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This chapter includes the pathogens that can cause meningoencephalitis and
hearing loss (HL). For some pathogens, such as human immunodeciency virus
(HIV), HL may result from the direct effects of HIV, ototoxic drugs, and/or opportunistic infections in the middle ear and brain [3]. Since such distinction is challenging in most cases, the most common pathogens responsible for both
meningoencephalitis and HL will be reviewed. Congenital infections are a signicant cause of HL in the pediatric population [3]. Inammation in the brain parenchyma is seen in most congenital infections; therefore, this subject will also be
discussed under the topic of HL in meningoencephalitis.
H. Maraş Genç et al.
25.2 Definition
The diagnosis of encephalitis is based on the presence of brain parenchymal inammation associated with a neurologic decit. Although a neuropathological examination is the gold standard for diagnosis, it is rarely applied [1, 2]. Diagnosis is usually
based on clinical, laboratory, electroencephalography (EEG), and neuroradiological
features in clinical practice. In 2013, the International Encephalitis Consortium
(IEC) presented a consensus on the case denition of encephalitis and diagnostic
guidelines to investigate infectious or autoimmune etiologies in patients with suspected encephalitis [4].
According to IEC, the diagnostic criteria for encephalitis include altered mental
status (dened as an altered level of consciousness or personality change) for more
than 24h without any denable etiology as a major criterion and the presence of the
following additional minor criteria (two for possible and three or more for probable
or conrmed diagnoses): fever higher than 38°C within 72h, seizures not related to
a preexisting epileptic disorder, new-onset focal neurologic ndings, cerebrospinal
uid (CSF) leukocyte count greater than 5/mm3, brain parenchymal changes in neuroimaging, and EEG abnormalities consistent with encephalitis. Conrmed cases
require pathological, microbiological, or serological evidence of a pathogen known
to cause encephalitis [4].
The upper limit of the CSF leukocyte count is accepted as 15/mm3 in newborns
aged ≤28days and 9/mm3 in infants aged 29–60days [4, 5]. It is important to differentiate encephalopathy from encephalitis. Encephalopathy is diffuse cerebral
dysfunction associated with alteration in mental status or behavior. Encephalopathy
is a broader term encompassing various etiologies, including toxic–metabolic and
endocrine disorders (e.g., hypoglycemia, hyperammonemia, hepatic failure,
hypoxia, and diabetic ketoacidosis) and systemic or central nervous system (CNS)
infections [6, 7]. Encephalopathy lasting >24h is a major criterion of encephalitis,
but additional ndings are required, as described above [4].
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25.3 Pathogenesis
In infectious encephalitis, the pathogen can enter the CNS via different routes,
mainly the bloodstream, as in cases of enteroviruses, human parechoviruses, arboviruses, and most bacteria. The pathogen crosses the blood–brain barrier through
the choroid plexus or vascular endothelium. The intra-neuronal route by retrograde
axonal transport is used by viruses, such as the herpes simplex virus (HSV)-1 and
rabies [1, 2].
Viruses can cause neurologic manifestations either directly by invading the brain
parenchyma or post-infectiously by triggering an autoimmune response, leading to
acute disseminated encephalomyelitis (ADEM), or the combination of both mechanisms as observed in patients with post-herpetic autoimmune encephalitis [8, 9].
Neurotropic viruses, such as enteroviruses, human parechoviruses, HSV-1, arboviruses, and rabies, directly invade neurons. Herpes simplex virus 1 can cause encephalitis during the primary infection (usually in children) or the reactivation of the
latent virus (usually in adults) [1]. In HSV-1 encephalitis, host susceptibility is seen
in patients with Toll-like receptor 3 (TLR3) deciency [10].
For some pathogens, including inuenza and Bartonella henselae, the pathogen
cannot be identied through a brain biopsy or CSF analysis, but there is evidence of
a recent infection. The mechanisms by which these pathogens cause neurologic
symptoms are not well understood. In inuenza-associated encephalopathy/encephalitis, edema and apoptosis of neurons are seen. However, the direct invasion of the
brain by inuenza is almost never revealed. Therefore, it has been suggested to use
the term “encephalopathy” instead of “encephalitis.” The cytokine storm is proposed to be responsible for neurological complications in inuenza-associated
encephalopathy/encephalitis [1, 2, 7].
25.4 Etiology
Meningoencephalitis may be due to an infectious or non-infectious etiology, such as
autoimmune encephalitis and ADEM.The underlying etiology can be dened in
only less than half of the cases diagnosed with encephalitis, even with extensive
testing [4, 11]. Among infectious causes, viruses are the most common pathogens,
while bacteria, fungi, and parasites can also be the causative agents for encephalitis.
