386 SECTION 16 INFECTIOUS DISEASES

Infectious mononucleosis usually resolves in 2-4 weeks, but TABLE 100.1 Bacterial Causes of Meningitis
fatigue and malaise may wax and wane for several weeks to
months. EBV also is associated with numerous complications AGE MOST COMMON LESS COMMON
during the acute illness. Neurological complications include Neonatal Group B Listeria monocytogenes
seizures, aseptic meningitis syndrome, Bell palsy, transverse streptococcus Enterococcus faecalis
myelitis, encephalitis, and Guillain-Barré syndrome. Hema- Escherichia coli Neisseria meningitidis
tological complications include Coombs-positive hemolytic Other enteric Streptococcus pneumoniae
anemia, antibody-mediated thrombocytopenia, hemophagocytic gram-negative
Other Streptococci
syndrome, and, rarely, aplastic anemia. Corticosteroids have bacilli
been used for respiratory compromise resulting from tonsillar Citrobacter species
hypertrophy, which responds rapidly, and for thrombocytopenia, Salmonella
hemolytic anemia, and neurological complications. Splenic Pseudomonas aeruginosa
rupture is very rare. X-linked lymphoproliferative disease, Haemophilus influenzae
which results from a mutation of the SH2D1A gene located in the Staphylococcus aureus (NICU
Xq25 region, manifests as fulminant infectious mononucleosis only)
with primary EBV infection, and progresses to malignant >1-3 months S. pneumoniae N. meningitidis
lymphoproliferative disease or dysgammaglobulinemia. Gram-negative
EBV infection, as with other herpesviruses, persists for life, bacilli
but no symptoms are attributed to intermittent reactivation Group B
in immunocompetent hosts. EBV is causally associated with streptococcus
nasopharyngeal carcinoma; Burkitt lymphoma; Hodgkin disease; >3 months S. pneumoniae Gram-negative bacilli
leiomyosarcoma in immunocompromised persons; and EBV Neisseria Group B streptococcus
lymphoproliferative disease, especially in posttransplant patients meningitidis
and in those with acquired immunodeficiency syndrome (AIDS).
NICU, Neonatal intensive care unit.
Lymphadenitis caused by nontuberculous mycobacteria has
an excellent prognosis. Surgical excision of cervical lymphad-
enitis caused by nontuberculous mycobacteria is curative in
>97% of cases. after the introduction of targeted vaccines. The bacteria causing
neonatal meningitis are the same as those causing neonatal
sepsis (see Chapter 65). In older children, S. pneumoniae and
PREVENTION N. meningitidis remain the most common causes of bacterial
The incidence of suppurative regional lymphadenitis reflects meningitis. Staphylococcal meningitis primarily occurs after
the incidence of predisposing conditions, such as dental disease, neurosurgery or penetrating head trauma.
streptococcal pharyngitis, otitis media, impetigo, and other Partially treated meningitis refers to bacterial meningitis
infections involving the face and scalp. There are no guidelines complicated by antibiotic treatment before the lumbar puncture
to prevent lymphadenitis caused by nontuberculous (LP), which may result in negative CSF cultures, although other
mycobacteria. CSF findings suggestive of bacterial infection persist. In this
case, the etiology can sometimes be confirmed by polymerase
chain reaction (PCR) of the CSF.
The most common viruses causing meningitis are entero-
viruses and parechoviruses. Other viruses that can cause
100
CHAPTER meningitis include herpes simplex virus (HSV), Epstein-Barr
virus (EBV), cytomegalovirus (CMV), lymphocytic choriomen-
Meningitis ingitis virus (LCMV), many arboviruses (see Chapter 101), and
human immunodeficiency virus (HIV). The mumps virus can
ETIOLOGY cause meningitis in unvaccinated children. Less frequent infec-
tious causes of meningitis include Borrelia burgdorferi (Lyme
Meningitis, inflammation of the leptomeninges, can be caused disease), Bartonella henselae (cat-scratch disease), Mycobacterium
by bacteria, viruses, or—rarely—fungi. The term aseptic tuberculosis, Toxoplasma, fungi (Cryptococcus, Histoplasma,
meningitis principally refers to viral meningitis, but meningitis Blastomycosis, and Coccidioides), and parasites (Angiostrongylus
with negative cerebrospinal fluid (CSF) bacterial cultures may cantonensis, Naegleria fowleri, and Acanthamoeba).
