluid is infused. She is also
given an IV dose of ceftriaxone. She begins to have
extensor posturing with arching of her back. She keeps
her head to the right. She also develops tonic-clonic
movements of her left upper extremity, and is therefore
given a IV lorazepam followed by phenytoin.
What work-up would you recommend?
Because of the infant's fever, nuchal rigidity,
lethargy, and focal neurologic abnormalities, a
diagnosis of meningitis and/or encephalitis is
suspected. A lumbar puncture is performed which
shows fluid that is questionably hazy (minimally). She
is given IV acyclovir and vancomycin (ceftriaxone was
given earlier). The laboratory analysis of the CSF
shows 105 RBCs and 40 WBCs per cubic mm with 10%
segs, 80% lymphs, and 10% monos, glucose 75,
protein 59. The Gram stain shows no organisms.
These clinical and laboratory findings are most
consistent with which of the following possibilities:
Shaken infant syndrome
The CSF analysis is consistent with aseptic
meningitis, but since this is usually a benign clinical
entity, this child who is very sick, is not likely to have
just aseptic meningitis. Bacterial meningitis is not likely
(practically not possible) given this CSF analysis.
Tuberculous meningitis is possible, but the clinical
course is too acute for this. Viral encephalitis is the
most likely since the CSF analysis suggests a viral
picture and the patient's poor neurological status is
consistent with an acute encephalitis. Additionally, the
skin lesions on the patient's face may be herpes
simplex lesions. Brain abscess is another possibility
which needs to be ruled out by imaging.
Cerebrovascular accident cannot be ruled out, but it is
less likely. Shaken infant syndrome is usually
associated with CSF which is grossly bloody. Brain
imaging studies will help to obtain a more definitive
diagnosis. A CT and a MRI are performed.
View her CT scan.
The CT scan without contrast demonstrates (upper
two images) some hypodensity in the thalami and
temporal lobes, indicative of bilateral cortical and
subcortical edema. After the administration of IV
contrast (lower two images), there is meningeal
enhancement at the margins of the abnormal
parenchyma, as well as mild central enhancement. This
is consistent with a breach in the blood-brain barrier
following vasculitis. There is no evidence of herniation.
View her MRI scan.
The areas of increased signal intensity in the MRI
scan indicate the presence of abnormal water,
consistent with the CT scan findings of
cortico-medullary edema in the bilateral
temporoparietal lobes. There is also meningeal
enhancement over the affected areas of the brain.
The above findings are compatible with bilateral
temporoparietal lobe meningoencephalitis.
What additional tests would you request?
The CSF sample is positive for herpes simplex virus
(HSV) DNA by polymerase chain reaction (PCR)
although the viral culture of the CSF is negative.
Her EEG is abnormal. It is diffusely slow for her
age. These results are compatible with a diffuse
encephalopathic process. In addition, there are some
sharp waves emanating from the right frontotemporal
and right frontal central regions, consistent with seizure
foci in the affected areas shown on her brain CT and
What is the classic presentation for an infant with
HSV encephalitis? What is the relationship between
HSV encephalitis and the presence of mucocutaneous
skin lesions? What is the prognosis for HSV
Encephalitis is an infection of the parenchyma of the
brain (in contrast to meningitis, an infection of the
meninges). The most common cause of viral meningitis
is enterovirus infection, whereas one of the more
common causes of viral encephalitis is HSV. The major
manifestations of viral meningitis include fever,
headache, irritability, mild lethargy or drowsiness, and
some degree of nuchal rigidity. On the other hand,
encephalitis often presents with significant neurologic
signs and symptoms in addition to an acute febrile
illness. In the usual case of viral meningitis, the
disease is relatively benign and self-limiting.
Encephalitis, however, is a disease which can be
associated with significant morbidity and mortality (1).
It is not unusual for encephalitis and meningitis to
coexist in the same patient as meningoencephalitis.
Encephalitis must also be distinguished from
cerebritis. Cerebritis is a highly destructive
inflammatory condition of the brain, which may be
bacterial in origin, often leading to abscess formation.
Encephalitis is most commonly viral in nature and the
extent of parenchymal damage is variable.
