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This paper seeks to discuss the differential diagnosis of childhood en- RSUM : Le prsent article porte sur le diagnostic diffrentiel de len-
cephalitis and to review the course of investigation in a child presenting cphalite infantile et sur lapproche de linvestigation dun enfant atte-
with encephalopathy, encephalitis and meningoencephalitis. The paper int dencphalopathie, dencphalite ou de mningoencphalite. Il
also reviews the current understanding of acute demyelinating encepha- examine galement les connaissances actuelles de lencphalomylite
lomyelitis (ADEM) and presents the crucial therapeutic alternatives in the dmylinisante aigu (EDA) et prsente les possibilits thrapeutiques
management of childhood encephalitis, including ADEM and infectious cruciales dans la prise en charge de lencphalite infantile, incluant
diseases. lEDA et les maladies infectieuses.
Correspondence and reprints: Dr Elizabeth Lee Ford-Jones, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8.
Telephone 416-813-6273, fax 416-813-5032, e-mail lee.ford-jones@mailhub.sickkids.on.ca
the CNS and recruit neutrophils, triggering massive mul- blood during the initial and convalescent phases (two to
tifocal tissue destruction. Macrophages and lymphocytes six weeks) of illness, testing of CSF and ideally MRI, to in-
predominate. In contrast, in acute hemorrhagic leukoen- vestigate possible ADEM.
cephalitis, there is a profound neutrophilic response (4). In Canada, children with encephalitis who have no
Isolated angitis of the CNS may also occur. It is most clinically obvious cause of infection (eg, exanthem of vari-
commonly related to varicella zoster virus (VZV) infection cella or measles) and in whom an etiology is determined
but also to Bartonella henselae (cat scratch) infection, through laboratory testing are most likely to have an in-
parvovirus, mycoplasma, Epstein-Barr virus, group A fection associated with an enterovirus, herpes simplex vi-
streptococcus, human immunodeficiency virus infection rus (HSV), influenza virus, human herpesvirus 6,
and others (9). Epstein-Barr virus or an arbovirus. Mycoplasma pneu-
moniae and Bartonella henselae also appear to be
ETIOLOGICAL AGENTS emerging as important causes of encephalitis. Infections
A list of many of the possible etiological agents, their that may mimic viral encephalitis include brain abscess,
clinical clues and recommended tests are provided in Ta- bacterial meningitis or sepsis, parameningeal infections,
bles 2 to 4. Diagnosis depends on timely collection of subacute bacterial endocarditis, tuberculosis, fungal in-
Diagnostic imaging/
electroencephalogram/
Etiology Possible exposure Symptoms and signs other Comments
Arbovirus ! Summer or fall ! California abrupt onset of
In Canada Powassan, Known insect bite seizures
California, St Louis, (mosquitos, ticks) or
Eastern and Western exposure, eg,
Equine encephalitis camping, outdoors
In United States and else- ! Warm damp region
where St Louis en- ! Travel
cephalitis, Western
equine encephalitis,
Japanese B, other
Eastern equine ! Southeastern Canada, ! Influenza-like prodrome ! Diffuse or focal, mimics ! Frequently polymorpho-
encephalitis United States (east of with fever, headache, vom- herpes simplex virus; nuclear response
Mississippi), July to iting, malaise; convulsions normal in 50% of cases
October, contact progressing to coma
with horses
Cat scratch disease ! Variable history of ! Variable signs of innocula- ! Bartonella antibody titres of
Bartonella henselae kitten or cat scratches tion (scratch, lick, bite) or 1:512 or higher
formerly Rochalimaea ! Other exposures papule
species ! Variable history of lympha-
denopathy
! Two to six weeks after re-
gional lypmphadenopathy
(if present) in 1% to 2% of
cat scratch disease
! May have pleurisy, hemo-
lytic anemia, glomeru-
lonephritis
Enterovirus ! Predominantly ! Variable nausea, vomiting ! Focal encephalitis, may ! Enteroviruses 70/71 pro-
summer-fall, but year ! Erythematous rash, may be mimic herpes simplex virus duce severe encephalitis
round vesicular versus other enterovi-
ruses (Coxsackie, ECHO)
producing benign viral
meningoencephalitis