The most common viral causes in children are enteroviruses, herpesviruses, human
parechovirus, and arboviruses [12–16]. A prospective multicenter study from
Australia evaluated 526 children (0–14years old) suspected of encephalitis over a
period of 3.5years. Among 287 children who met the criteria for conrmed encephalitis, 57% had infectious causes (enterovirus in 10%, parechovirus in 10%, bacterial meningoencephalitis in 8%, inuenza in 6%, HSV in 6%, and Mycoplasma
pneumonia in 6%) and 25% had immune-mediated encephalitis [14]. Severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19,
was also identied as a cause of meningoencephalitis in rare cases [17, 18].
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The immune-mediated causes of encephalitis include ADEM and autoimmune
encephalitis, e.g., anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.
Among the unexplained causes of encephalitis, autoimmune encephalitis presents
the most common etiology, according to studies conducted in recent years [19, 20].
H. Maraş Genç et al.
25.5 Clinical Features
Clinical ndings depend on the pathogenicity of the offending agent, host factors,
anatomic localization of the affected part of the CNS, and the severity of involvement [2]. Initial manifestations include nonspecic symptoms, such as fever, sore
throat, headache, abdominal complaints, nausea, and vomiting, followed by altered
mental status, irritability, behavioral changes, and seizures. Hemiparesis, cranial
nerve palsies, and bladder/bowel dysfunction can also be seen. Neurologic ndings
may be stable, uctuating, or progressive. Cerebellar ndings can be observed in
varicella encephalitis. Patients with anti-NMDAR encephalitis can also present with
psychiatric symptoms, orofacial dyskinesia, and autonomic instability [1, 2, 14].
25.6 Diagnosis
A detailed patient history, including immunization, travel history, contact with animals, geographic risk factors, and immune status, should be obtained. The physical examination should include the assessment of the mental status, with particular
attention to focal neurologic ndings, e.g., cranial nerve palsies, paresis in the
extremities, cerebellar signs, and increased intracranial pressure signs. Alteration in
mental status may be difcult to dene in infants and young children who usually
present with irritability. A lumbar puncture (LP) should be performed if there are
no contraindications (coagulopathy, suspected mass lesion, increased intracranial
pressure, etc.). Neuroimaging is usually performed before LP to exclude intracranial mass lesions or intracranial hypertension with mass effect. Magnetic resonance
imaging (MRI) is the preferred neuroimaging modality, but computed tomography
(CT) can be performed before LP if this modality is unavailable. However, MRI is
more sensitive and specic than CT in the setting of encephalitis [2]. Patients suspected of encephalitis should also undergo EEG, which can show nonspecic generalized slowing or distinctive patterns, such as periodic lateralizing epileptiform
anomalies in temporal regions suggestive of HSV encephalitis. EEG is also diagnostic in non-convulsive status epilepticus, which presents with encephalopathy and
is included in the differential diagnosis of encephalitis [1, 2, 21]. The International
Encephalitis Consortium has proposed a diagnostic algorithm for children with suspected encephalitis: CSF analysis, including opening pressure, protein, glucose, cell
count, gram stain, culture, HSV-1/2 polymerase chain reaction (PCR) test, enterovirus PCR test; routine blood cultures, serology including Epstein–Barr virus (EBV)
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and M. pneumonia, holding acute serum, and convalescent serum at 10–14days for
possible paired antibody testing, neuroimaging (MRI if available), EEG, M. pneu-
monia PCR on a throat swab sample, or throat and stool cultures; and further tests if
additional CNS involvement is present. Additional tests are recommended according to host factors, geographic factors, exposure, and specic signs and symptoms
[3]. Rapid multiplex PCR assay to detect several microbial targets (bacteria, viruses,
and fungi) simultaneously, and in the COVID era, SARS-CoV-2 PCR testing are
routinely used in most clinics in patients with suspected meningoencephalitis.
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25.7 Treatment
Encephalitis is a neurologic emergency with signicant morbidity and mortality.
Treatment is supportive for each system involved. Patients usually require intensive
care due to cardiorespiratory compromise, altered mental status, bulbar dysfunction, intracranial hypertension, and/or refractory seizures.
Empirical antibacterial and acyclovir treatment should be started promptly for
patients with suspected meningoencephalitis. Antibacterial treatment can be stopped
after the CSF culture is conrmed to be sterile. Acyclovir treatment should be continued until HSV encephalitis is ruled out.