Arboviruses are the most common cause of episodic
viral encephalitis. Two of the most common forms of
arboviral encephalitis are: 1) St. Louis encephalitis,
which is mainly found in urban areas around the
Mississippi River, and 2) California encephalitis, which
is principally found in rural areas of the northern
Midwest and East. Eastern equine encephalitis is one
of the most severe causes of arboviral encephalitis, but
it is uncommon (mostly in the New England area).
Western equine encephalitis is most prevalent in the
rural areas west of the Mississippi (2). The arboviruses
tend to have a seasonal preference for the summer and
early fall months because they are largely transmitted
via arthropod vectors.
HSV is the most common cause of sporadic viral
encephalitis in the United States, accounting for
approximately 10 to 20 percent of all cases. It is
estimated that about 2 persons per million per year will
suffer from HSV encephalitis. HSV-1 is acquired more
frequently and earlier in life than HSV-2. By the fifth
decade of life, more than 90 percent of adults will be
HSV-1 seropositive. It has been also estimated that
about 22 percent of the adults in the United States are
HSV-2 seropositive. HSV-1 accounts for more than 95
percent of all cases of HSV encephalitis (3). Unlike
other sources of viral encephalitis, HSV encephalitis
has no seasonal pattern. HSV encephalitis is most
prevalent in the neonatal, 5 to 30, and over 50 age
Neonates (infants less than 6 weeks old) have the
highest incidence of HSV visceral and/or CNS infection
among all age groups. Untreated, neonatal herpes
infection disseminates or invades the CNS in greater
than 70 percent of cases. In contrast to childhood/adult
HSV encephalitis, 70 percent of neonatal HSV infection
is caused by HSV-2, acquired from contact with
infected genital secretions at time of birth (3). The
incidence is about 1:3500-5000 deliveries, with signs
and symptoms manifesting 4-11 days after delivery (4).
The herpes virus can also be acquired postnatally from
contact with immediate family members who may be
shedding virus from a symptomatic or asymptomatic
Varicella-zoster virus causes a deadly encephalitis
in immunocompromised patients and has an incidence
of 1:2000 infected persons. Toxoplasma
encephalopathy is prevalent among HIV+ patients.
Measles is responsible for two types of encephalitis,
post-infectious, with an incidence of 1:1000 infected
persons, and subacute sclerosing panencephalitis, with
an incidence of 1:100,000 infected persons. Rabies
accounts for 0-3 cases of encephalitis yearly in the US.
The most common form of encephalitis outside the
US is Japanese encephalitis, which affects persons in
Japan, SE Asia, China, and India (2).
Arboviruses require a mosquito or tick vector (hence
the name "arthropod borne" virus). In general, the virus
replicates outside the CNS and gains entry by
The herpes simplex virus (HSV) is a
double-stranded DNA virus which can infect
mucocutaneous surfaces, the central nervous system,
and, less commonly, visceral organs. The virus may
remain latent in neuronal ganglia and may
subsequently be reactivated, resulting in viral
replication. HSV is usually transmitted via contact with
active ulcerative lesions. However, individuals with
subclinical disease may also shed infectious virus.
Subclinical transmission of HSV may partially account
for the continued rise in worldwide seroprevalence.
HSV gains entry at mucosal surfaces or abraded
skin and replicates within the epidermis and dermis.
Often, the primary infection is subclinical. However,
sufficient numbers of virus may still be present to infect
peripheral sensory or autonomic nerve endings. Once
inside the neuron, the virus travels intraaxonally to the
nerve cell bodies in ganglia, where replication occurs.
The virus can also migrate to other tissues either
proximally, by contiguous spread, or distally through a
neuronal network. After the primary infection has
resolved, the herpes simplex virus can no longer be
found in the ganglia. However, about 10 to 50 percent
of ganglion cells in the area of the initial infection may
harbor viral DNA. Approximately 1 percent of these
cells possess latency-associated transcripts of RNA.