Epstein-Barr virus ! Variable syndrome of infec-
tious mononucleosis
Herpes simplex virus ! Bizarre behaviour, ! 90% focal temporal lobe ! Hemmorrhagic, lympho-
aphasia/dysphasia findings cytic pleocytosis
! Focal seizure or neurologi- ! 50% show low attenuation ! Treat empirically with
cal defects in frontal, temporal lobes acyclovir until disease
! Complex partial seizure wth scattered hemorrhages ruled out through elec-
+/ secondary generaliza- troencephalogram, diag-
tion nostic imaging,
! Hemiparesis with greater cerebrospinal fluid
involvement of the face examination and clinical
and arm course
! Superior quadrant visual ! Treat before loss of con-
field defects sciousness, within four
days of illness
Human herpes virus 6 ! Primary encephalitis ! Requires further study
! Recurrent febrile seizures
Influenza ! Fall, winter ! Variable history of ! May preferentially affect
respiratory disease thalamus, pons
Diagnostic imaging/
electroencephalogram/
Etiology Possible exposure Symptoms and signs other Comments
Mycoplasma pneumoniae ! May have antecedent
bronchitis, pneumonia,
upper respiratory infection
Rabies ! Often no history of ! Paresthesia at bite site ! Discuss the regional
animal exposure or ! Hyperalert likelihood of rabies with
travel to endemic ! Laryngospasm local medical officer of
area ! Progressive peripheral health
! Animal (domestic, neuropathy
bat, fox, raccoon,
skunk) bite in ap-
proximately 50% of
cases
Rubella ! Unimmunized
Rocky Mountain spotted ! Travel to endemic ! Petechiae
fever area
Shigella ! Bloody diarrhea, seizure
Varicella ! May occur with primary
viremia preceding exan-
them by approximately
10 days
! During exanthem or its
resolution
fection, parasitic infection (Naegleria species, cysticerco- variable features, there are ultimately characteristic CSF
sis, toxoplasmosis), Rocky Mountain spotted fever, findings, EEG abnormalities, abnormalities in neuroi-
syphilis and leptospirosis (2). maging studies and, at some point in the illness, fever
(2,10).
HISTORY
Information to be obtained in in a history includes du- PHYSICAL EXAMINATION
ration of illness before admission, temporally associated On physical examination, general physical findings
illness (eg, VZV, diarrhea, skin lesions), recent immuni- should be noted including heart rate, respiratory rate,
zations, animal exposures including bites or scratches, blood pressure, presence or absence of meningismus,
insect exposure including ticks and mosquitoes, travel, and signs of involvement of other systems, particularly
camping, the nature of the symptoms, the poorest level of skin rashes and lymph nodes, as well as signs of trauma.
consciousness (normal, disoriented, stuporous [rousable], Fundoscopical examination including indirect ophthal-
unconscious [unrousable] and the occurrence of convul- moloscopy may elucidate the shaken baby syndrome or
sions [one, focal, generalized]). Information obtained on vasculitis. Neurological findings depend on which part of
history may lead the physician to the diagnosis before the the brain is primarily involved. Findings may predomi-
microbiological testing is complete (Table 3). nate in any part of the brain or non-CNS sites may pre-
Nonspecific prodromal findings may include malaise, dominate (2).
anorexia, vomiting, myalgia and headache with or without Specific neurological findings include mental status,
symptoms of viral respiratory or enteric disease. In Glasgow Coma Score, state (alert, disoriented/awake,
ADEM, the symptoms follow a vague viral syndrome by stuporous, coma/decorticate or coma/decerebrate), the
days or weeks, and findings are characterized by symp- presence of photophobia, aphasia, abnormalities of cra-
toms of demyelination, either focal or diffuse. Direct nial nerves (ophthalmoplegia, facial paralysis, ptosis),
brain involvement may be heralded by a prodrome of deep tendon reflexes, motor (hemiparesis) and sensory
lethargy, drowsiness or stupor and disorientation, hallu- and cerebellar (ataxia) defects. Findings should be de-
cinations, behaviour and speech disturbances, and irrita- scribed as to whether they are intact or abnormal, their
bility lasting 24 h or longer. symmetry and focality.
