Download Chapter 109 - Central Nervous System Infections

CHAPTER 109 Central Nervous System
Infections
William J. Meurer
PERSPECTIVE
Background
Central nervous system (CNS) infections have always been among
the most perplexing and devastating illnesses. “Epidemic cerebrospinal fever,” classically described by Vieusseux in 1805, was associated with almost universal mortality.1 The first American epidemic
of meningococcal meningitis was recorded in 1806.2 Since that
time, epidemiologic changes have occurred in concert with
advances in understanding of disease processes and evolution of
effective treatment strategies.
The etiologic spectrum of CNS infection has changed considerably as a result of the development and aggressive use of antibiotics and the epidemic emergence of diseases and conditions that
impair the immune system, such as infection with the human
immunodeficiency virus (HIV). Some of the research on CNS
infections at the cellular and molecular levels has provided insights
into pathogenesis, including the role of host mechanisms such as
cytokines and other immune components.
Likewise, diagnostic tools have been developed that allow
precise pathogen identification, most recently by molecular technologies such as polymerase chain reaction (PCR) tests for viral
nucleic acids in cerebrospinal fluid (CSF). The initial treatment
methods began by demonstrating the efficacy of antiserum treatment by Flexner in 1913 and of antibiotics by Colebrook and
Kenny in 1936.3,4 Mortality rates in CNS infections were decreased
further with the use of high-dose penicillin by Dowling and colleagues in the 1940s.5 Unfortunately, despite historical advances,
the morbidity and mortality of these disorders remain considerable.6 The use of pneumococcal, Haemophilus influenzae type b,
and meningococcal vaccines has led to dramatic reductions in the
incidence of meningitis caused by these bacteria.7-10
Definitions
CNS infections comprise a broad spectrum of disease entities.
Meningitis is defined as inflammation of the membranes of the
brain or spinal cord and is also called arachnoiditis or leptomeningitis. Encephalitis denotes inflammation of the brain itself,
whereas myelitis refers to inflammation of the spinal cord. The
terms meningoencephalitis and encephalomyelitis describe more
diffuse inflammatory processes. Collections of infective and purulent materials may form within the CNS as abscesses. Brain
abscesses may be intraparenchymal, in epidural or subdural intracranial locations, or may be found in intramedullary or epidural
spinal locations.
This chapter focuses on the more common acute and subacute
CNS infections. Infections of the nervous system with HIV or
human T-lymphotropic virus, rabies virus, poliovirus, hepatitis
viruses, Borrelia burgdorferi (Lyme disease), Treponema organisms
(syphilis), parasites, or Rickettsia and the chronic and slow infections of the CNS (subacute sclerosing panencephalitis; progressive
multifocal leukoencephalopathy; and the prion-mediated spongiform encephalopathies, such as Creutzfeldt-Jakob disease, bovine
spongiform encephalopathy, and kuru) are not addressed in detail.
Of note, the incidence of neurocysticercosis is on the rise in the
United States.11
Epidemiology
Bacterial meningitis is a common disease worldwide. Meningococcal meningitis is endemic in parts of Africa, and epidemics
commonly occur in other countries, including the United States.
A variety of other pathogens are also causative.12-16 The overall
incidence of bacterial meningitis in the United States is 5 to 10
cases per 100,000 people per year.17 Men are affected more often
than women are.17 Approximately 80% of cases in the United
States are caused by either Streptococcus pneumoniae or Neisseria
meningitidis.18 In regions where vaccination is common, the epidemiology of bacterial meningitis has substantially changed.7-10,19
The incidence of bacterial meningitis increases in late winter and
early spring, but the disease may occur at any time of the year.
Because most cases go unreported, the actual incidence of viral
meningitis is unknown. It is estimated to affect between 11 and
27 individuals per 100,000 people.20 A prominent increase of cases
is seen in summer months, which is concurrent with seasonal
predominance of the enterovirus group of the picornaviruses.
The same organisms responsible for viral meningitis may also
be associated with encephalitis. Encephalitis is far less common,
however, and the ratio of cases of meningitis to encephalitis varies
according to the specific pathogen. Arbovirus infection is transmitted by an insect vector, although clinical disease develops in
only a small percentage of the people bitten. Before 1999, there
were approximately 19,000 hospitalizations in the United States
annually for cases of encephalitis. Since then, there has been a
rapid increase because of emergence of West Nile virus (WNV).