The molecular mechanisms of latency and reactivation
are not well understood. Factors linked to reactivation
include: ultraviolet light, immunosuppression, and
trauma to the skin or ganglia. The maintenance of
latency, the frequency of reactivation, and the severity
of illness ultimately depend upon the host immune
The exact pathogenesis of HSV encephalitis is not
well known. One hypothesis is that the virus gains
entry into the CNS directly from a peripheral route via
either the trigeminal or olfactory nerve. HSV
encephalitis is the result of a primary infection in about
1/3 of cases (4). In children and in adults, HSV
encephalitis is generally localized to the inferior and
medial regions of the temporal lobe and the orbital gyri
of the frontal lobes. In neonates, brain involvement
tends to be more diffuse. The disease is necrotizing
and often hemorrhagic in the most severely affected
In general, a patient with encephalitis presents with
diffuse or focal neurologic signs and symptoms,
including an altered mental state and level of
consciousness, behavioral or personality changes,
nuchal rigidity, photophobia, and generalized or focal
seizures. Depending upon the type of virus, the patient
may present with additional signs and symptoms. For
example, patients with varicella zoster or measles
encephalitis will typically have a rash,
lymphadenopathy, hepatosplenomegaly, and parotid
enlargement. Patients with St. Louis encephalitis will
present with dysuria and pyuria (2).
In the case of HSV encephalitis, the patient will
generally present with an altered state of
consciousness, an abnormal mental state, and focal
neurologic signs and symptoms, in addition to the acute
febrile illness characteristic of viral meningitis. The
level of consciousness may vary from mild lethargy to a
comatose state. The patient is not mentally alert and is
often confused, delirious, or disoriented. The patient
may also suffer hallucinations and exhibit personality
and/or behavioral changes, sometimes escalating into
frank psychosis. Focal neurologic changes depend
upon the site of infection within the brain. Common
neurologic abnormalities include: aphasia, ataxia,
cranial nerve deficits, hemiparesis, hyperactive tendon
reflexes, and involuntary movements, such as
myoclonic jerks (1). Prolonged seizures, or status
epilepticus, which are refractory to anticonvulsants are
also common in the presentation of encephalitis.
In children and adults, there is no relationship
between the presence of mucocutaneous lesions and
HSV encephalitis (4). In fact, only about 10% of
patients have a positive history of prior labial herpes
(5). Thus, the presence or absence of such lesions is
of no diagnostic value.
By contrast, neonates often have pathognomonic
lesions. Neonates with HSV encephalitis may present
with lethargy, poor feeding, irritability, tremors,
seizures, temperature instability, a bulging fontanelle,
and pyramidal tract signs. With disseminated disease,
the neonate may present with systemic signs and
symptoms such as jaundice, shock, bleeding, or
respiratory distress (4).
Once the diagnosis of encephalitis is suspected, the
patient should be given intravenous acyclovir
immediately. The cause of the encephalitis is assumed
to be HSV until proven otherwise. HSV encephalitis
has specific antiviral chemotherapy and the patient's
prognosis relies heavily upon the expediency of this
The clinician must be wary of non-viral causes of
encephalopathy, including infectious and non-infectious
agents. Among the non-viral infectious etiologies are
abscesses, as well as bacterial, fungal, parasitic,
rickettsial, and tuberculous infections. Non-infectious
causes of encephalopathy include tumors, hematomas,
vascular insults, toxic encephalopathy, and systemic
Hundreds of viruses have been implicated in viral
encephalitis and it is difficult to clinically distinguish
HSV encephalitis from the other viral forms. Therefore,
confirmation of HSV encephalitis depends upon
laboratory work-up; however, this should not delay the
immediate initiation of acyclovir treatment. The CSF
profile in viral encephalitis mimics that of viral
meningitis, with a lymphocytic pleocytosis, an elevated
protein content, and a normal glucose level. The
lymphocytic pleocytosis is found in more than 95
percent of patients with viral encephalitis. Thus, given
an immunocompetent patient, the absence of a
pleocytosis should raise the suspicion of a non-viral
cause of the encephalopathy. Similarly, a decreased
glucose level should also prompt the search for a
non-viral cause. About 20 percent of patients with
encephalitis will have RBCs in their CSF profile
following a non-traumatic tap, indicating a hemorrhagic
encephalitis such as that associated with HSV,
Colorado tick fever virus, and sometimes California
encephalitis virus (1).