In severe acute encephalitis including AHLE, patients Alterations in sensorium may range from mild somno-
experience an abrupt onset of convulsions, altered con- lence and lethargy to intense irritability and deep coma
sciousness and focal neurological deficit over two to seven (1). In infants, findings are commonly as vague as somno-
days (1). While seizures and focal neurological signs are lence, irritability, high-pitched cry, diffuse hyper-reflexia,
TABLE 4: Diagnostic testing and potential therapy for acute childhood encephalitis and meningoencephalitis
or a full or bulging fontanel and symptoms of poor feeding NONMICROBIOLOGICAL DIAGNOSTIC STUDIES
and vomiting (1). Some manifestations are the result of From the therapeutic point of view, the detection of the
the increase in intracranial pressure. Findings of in- focal findings of possible HSV infection, the MRI changes
creased intracranial pressure (1) rather than direct brain in ADEM, the presence of continuous seizures and in-
infection include papilledema, abnormal respiratory pat- creased intracranial pressure are most important. All pa-
tern, flexor or extensor posturing, ophthalmoplegia or tients require prompt clinical evaluation, usually
pupillary abnormalities, and bradycardia. including neuroimaging studies, examination of the CSF
The etiology can rarely be determined on clinical ex- and an EEG (1) (Table 5).
amination alone unless it is associated with an exanthe- Diagnostic imaging: Neuroimaging studies such as MRI
matous illness such as varicella or measles. The National or cranial CT scan with and without contrast should be
Institute of Allergy and Infectious Diseases (NAIAD) Col- undertaken in children with clinical encephalitis. If the
laborative Antiviral Study Group found no statistical dif- child has evidence of increased intracranial pressure with
ferences in the presenting signs and symptoms of patients a closed fontanel or focal signs, this is usually undertaken
with biopsy-proven herpes simplex encephalitis that dis- before a lumbar puncture in order to rule out other le-
tinguished them from those without that infection (5). sions, such as abscess, subarachnoid hemorrhage, tu-
mours and stroke, and to localize lesions (2). The need for
TABLE 5: Minimal investigations to be considered after his-
diagnostic imaging will likely require prompt transfer of
tory and physical examination in a severely ill child or child
the child to a centre where such study is possible unless who is not improving
the cause is very obvious, eg, varicella or the child is only
Neuroimaging
very transiently encephalopathic and completely normal
! One or more of cranial magnetic resonance imaging
within a short period of time, eg, 24 h. MRI may provide
(particularly if acute demyelinating encephalomyelitis is
improved resolution and indeed suggest the etiology of considered), computed tomography, brain scan
ADEM (3) or a newly recognized multifocal or diffuse HSV Cerebrospinal fluid
encephalitis variant in preschoolers, requiring acyclovir ! Routine (protein, glucose, white blood cell differential,
therapy (4,11). CT scan may be preferable for sinuses and bacterial culture)
parameningeal foci. Brain scan may show early signs of ! Polymerase chain reaction (PCR) as indicated
HSV encephalitis that are not identifiable on CT scan. ! Hold 1 to 2 mL for possible future tests
Paired sera (two to six weeks apart)
CSF examination: The usual CSF findings are elevated
! Minimum 5 mL
protein, normal glucose levels and a pleocytosis (7 cells/"L
! Arbovirus, herpes simplex virus, Mycoplasma pneumoniae,
or more) with a predominance of mononuclear cells. An immunoglobulin M, Bartonella henselae, etc, as indicated
exception is AHLE in which polymorphonuclear cells pre- ! Hold 3 to 5 mL acute sera for possible future tests
dominate. Also, especially early in the course of illness Viral detection (culture, PCR)
and hospitalization, CSF may be normal or show hypogly- ! Cerebrospinal fluid
corrachia and a predominance of polymorphonuclear ! Throat, stool, urine, blood samples
cells. Approximately 3% to 5% of patients with severe vi- ! Other tissue, if applicable
ral infections of the CNS have no CSF pleocytosis on ini- Neurophysiological
tial CSF examination. While pleocytosis should not be ! Electroencephalogram
! Evoked potentials as indicated
attributed to status epilepticus until all other causes
have been ruled out, a white blood cell count of more
than 6106/L or one or more polymorphonuclear leu-
kocytes have been found in 22% of these patients (12). quired for virological studies. CSF is useful for the isola-
While red blood cells may be suggestive of HSV infection tion of enterovirus and mumps. Although the cell lines
or AHLE, they may be present or absent in these condi- used for viral isolation will also permit isolation of HSV, it
tions (13). is not usually isolated. Rapid diagnostic methods are be-
While results of a second lumbar puncture 5 to 8 h af- ing developed, most notably PCR for the herpes viruses
ter the first may demonstrate a shift in cells from poly- and enteroviruses (14). The number of agents that can be
morponuclear to monocyte response, it is generally not detected by molecular methods is increasing rapidly, and
considered clinically useful (14). physicians are encouraged to check regularly with their
Electroencephalography: Electroencephalography may laboratory to determine what is available. These methods
further support the diagnosis by showing general findings are usually available only at reference laboratories. Inter-
compatible with encephalopathy. Of particular value in pretation of both positive and negative results should be
herpes simplex encephalitis is its characteristic periodic undertaken very cautiously because the sensitivity and
high voltage spike wave activity in the temporal regions specificity of these tests outside of research protocols re-
and slow wave complexes (intervals of 2 to 3 s). mains to be determined.