Acyclovir is recommended for HSV and varicella-zoster virus (VZV), ganciclovir for cytomegalovirus (CMV), and antiretroviral treatment for human immunodeciency virus (HIV). Oseltamivir is prescribed for inuenza-associated encephalitis/
encephalopathy, although it has not been proven to be efcacious. Intravenous
immunoglobulin (IVIG) and steroids can be added to the treatment if the cytokine
storm is suspected in the pathogenesis of inuenza-associated encephalitis/encephalopathy. Mycoplasma pneumonia infections can be treated with macrolides,
although there is no evidence that they affect outcomes. All bacterial, fungal, and
protozoal pathogens have specic treatments [1, 2, 13, 22].
The rst-line treatment of ADEM and autoimmune encephalitis includes immune
therapy with steroids and immunoglobulins. Immunotherapy can be started with
antibiotic and antiviral treatments while waiting for the results of microbiological
analyses [23].
25.8 Prevention
Vaccination for mumps, measles, varicella, inuenza, and pertussis signicantly
decreases the risk of encephalitis caused by these agents. Postexposure prophylaxis
with the rabies vaccine and immunoglobulin is recommended for rabies-related
encephalitis. Protection against tick bites and mosquitoes decreases the risk of arboviral and tick-borne encephalitis [1, 12, 24].
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H. Maraş Genç et al.
25.9 Prognosis
The prognosis depends on the pathogen, clinical features, and host factors. Younger
age at presentation, seizures, focal neurologic signs, coma, duration of hospital stay,
and abnormal neuroimaging ndings are associated with poorer outcomes [2].
Intensive care unit admission is required in 40–49% of children with encephalitis
[13, 14]. Mortality ranges from 0.8% to 5.7% [16, 24–26].
Neurologic sequelae, including cognitive and motor decits, behavioral problems, epilepsy, visual defects, and hearing impairment, are reported in approximately half of the children with encephalitis [2, 27–29]. In a study investigating
minor neurologic dysfunction and cognitive performance in 42 children with
encephalitis, 71% of the patients had minor neurologic dysfunction, and 13% had
an intelligence quotient (IQ) <85 [30].
Herpes simplex virus encephalitis is associated with poorer outcomes, while
enteroviral encephalitis has better outcomes except in neonates with disseminated
disease [31]. West Nile virus (WNV) encephalitis has a better prognosis in children
than in adults. Rabies and Naegleria fowleri encephalitis have a mortality rate
reaching almost 100% [1].
25.10 Hearing Loss inMeningoencephalitis
Hearing loss can be seen after meningoencephalitis, although it is not as frequent
as in bacterial meningitis [31]. Viral causes account for most cases of meningoencephalitis. In a study of 34 patients with sensorineural HL (SNHL), the objective
signs of viral infection were found in 12 patients (VZV in nine, mumps in two, and
herpes virus hominis in one). High-frequency HL was observed in seven cases, and
the low-frequency type in ve cases. Most patients had pleocytosis and an increased
protein level in the CSF analysis. Hearing improved in all cases and returned to
normal in 10 patients. The authors concluded that reversible SNHL could occur due
to viral-induced meningoencephalitis [32]. Etiologic agents responsible for HL and
encephalitis are summarized in Table25.1.
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Table 25.1
Etiology
Congenital infections
Cytomegalovirus
(CMV)
Rubella virus Cataracts,
Toxoplasma
gondii
Summary of pathogens causing meningoencephalitis and hearing loss
Clinical presentation Diagnosis
Asymptomatic or
intracranial
calcications,
hepatosplenomegaly,
microcephaly,
cataract,
chorioretinitis,
anemia,
thrombocytopenia,
developmental delay,
bone abnormalities
microphthalmia,
chorioretinitis,
microcephaly,
congenital heart
disease,
hepatosplenomegaly,
developmental delay
Chorioretinitis,
intracranial
calcication,
hepatosplenomegaly,
developmental delay
From birth to
3weeks: viral
culture or PCR
test from the
urine or saliva
samples;
detection of
CMV by PCR
test in the
newborn
screening
dried blood
spot
IgM,
persisting high
titers of
rubella-IgG,
PCR test, or
virus isolation
CSF PCR and
serologic
testing
(positive IgM
and/or IgA or
increase in
IgG during the
rst year) in
patients with
typical clinical
ndings or the
presence of
maternal
toxoplasma
infection
Association
with hearing
loss
Hearing loss is
the most
common
complication;
1/3 of
symptomatic,
1/10 of
asymptomatic
children with
congenital
CMV will
develop
hearing loss
Most common
complication;
90% of
congenital
rubella cases
have SNHL
In congenital
toxoplasmosis,
the prevalence
of SNHL is
28% in the
untreated
group, 12% in
the treated
group
Treatment and
prevention
Ganciclovir or
valganciclovir;
no effective
vaccine is
present;
neonatal
screening
program is
recommended
in some
countries
Supportive
treatment;
immunization
early in
childhood and
rubella
antibody
screening
before
pregnancy
Treatment is
recommended
in congenital
toxoplasmosis
(antiparasitic
treatment and
folinic acid)
and pregnant
women with
acute
toxoplasmosis;
prevention by
avoiding
exposure
(continued)
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H. Maraş Genç et al.