be seen with other infectious organisms (Lyme disease, syphilis,
tuberculosis), parameningeal infections (brain abscess, epidural
abscess, venous sinus empyema), chemical exposure (nonste- EPIDEMIOLOGY
roidal antiinflammatory drugs, intravenous immunoglobulin), The incidence of bacterial meningitis is highest among children
autoimmune disorders, and other diseases, including Kawasaki under 1 year of age, especially infants <2 months. Extremely
disease. high rates are found in Native Americans, Alaskan Natives,
The organisms commonly causing bacterial meningitis (Table and Australian aboriginals, suggesting that genetic factors play
100.1) before the availability of current conjugate vaccines were a role in susceptibility. Other risk factors include acquired
Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria or congenital immunodeficiencies, functional or anatomical
meningitidis. In the United States, the rates of H. influenzae type asplenia, cochlear implantation, penetrating head trauma, recent
b and S. pneumoniae meningitis have declined substantially neurosurgical procedure, and crowding, such as that which
 CHAPTER 100 Meningitis 387

occurs in some daycare centers or college and military dormi- Preceding upper respiratory tract symptoms may occur; however,
tories. A CSF leak (fistula), resulting from congenital anomaly rapid onset is typical of infections with S. pneumoniae and N.
or following a basilar skull fracture, increases the risk of meningitidis. Indications of meningeal inflammation include
meningitis, especially that caused by S. pneumoniae. headache, irritability, nausea, nuchal rigidity, lethargy, photo-
Enteroviruses and parechoviruses cause meningitis with phobia, and vomiting. Fever is usually present. Kernig and
peaks during summer and fall in temperate climates. These Brudzinski signs of meningeal irritation are often positive in
infections are more prevalent among infants and school-age children older than 12 months. In young infants, signs of
children and immunocompromised persons. The prevalence of meningeal inflammation may be minimal with only irritability,
arboviral meningitis or encephalitis is determined by geographic depressed mental status, and/or poor feeding present. Focal
distribution and seasonal activity of the arthropod (mosquito) neurological signs, seizures, arthralgia, myalgia, petechial or
vectors. In the United States, most arboviral infections occur purpuric lesions, sepsis, shock, and coma may occur. Symptoms
during the summer and fall. of increased intracranial pressure include headache, diplopia,
and vomiting; a bulging fontanelle may be present in infants.
Papilledema is uncommon unless there is occlusion of the
CLINICAL MANIFESTATIONS venous sinuses, subdural empyema, or brain abscess.

Decision-Making Algorithms
Available @ StudentConsult.com LABORATORY AND IMAGING STUDIES
If bacterial meningitis is suspected, a LP should be performed
Apnea
unless there is evidence of cardiovascular instability or of
Stiff or Painful Neck
increased intracranial pressure (due to the risk of herniation).
Headaches
Routine CSF examination includes a white blood cell count
Hearing Loss
with differential, protein and glucose levels, and Gram stain
Fever Without a Source
(Table 100.2). CSF should be cultured for bacteria and, when
Irritable Infant
appropriate, fungi and mycobacteria. PCR is used to diagnose

TABLE 100.2 Cerebrospinal Fluid Findings in Various Central Nervous System Disorders

PRESSURE PROTEIN (mg/

CONDITION (cm H2O) LEUKOCYTES (cells/µL) dL) GLUCOSE (mg/dL) COMMENTS
Normal 10-20 <5; 60-70% lymphocytes, 20-45 >50% of serum WBC up to 10-20 cells/μL
30-40% monocytes, 1-3% glucose can be normal in
neutrophils neonates
Acute bacterial Usually elevated >100; usually thousands; 100-500 Usually <40 or <40% Organisms may be seen
meningitis (>25) PMNs predominate of serum glucose on Gram stain and
recovered by culture
Partially treated Normal or 1-10,000; PMNs usual but >100 Depressed or Organisms may be seen;
bacterial meningitis elevated mononuclear cells may normal pretreatment may render
predominate if CSF sterile but bacteria
pretreated for extended may be detected by PCR
period
Tuberculous Usually elevated; 10-500; PMNs early but 100-500; may be Usually <50; Acid-fast organisms may
meningitis may be low lymphocytes and higher in presence decreases with time be seen on smear;
because of CSF monocytes predominate of CSF block if treatment not organisms can be
block in advanced later provided recovered in culture or by
stages PCR. Adenine deaminase
or gamma interferon
levels can be used to aid
in the diagnosis.