PCR amplification of viral nucleic acid in the CSF is
a sensitive (75-98%) and specific (100%) test for HSV
encephalitis within the first 25-45 hours (2). PCR
analysis of the CSF is less invasive and less costly
than the traditional brain biopsy, and is therefore
becoming the diagnostic test of choice. A brain biopsy
does have the advantage, however, of potentially
identifying alternative causes of the encephalopathy
(1). The PCR test for HSV is not routinely done on CSF
samples and must be specifically requested. Results
are usually available within 24 hours (4). The initial
result may return negative and should be redone if
clinical suspicion remains high (6,7).
HSV antibody detection in the CSF yields the best
results after a week into the illness. Thus, its
usefulness is limited to a retrospective confirmation of
HSV infection rather than for acute diagnostic
purposes. CSF culture for HSV is unreliable and is
invariably negative in cases of HSV-1 encephalitis (1).
CT, MRI, and EEG are helpful to identify or exclude
alternative diagnoses and in determining whether the
disease is focal or widespread. Such tests for HSV
encephalitis tend to yield focal abnormalities, such as:
1) periodic focal spikes and slow-wave or periodic
sharp wave patterns over the temporal lobes on EEG;
2) areas of low absorption, mass effect, and contrast
enhancement in the temporoparietal regions of the
brain on CT; 3) areas of increased signal intensity in
the frontotemporal, cingulate, or insular regions on
T2-weighted spin-echo MRI images. The
aforementioned findings, however, are not pathognomic
for HSV encephalitis (1,4).
MRI is a more sensitive test than CT. However, CT
is fast and is useful to rule out other causes of
encephalopathy, such as acute hemorrhage, shaken
infant syndrome, brain tumor, or some conditions that
requires immediate neurosurgery. Many authorities
recommend performing a CT scan of the head, with and
without contrast, prior to obtaining a lumbar puncture
A patient with encephalopathy should be evaluated
and treated for shock or hypotension. The clinician
may place the patient on prophylactic anticonvulsant
medication and also consider airway protection in
patients with altered states of consciousness. For
patients with signs of hydrocephalus and increased
intracranial pressure, coughing and straining should be
controlled. If the patient is stable, the head should be
elevated and neurologic status should be monitored.
When aggressive intervention is required, the clinician
may consider the use of diuretics (if the patient's
circulatory volume is protected) or hyperventilation in
an emergency situation. Cerebral edema can also be
controlled with steroids, but the use of steroids in HSV
encephalitis is controversial (4). Intracranial pressure
monitoring is also controversial (2).
In general, with the exception of HSV and varicella
zoster virus, the viral encephalitides lack specific
treatment (Cytomegalovirus and toxoplasma
encephalitis do have specific treatments, but they are
not usually initiated in the ED) (2).
The consensus report on the diagnosis of HSV
encephalitis published in 1996 recommends that
intravenous acyclovir be given to the patient as soon as
the diagnosis is suspected, since early intervention is
key (6). Even if the CSF PCR returns negative for
HSV, treatment with acyclovir should continue if
clinicial suspicion remains high, since the drug is
relatively non-toxic, with the major side-effect being
transient renal insufficiency (8). Acyclovir should be
given at a dose of 10 mg/kg every 8 hours (for a total of
30 mg/kg per day) for 14 days (Acyclovir should be
infused slowly over one hour to minimize the risk of
renal insufficiency. The dose of 30 mg/kg per day is
double that for mucocutaneous/visceral infections
because CSF levels of acyclovir only reach 30-50
percent of plasma levels). The dosage should be
adjusted for patients with existing renal dysfunction (3).
For HIV+ patients, foscarnet (Foscavir), may be a
suitable substitute for acyclovir, given the increased
incidence of acyclovir-resistant strains of HSV (2).
Patient prognosis is dependent upon several host
factors as well as the virulence of the virus. For
example, rabies, eastern equine encephalitis, and
Japanese encephalitis are associated with significant
mortality and morbidity, including severe neurologic
sequelae. California encephalitis and western equine
encephalitis tend to be milder diseases (2).