Paired serology: In many patients, paired serology will ul-
MICROBIOLOGICAL TESTING timately be helpful to establish the diagnosis, either be-
Obtaining an etiological diagnosis has been notori- cause of a protracted and complicated course or the
ously difficult in the past. A broad range of etiological presence of adverse sequelae. The importance of timely
agents are summarized in Table 3 while the diagnostic collection of acute serum cannot be overstated. A mini-
tests and potential for therapy are summarized in Ta- mum of 5 mL of blood should be taken in the acute phase,
ble 4. With prompt, complete recovery within one to two followed by a second serum two to six weeks later. Testing
days, testing may not be necessary. of paired sera can confirm the etiology of the infection
Specimen collection: In general, CSF, blood, throat, through demonstration of seroconversion or a fourfold
stool and urine specimens should be obtained for viral rise in antibody titre. As well, IgM antibody testing can be
studies. These specimens can be held in the hospital labo- done for certain agents, such as EBV, measles and arbovi-
ratory for immediate evaluation and possible subsequent rus.
analysis in a reference laboratory, depending upon the Determination of antiviral antibody synthesis in the
childs course. It is vitally important to collect and save CSF is usually not undertaken because it has not been
adequate amounts of body fluids, specifically CSF and se- considered useful in the diagnosis of HSV infections
rum, should the need for confirmation of a diagnosis be- (14,15). Occasionally it might be useful to test for in-
come imperative. trathecal synthesis of viral specific antibodies against
A minimum of 2 mL and preferably 3 mL of CSF is re- other organisms, eg, measles in subcutaneous sclerosing
panencephalitis and Japanese encephalitis. It should be HSV is not the most common cause of encephalitis, em-
emphasized that additional amounts of CSF and serum piric acyclovir therapy is justified until data from several
must be obtained to allow for this testing when these diag- sources (EEG, diagnostic imaging, clinical course) are
noses are suspected. available. The use of acyclovir in varicella depends on the
Of 145 patients admitted with encephalitis-like illness timing of illness, with benefit likely only when the infec-
to The Hospital for Sick Children, Toronto in 1994 and tion occurs before the rash or early in its course rather
1995, 50 patients hospitalized 72 h or more underwent than as a postinfectious illness. The role of therapy in en-
standardized microbiological investigations. A confirmed cephalitis caused by M pneumoniae and cat scratch dis-
or very probable etiological agent was identified in 20 pa- ease is unproved. ADEM commonly responds to steroid
tients (40%); organisms included M pneumoniae (n=9), therapy, as may vasculitis. In the child who fails to improve
M pneumonia and enterovirus (n=2), HSV (n=4), EBV after several days of illness, the use of empiric steroids
(n=1), human herpesvirus 6 (n=1), human herpesvirus 6 should be discussed with neurology colleagues. The impor-
and influenza A (n=1), influenza A (n=1) and Powassan tance of recognizing and treating continuous seizures and
virus (n=1). In 13 cases (26%), a possible pathogen was increased intracranial pressure cannot be overemphasized.
identified based on lesser microbiological evidence, includ-
ing nine M pneumoniae cases (17). PROGNOSIS AND FOLLOW-UP
Brain biopsy: This should be reserved for patients who The spectrum of illness is highly variable and ranges
do not respond to acyclovir and supportive care and for from a short benign illness to a devastating one with se-
whom there is an abnormality of unknown etiology on vere sequelae and death. Physicians should understand
neuroimaging studies and a deteriorating clinical condi- that a child can make an apparently complete recovery
tion. following weeks of depressed consciousness in hospital.