Fungal Usually elevated 10-500; PMNs early; 20-500 Usually <50; Budding yeast may be
mononuclear cells decreases with time seen; organisms may be
predominate later if treatment not recovered in culture; India
provided ink preparation and
antigen may be positive
in cryptococcal disease
Viral meningitis or Normal or slightly 10-1,000; PMNs early; <50 Generally normal; Viruses may be detected
meningoencephalitis elevated mononuclear cells may be depressed by PCR
predominate later to 40 in some viral
diseases (in 15-20%
of mumps)
Abscess Normal or 0-100 PMNs unless 20-200 Normal Profile may be completely
(parameningeal elevated rupture into CSF normal
infection)
CSF, Cerebrospinal fluid; HSV, herpes simplex virus; PCR, polymerase chain reaction; PMNs, polymorphonuclear leukocytes.
388 SECTION 16 INFECTIOUS DISEASES

viral meningitis; it is more sensitive and rapid than viral culture. inappropriate antidiuretic hormone (SIADH), seizures, increased
Peripheral leukocytosis is common, and blood cultures may intracranial pressure, apnea, arrhythmias, and coma. Adequate
be positive depending on the organism and whether there was cerebral perfusion must be maintained in the presence of cerebral
antibiotic pretreatment. Ideally, CSF should be obtained prior edema.
to empiric therapy; however, antibiotics should not be delayed
if there is an inability to perform an LP. If imaging is required
prior to the LP, blood cultures should be sent and antibiotics COMPLICATIONS AND PROGNOSIS
started, prior to a computed tomography (CT) scan. Interpreta-
tion of CSF in children who received prior antibiotics is Decision-Making Algorithm
complicated. In meningococcal meningitis, CSF can rapidly Available @ StudentConsult.com
become sterile, often within 1-2 hours, and most commonly Hearing Loss
with a single dose of therapy. Sterilization of the CSF in S.
pneumoniae meningitis may also occur within a few hours.
SIADH may complicate meningitis and necessitates monitoring
of urine output and fluid administration. Persistent fever is
DIFFERENTIAL DIAGNOSIS common during treatment but also may be related to ineffective
Many disorders other than meningitis and encephalitis may treatment or immune complex-mediated pericardial or joint
show signs of meningeal irritation and increased intracranial effusions, thrombophlebitis, drug fever, or nosocomial infection.
pressure, including trauma, hemorrhage, rheumatic diseases, A repeat LP after 48 hours of therapy should be considered for
and malignancies. Seizures can be associated with central those whose condition has not improved or has worsened,
nervous system (CNS) infection or can be the sequelae of brain gram-negative meningitis, and for those who received adjunct
edema, cerebral infarction or hemorrhage, or vasculitis. steroids, which can interfere with the ability to monitor clinical
response. CNS imaging should be considered in children who
demonstrate focal neurological signs or symptoms or persistently
TREATMENT positive CSF cultures. CT with contrast, or magnetic resonance
Treatment of bacterial meningitis focuses on sterilization of imaging, is used to detect subdural effusions with S. pneumoniae
the CSF by antibiotics (Table 100.3) and maintenance of adequate and H. influenzae meningitis or brain abscess associated with
cerebral and systemic perfusion. Due to increasing S. pneumoniae gram-negative organisms. Citrobacter koseri produces neonatal
resistance, an empiric third-generation cephalosporin plus meningitis with a high incidence of brain abscess formation.
vancomycin should be administered until culture results and Neurosurgery should be consulted to consider drainage if a
antibiotic susceptibility testing are available. Cefotaxime or brain abscess is present.