Mortality in untreated patients with HSV encephalitis
is about 70%, and many survivors are left with
neurologic abnormalities (4). According to National
Institute of Allergy and Immune Diseases-Collaborative
Antiviral Study Group (NIAID-CASG) trials, of 32
acyclovir treated patients, 81 percent survived. Among
the survivors, 46 percent suffered little or no neurologic
sequelae, 12 percent were moderately impaired, and
42 percent were severely impaired, requiring
continuous supportive care (1). 5-10 percent of
surviving patients relapse days to weeks after
completion of treatment (4).
Factors important in the prognosis of HSV
encephalitis are the timeliness of intervention, the age
of the patient, and the level of consciousness at the
initiation of therapy. For example, patients with a
Glasgow coma score of less than or equal to 6, either
died or suffered severe neurologic sequelae. Acyclovir
can reduce neonatal death by 25 percent, but the rate
of morbidity, especially with HSV-2 infections, is still
very high (1,3). 40-60 percent of neonatal survivors
have developmental abnormalities after 2 years of
follow-up care (4).
1. HSV is the most common cause of viral
encephalitis in the United States, accounting for 10 to
20 percent of all cases.
2. Neonates (infants less than 6 weeks old) have the
highest incidence of HSV visceral and/or CNS infection
among all age groups.
3. Individuals with subclinical disease may still shed
4. In children and adults, there is no relationship
between the presence of mucocutaneous lesions and
HSV encephalitis. Thus, the presence or absence of
such lesions is of no diagnostic value. For neonates,
however, pathognomonic lesions have positive
5. Neonates often present with disseminated
disease and thus may have signs and symptoms of
jaundice, shock, bleeding, or respiratory distress
6. PCR amplification of viral nucleic acid in the CSF
is a sensitive and specific test for HSV encephalitis,
and is becoming the diagnostic test of choice. The
PCR test for HSV is not routinely done on CSF samples
and must be specifically requested.
7. The initial PCR result may return negative and
should be redone if clinical suspicion remains high.
8. MRI is the preferred imaging study for HSV
encephalitis, especially T2 weighted and FLAIR
9. Intravenous acyclovir should be given to the
patient as soon as the diagnosis of HSV encephalitis is
suspected (ie., prior to confirmation).
10. Even if the CSF PCR returns negative for HSV,
treatment with acyclovir should continue if clinicial
suspicion remains high, since the drug is relatively
1. Tyler KL. Aseptic Meningitis, Viral Encephalitis,
and Prion Diseases. In: Fauci AS, Braunwald E,
Isselbacher KJ, Wilson JD, Martin JB, Kasper DL,
Hauser SL, Longo DL (eds). Harrison's Principles of
Internal Medicine, 14th edition. USA, McGraw-Hill,
1998, pp. 2440-2445.
2. Lazoff M. Encephalitis.
www.emedicine.com/emerg/topic163.htm (no date,
reviewed online September 2000).
3. Corey L. Herpes Simplex Viruses. In: Fauci AS,
Braunwald E, Isselbacher KJ, Wilson JD, Martin JB,
Kasper DL, Hauser SL, Longo DL (eds). Harrison's
Principles of Internal Medicine, 14th edition. USA,
McGraw-Hill Co., Inc., 1998, pp. 1080-1084.
4. Pritz T. Herpes Simplex Encephalitis.
www.emedicine.com/emerg/topic247.htm (no date,
reviewed online September 2000).
5. Girolami UD, Anthony DC, Frosch MP. The
Central Nervous System. In: Cotran RS, Kumar V,
Collins T (eds). Robbins Pathologic Basis of Disease,
6th edition. Pennsylvania, W.B. Saunders Co., 1999,
6. Coren ME, Buchdahl RM, Cowan FM, Riches
PG, Miles K, Thompson EJ. Imaging and laboratory
investigation in herpes simplex encephalitis. Journal of
Neurology, Neurosurgery, and Psychiatry
7. Spuler A, Blaszyk H, Parisi JE, Davis DH.
Herpes simplex encephalitis after brain surgery: case
report and review of the literature. Journal of
Neurology, Neurosurgery, and Psychiatry
8. Carlini ME, Shandera WX. Infectious Diseases:
Viral and Rickettsial. In: Tierney LM, McPhee SJ,
Papadakis MA (eds). Current Medical Diagnosis and
Treatment, 38th edition. Connecticut, Appleton and
Lange, 1999, pp. 1256-1259.
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