Persons taking part in bedside conversations should be
THERAPY aware that the child may make a full recovery with mem-
The infections for which there may be specific therapy ory of such events. Conversely, children with apparently
are outlined in Table 4. The minimum investigations to be benign illness may show steady and profound deteriora-
considered in the child who is severely or persistently en- tion in the subsequent weeks and months following hos-
cephalopathic are listed in Table 5. The efficacy of specific pital discharge. Both short term and long term follow-up
antiviral therapy has only been demonstrated for HSV, of patients with encephalitis is important. The known
and questions about acylovir dosage, duration of therapy, risk of recurrence in patients with HSV encephalitis
and detection and management of relapses remain. While should be recognized.
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adiculopathy of infectious or parainfectious etiology a new entity? 1984;6:608-18.
Clin Infect Dis 1995;20:945-53. 14. Jeffrey JKM, Read SJ, Peto TEA, et al. Diagnosis of viral infections
6. Whitley R. Viral encephalitis. N Engl J Med 1990;323:242-50. of the central nervous system: clinical interpretation of PCR results.
7. Johnson R. The pathogenesis of acute viral encephalitis and Lancet 1997;349:313-7.
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1987;155:359-64. herpes simplex encephalitits: application of polymerase chain
8. Tselis AC, Lisak RP. Acute disseminated encephalomyelitis and reaction to cerebrospinal fluid from brain-biopsied patients and
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Curr Opin Neurol 1995;8:277-9. 16. Lipkin WI. European consensus on viral encephalitis. Lancet
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1. The following statements correctly refer to acute de- 3. Contemporary management of the child with suspected
myelinating encephalomyelitis (ADEM) except for: acute encephalitis who is severely ill or fails to recover
(a) generally follows acute non-neurological in 24 to 48 h includes the following except:
infectious illness by one to three weeks; (a) neuroimaging;
(b) disease of the white matter characterized by (b) CSF examination;
demyelination; (c) diagnostic testing of (1) blood collected acutely
(c) encephalopathy (altered or fluctuating state of (5 mL) and in convalescence (two to six weeks
consciousness including profound lethargy) later) and (2) viral detection with either culture
and variable neurological findings including or antigen detection (CSF, throat, stool, urine,
ataxia, decreased deep tendon reflexes, blood as applicable);
urinary retention and bilateral optic neuritis (d) EEG +/- evoked potentials;
are present; (e) no transfer to tertiary care centre.
(d) highly suggestive magnetic resonance imaging 4. Noninfectious conditions that can cause encephalopa-
findings with variable cerebrospinal fluid thy include the following except:
(CSF) findings; (a) endocrine and metabolic disorders;
(e) lack of responsiveness to steroid therapy. (b) sprained ankle;
2. The following statements correctly refer to acute viral (c) hepatic or renal failure;
encephalitis: (d) intoxication;
(a) represents an uncommon response to a (e) mitochondrial defects and inborn errors of
common infection; metabolism.
(b) disease of grey matter; 5. Infections that can mimic viral encephalitis include the
(c) encephalopathy (altered or fluctuating state of following except:
consciousness including profound lethargy) (a) bacterial sepsis;
and variable neurological findings including (b) brain abscess and parameningeal infection;
ataxia, decreased deep tendon reflexes, urinary (c) subacute bacterial endocarditis;
retention, and bilateral optic neuritis are (d) tuberculosis;
present; (e) ringworm.
(d) inflammation of the brain parenchyma 6. Therapy is available for encephalitis of the following
manifest as CSF pleocytosis at some point in etiologies except for:
illness but not necessarily on admission to (a) arbovirus;
hospital; (b) ADEM;
(e) the outcome, favourable or otherwise, can be (c) cat scratch disease;
reliably predicted clinically within the first (d) herpes simplex;
weeks of illness. (e) Lyme disease.