ceftriaxone are also adequate to treat N. meningitidis, H. With current management, the mortality rate for bacterial
influenzae, and some E. coli. For infants younger than 2 months meningitis in children remains significant, up to 15% depend-
of age, ampicillin is added to cover the possibility of Listeria ing on the organism and the study. Morbidity and mortality
monocytogenes. Duration of treatment is 5-7 days for N. are highest with S. pneumoniae. Of survivors, up to 30% have
meningitidis, 7-10 days for H. influenzae, and 10-14 days for sequelae, including deafness, seizures, blindness, paresis, ataxia,
S. pneumoniae. Meningitis caused by gram-negative bacilli or hydrocephalus. All patients with meningitis should have a
should generally be treated a minimum of 21 days or 14 days hearing evaluation before discharge and at follow-up. Learn-
beyond the first negative CSF culture, whichever is longer. ing disabilities and behavioral problems may be more subtle,
Dexamethasone as adjunctive therapy initiated just before long-term consequences of infection. Careful developmental
or concurrently with the first dose of antibiotics, significantly follow-up is important. Poor prognosis is associated with young
diminishes the incidence of hearing loss resulting from H. age, long duration of illness before effective antibiotic therapy,
influenzae meningitis. The role of adjuvant steroids for diminish- seizures, coma at presentation, shock, low or absent CSF white
ing neurological sequelae and mortality for pneumococcal and blood cell count in the presence of visible bacteria on CSF
meningococcal meningitis in children is less clear. Gram stain, and immunocompromised status.
Supportive therapy involves treatment of dehydration, Rarely relapse may occur 3-14 days after treatment, possibly
shock, disseminated intravascular coagulation, syndrome of from parameningeal foci or resistant organisms. Recurrence
may indicate an underlying immunological or anatomical defect
that predisposes the patient to meningitis.
TABLE 100.3 Initial Antimicrobial Therapy by Age for
Presumed Bacterial Meningitis
PREVENTION
RECOMMENDED ALTERNATIVE Routine immunizations against H. influenzae and S. pneumoniae
AGE TREATMENT TREATMENTS
are recommended for children beginning at 2 months of age.
Newborns (0-28 Cefotaxime plus ampicillin Ampicillin plus Quadrivalent vaccines against N. meningitidis (serotypes A, C,
days) with or without gentamicin
gentamicin
Y, and W-135) are recommended at age 11 or 12 years with a
booster dose at 16 years, and for children >2 months of age
Infants and toddlers Ceftriaxone or cefotaxime who are at high-risk of infection, including functional asplenia,
(1 month to 4 years) plus vancomycin
complement deficiencies and travelers to or residents of
Children and Ceftriaxone or cefotaxime Cefepime plus hyperendemic areas. A newer vaccine against N. meningitidis
adolescents (5-13 plus vancomycin vancomycin
years) and adults
serotype B is currently recommended for high-risk patients 10
years and older. Chemoprophylaxis with rifampin, ciprofloxacin,
 CHAPTER 101 Encephalitis 389

azithromycin, or ceftriaxone to eradicate the carrier state and but, more commonly, is insidious in onset (see Chapter 125).
decrease transmission is recommended both for index cases Other less common viral causes of encephalitis include measles,
with N. meningitidis and for their close contacts. For invasive JC virus, lymphocytic choriomeningitis virus (LCMV), rabies,
H. influenzae type B, prophylaxis consists of rifampin. influenza, and Japanese encephalitis. Numerous other infectious
etiologies for encephalitis are possible in the appropriate setting,
including prion-diseases (e.g., Creutzfeldt-Jakob disease) and
parasites such as amoeba, Bartonella henselae, Mycobacterium
tuberculosis, Plasmodium falciparum, and Mycoplasma pneu-
101
CHAPTER moniae. Encephalitis also may result from metabolic, toxic, and
neoplastic disorders. In many cases, the cause remains unknown.