Table 25.1
Etiology
Zika virus (ZV) Severe microcephaly,
Lymphocytic
choriomeningitis
virus (LCMV)
Congenital and acquired infections
Treponema
pallidum
Human
immunodeciency
virus (HIV)
(continued)
Clinical presentation Diagnosis
hydrocephaly,
intracranial
calcication,
spasticity,
subcortical
calcication, gyral
anomaly, optic
atrophy
Microcephaly,
hydrocephaly,
pachygyria,
intracranial
calcication,
chorioretinitis
Congenital infection:
Fever, hepatomegaly,
lymphadenopathy,
bone marrow
suppression, rash,
rhinitis, bone lesions,
meningitis
Neurologic
involvement in HIV
infection may be
associated with
primary infection
with HIV,
opportunistic
infections, and
adverse events
related to treatment
RNA in serum,
urine, or CSF
from birth to
2days;
negative RNA
does not
exclude
diagnosis;
positive IgM
test and
negative RNA
test indicate
probable
infection
Serologic
testing is
reliable since
population
seroprevalence
is low
CSF Venereal
Disease
Research
Laboratory
(VDRL) test
(sensitive but
not specic),
serum rapid
plasma reagin
(RPR) with
uorescent
treponemal
antibody
absorption test
Serology, HIV
DNA or RNA;
HIV nucleic
acid testing to
detect HIV
DNA or RNA
in infants born
to HIVinfected
mothers
Association
with hearing
loss
SNHL is
reported in
5.8% of
patients with
microcephaly
SNHL is rare
(visual
impairment is
more
common)
SNHL occurs
as a late
nding in
congenital
syphilis
(between 8
and 10years
of age)
Otitis is the
most common
opportunistic
infection;
conductive
hearing loss is
more common;
hearing loss is
reported at
6–84%
Treatment and
prevention
No treatment,
prevention by
avoiding
exposure
(mosquitoborne)
No proven
treatment,
prevention by
avoiding
exposure
(rodent-borne)
Penicillin
treatment;
screening of
pregnant
women for
syphilis
Antiretroviral
treatment and
treatment of
opportunistic
infections
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Table 25.1
Etiology
Herpes simplex
virus (HSV) type
1–2
Acquired infections
Measles virus Fever, cough, nasal
Mumps Fever, headache,
(continued)
Clinical presentation Diagnosis
May be acquired
prenatally, perinatally
(most common),
or postnatally;
characteristic
presentations:
localized disease
with skin, eye, and
mucous membrane
involvement; CNS
involvement;
disseminated disease
(sepsis, multiorgan
involvement, high
mortality)
congestion,
conjunctivitis, rash,
and runny nose,
maculopapular rash;
complications
include pneumonia,
subacute sclerosing
panencephalitis
myalgia, followed by
parotitis;
complications
include orchitis,
pancreatitis, aseptic
meningitis,
encephalitis
Association
with hearing
loss
Blood-CSF
PCR testing;
false-negative
results may
occur; if
clinical
suspicion is
strong, repeat
lumbar
puncture and
CSF PCR test
IgM, viral
culture, or
PCR test
IgM, PCR test 3.5% of
In HSV
encephalitis,
hearing loss is
rare, but when
present, it is
bilateral and
severe; hearing
loss may be
independent of
encephalitis;
seropositivity
is high in
idiopathic
sudden SNHL
Before
vaccination,
5–10% of
patients with
measles have
profound
hearing loss
patients with
mumps had
hearing loss;
hearing loss
is usually
unilateral and
may be seen in
asymptomatic
patients
Treatment and
prevention
Acyclovir
treatment; in
the presence of
maternal
genital herpes
infection,
acyclovir
treatment may
be given to
reduce the risk
of transmission
Supportive
treatment,
ribavirin in
selected
patients,
vitamin A;
vaccinepreventable
disease
Supportive
treatment,
vaccinepreventable
disease
(continued)
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H. Maraş Genç et al.