Encephalitis Acute disseminated encephalomyelitis (ADEM) is the
abrupt development of multiple neurological signs related to
ETIOLOGY an inflammatory, demyelinating disorder of the brain and spinal
Encephalitis is an inflammatory process of the brain paren- cord. ADEM can follow childhood viral infections (such as
chyma, which usually presents with fever, headache, and mental measles and chickenpox) or vaccinations, and can clinically
status changes. Encephalitis is a challenging diagnosis in many resemble multiple sclerosis.
aspects, as determining its etiology is difficult and treatment Autoimmune encephalitis is a relatively common cause
options are quite limited. The term meningoencephalitis is of encephalitis and is associated with specific autoantibodies
used when meningeal inflammation is also present. Encephalitis directed to brain antigens, such as anti-N-methyl-D-aspartate
is usually an acute infectious process, but also may be a receptor antibodies. The presentation is often subacute with
postinfectious, autoimmune, part of a systemic disorder (lupus), psychological manifestations, cortical dysfunction, movement
or the result of an indolent viral infection. Encephalitis may disorders, autonomic dysfunction, and seizures.
be diffuse or localized. Organisms cause encephalitis by one
of two mechanisms: (1) direct infection of the brain parenchyma
via an extension of meningitis, secondary to viremia, or ret- EPIDEMIOLOGY
rograde spread via peripheral nerves or (2) a postinfectious, Arboviral and enteroviral encephalitides characteristically appear
immune-mediated response in the CNS that usually begins in clusters or epidemics that occur from midsummer to early
several days to weeks after clinical manifestations of the fall, although sporadic cases of enteroviral encephalitis occur
infection. throughout the year. Herpesviruses and other infectious agents
Viruses are the principal infectious causes of acute infectious account for additional sporadic cases throughout the year.
encephalitis (Table 101.1). The most common viral causes of Arboviruses tend to be limited to certain geographic areas,
encephalitis in the United States are enteroviruses, arboviruses, reflecting the reservoir and mosquito vector. In North America,
and herpesviruses. Human immunodeficiency virus (HIV) is West Nile virus and La Crosse encephalitis occur in the summer
also an important cause of subacute encephalitis in children time, resulting in a range of manifestations from asymptomatic
and adolescents and may present as an acute febrile illness infection to severe neurological involvement. La Crosse virus is
found in the Midwest and southeastern United States, whereas
West Nile virus is more disseminated across the country. The
principal vectors for West Nile virus are Culex mosquitoes, and
TABLE 101.1 Causes of Acute Encephalitis
a broad range of birds serves as its major reservoir.
VIRUSES BACTERIA Herpes simplex virus (HSV) encephalitis can occur in
Enteroviruses Borrelia burgdorferi (Lyme
neonates with or without skin lesions via perinatal or postnatal
disease) transmission. Beyond the neonatal period, HSV encephalitis
Parechoviruses
can result from primary or recurrent infection with HSV type
Herpes simplex viruses (types 1 Bartonella henselae (cat-scratch 1. In the immunocompromised host, other herpes viruses, such
and 2) disease)
as cytomegalovirus (CMV), Epstein-Barr virus (EBV), human
EBV Mycoplasma pneumoniae herpesvirus-6 (HHV-6) and varicella-zoster virus (VZV), as
Arboviruses (West Nile virus, St. Rickettsia rickettsii (Rocky well as Toxoplasma gondii and JC viruses can reactivate and
Louis, Japanese, LaCrosse, mountain spotted fever) cause encephalitis. Fungal infections of the CNS are rare but
Powassan and equine can also cause disease in this patient population.
encephalitis viruses)
Cytomegalovirus PARASITES
Human immunodeficiency virus Plasmodium falciparum CLINICAL MANIFESTATIONS
Rabies virus Naegleria fowleri
Decision-Making Algorithms
LCMV Acanthamoeba spp Available @ StudentConsult.com
VZV FUNGI
Stiff or Painful Neck
Influenza virus Cryptococcus neoformans Headaches
Mumps virus Coccidioides species Ataxia
Measles virus Histoplasma capsulatum Altered Mental Status
Hearing Loss Query
EBV, Epstein-Barr virus; LCMV, lymphocytic choriomeningitis virus; VZV, varicella- Polyuria
zoster virus.