Table 25.1
Etiology
Varicella-zoster
virus (VZV)
West Nile virus
(WNV)
Dengue virus Arthropod-born
Lassa virus Transmitted through
(continued)
Clinical presentation Diagnosis
Primary infection
results in chickenpox,
characterized by
vesicular lesions;
Herpes zoster results
from the reactivation
of the latent virus;
Ramsay Hunt or
herpes zoster oticus
results in ear pain,
ipsilateral peripheral
facial nerve palsy,
and a vesicular rash
on the ear or oral
mucosa
A common cause of
arthropod-borne
encephalitis; usually
asymptomatic; 20%
present with West
Nile fever, <1%
develop neurologic
complications
virus; transmitted
through mosquitoes;
asymptomatic or
may cause fever,
rash, headache,
myalgias,
hemorrhagic fever
contact with rodent
excretions; usually
asymptomatic;
symptomatic cases
present with fever,
cough, chest pain,
rarely pulmonary
edema, bleeding
from mucosal sites;
meningitis or
meningoencephalitis
is seen in 15% of
cases
Serum IgM,
PCR of skin
lesions, CSF
PCR
Serum IgM/
IgG, CSF IgM
Serum or CSF
IgM, PCR
IgM/IgG
antibodies,
Lassa virus
antigen in
serum, and
PCR analysis
Association
with hearing
loss
Residual
hearing loss is
reported at 5%
Rare; hearing
loss may be
transient or
permanent
Rare; mild but
irreversible
SNHL is the
most common
neurologic
complication,
and hearing
recovery is
achieved in
less than half
of the cases
Treatment and
prevention
Acyclovir,
valacyclovir,
or famciclovir,
and steroids
are
recommended;
vaccinepreventable
disease
Supportive
treatment;
protection
against
mosquito bites
is
recommended
for the
prevention
Supportive
treatment;
prevention by
mosquito
control and
vaccination
Supportive
treatment,
ribavirin
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Table 25.1
Etiology
Severe acute
respiratory
syndrome
coronavirus 2
(SARS-CoV-2)
Cryptococcus
neoformans,
Cryptococcus
gattii
CSF cerebrospinal uid, DNA deoxyribonucleic acid, Ig immunoglobulin, PCR polymerase chain
reaction, RNA ribonucleic acid, SNHL sensorineural hearing loss
(continued)
Clinical presentation Diagnosis
In pediatric cases,
usually
asymptomatic or
mild respiratory
symptoms;
neurologic
involvement is
reported but rare
Neurologic and
pulmonary
manifestations may
be seen;
cryptococcal
meningoencephalitis
is a common
opportunistic
infection
Association
with hearing
loss
PCR Rare Supportive
Serum or CSF
cryptococcal
antigen test;
direct
visualization
by India ink,
fungal culture
Mostly SNHL;
hearing loss is
reported at
8–73%
Treatment and
prevention
care; antiviral
treatment in
selected cases;
vaccination
available
Antifungal
treatment
25.11 Congenital Infections Causing Hearing Loss
Hearing loss is frequently reported after congenital infections. The acronym
TORCH complex, which stands for “toxoplasmosis, others, rubella, cytomegalovirus, and herpes simplex virus (HSV) infections,” is a group of congenital infections
transmitted vertically from the maternal host to the fetus during pregnancy or delivery or after birth. Other infections include Treponema pallidum, hepatitis viruses,
parvovirus B19, HIV, Zika virus, and lymphocytic choriomeningitis virus (LCMV)
infections [33–35]. TORCH infections cause multiorgan anomalies in the fetus.
Hearing loss is common in TORCH infections and is usually associated with CNS
involvement, including developmental delay, hydrocephaly, microcephaly, migrational neuronal abnormalities, and intracranial calcications [33, 36].
25.11.1 Cytomegalovirus (CMV) Infection
Cytomegalovirus belongs to the Herpesviridae family. Like other herpesviruses,
CMV enters a latent phase after primary infection and can be subsequently reactivated, especially in the immunocompromised states. Primary CMV infection occurs
in 1–4% of pregnancies and is usually asymptomatic or presents with u-like symptoms, fatigue, and rash. In mothers with primary infection, the rate of CMV transmission to the fetus is as high as 50%, while it is less than 2% in mothers with CMV
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