In 2003, more than 8000 additional hospitalizations were required
because of WNV alone.21,22
Approximately 2000 cases of brain abscess occur in the United
States annually.23 Although CNS abscesses may occur at any age
and any time of year, they are seen more commonly in men
than in women.24 CNS abscesses are associated with local con­
tiguous and remote systemic infections, injection drug use, neurologic surgery, and cranial trauma. Brain abscess secondary to
otitis media most often occurs in pediatric or older adult populations. When brain abscess is associated with sinusitis, it most often
arises among young adults. Increasingly, CNS abscesses are seen
1447
1448 PART III ◆ Medicine and Surgery / Section Seven • Neurology
in immunocompromised patients, particularly those with HIV
infection, and among bone marrow and solid organ transplant
recipients. However, antimicrobial prophylaxis of immuno­
suppressed patients and more aggressive treatment of otitis and
sinusitis have decreased the overall incidence to 0.9 per 100,000
person-years.23
PRINCIPLES OF DISEASE
Etiology
Meningitis
Meningeal inflammation may be caused by a variety of disease
processes, but the infectious causes predominate. Among the bacterial agents, Streptococcus pneumoniae remains the predominant
pathogen in adult patients, followed by Neisseria meningitidis
and Listeria monocytogenes.25 N. meningitidis is the predominant
organism in adults younger than 45 years. Five major serogroups
cause most meningococcal disease worldwide (A, B, C, Y, and
W-135). Serogroup A accounts for the majority of cases of meningococcal meningitis in developing nations.26 A new vaccine for
serogroup A may potentially reduce the impact of this disease in
nearly half a billion individuals at risk.27 Serogroup distribution
for invasive disease has changed markedly in the United States,
with B, C, and Y now most commonly responsible.28 These pathogens account for the bulk of cases in nontraumatic meningitis,
although virtually any organism can be encountered, particularly
among patients who are elderly, alcoholic, or immunosuppressed
and those who have cancer. Interestingly, higher case fatality has
been observed in N. meningitidis outbreaks versus sporadic cases,
probably because of increased virulence of outbreak-related
strains.29 Causes of aseptic meningitis, simply defined as all cases
with CSF cultures negative for bacteria, are listed in Box 109-1.30
Meningeal infection may also occur in association with a dural
leak secondary to neurosurgery or neurotrauma. S. pneumoniae,
Staphylococcus aureus, Pseudomonas aeruginosa, and coliform bacteria are seen most commonly in this population.
Viral meningitis may likewise be caused by a variety of etiologic
agents.31 Enteroviruses are statistically encountered most commonly.32 Unfortunately, precise identification of the etiologic
agent is often impossible. Fungal and parasitic meningitides are
additional concerns, particularly among immunocompromised
patients.14,15 Viral meningitis secondary to herpes simplex virus
(HSV) infection is actually relatively benign, especially in comparison with HSV encephalitis.33
Noninfectious meningitides include drug-induced meningitis,
carcinomatous meningitis, CNS involvement in serum sickness,
vasculitis, systemic lupus erythematosus, Behçet’s disease, sarcoidosis, and others. The differentiation of noninfectious from infectious causes can often be perplexing.
Encephalitis
Arboviruses and HSV, a human herpesvirus (HHV), are the most
common causes of epidemic and sporadic cases of encephalitis,
respectively. Children are the most vulnerable to infection with
these viruses, although adults are also commonly affected. Epidemics of viral encephalitis have been attributed to a wide variety
of viral agents. WNV, a flavivirus, first infected humans in the
New York City area and rapidly spread to 47 states by 2003.15,34
Varicella, herpes zoster, HHV types 6 and 7, and EpsteinBarr virus have been increasingly reported to be the cause of
encephalitis in immunocompetent hosts.35 Vaccinia encephalitis
has been recognized in those receiving vaccination for smallpox.36
Postinfectious encephalomyelitis is also induced by a variety of
viral pathogens, most commonly the measles virus.37 However,
BOX 109-1 Causes of Aseptic Meningitis
Infectious Causes
Viruses
Enteroviruses: polio,
Coxsackie, ECHO virus
Herpes group of viruses
Herpes simplex virus types
1 and 2
Varicella-zoster virus
Cytomegalovirus
Epstein-Barr virus
Human herpesvirus 6
(HHV-6)
Respiratory viruses
Adenovirus
Rhinovirus
Influenza virus types A and
B
Arboviruses
Mumps virus
Lymphocytic choriomeningitis
HIV
Bacteria
Partially treated meningitis
Parameningeal infection
Endocarditis
Mycoplasma pneumoniae
Mycoplasma tuberculosis
Ehrlichiosis
Borrelia burgdorferi
Treponema pallidum
Brucella
Leptospirosis
Fungi
Cryptococcus neoformans
Histoplasma capsulatum
Coccidioides immitis
Blastomyces dermatitidis
Candida
Parasites
Toxoplasma gondii
Neurocysticercosis
Trichinosis
Naegleria
Hartmannella
Bartonella henselae
Rickettsiae
Rocky Mountain spotted
fever
Typhus
Noninfectious Causes
Postinfectious/postvaccinial
Rubeola
Rubella
Varicella
Variola
Rabies vaccine
Pertussis vaccine
Influenza vaccine
Vaccinia
Yellow fever vaccine
Drugs
Nonsteroidal anti-inflammatory
drugs
Trimethoprim-sulfamethoxazole,
amoxicillin
Muromonab CD3 (OKT3)
Azathioprine
Intravenous immune globulin
Isoniazid
Intrathecal methotrexate
Intrathecal cytosine arabinoside
Allopurinol
Carbamazepine
Sulfasalazine
Systemic disease
Collagen vascular disorders
Systemic lupus erythematosus
Wegener’s granulomatosis
Central nervous system
vasculitis
Rheumatoid arthritis
Kawasaki disease
Sarcoidosis
Leptomeningeal cancer
Post-transplantation
lymphoproliferative disorder
Behçet’s disease
Vogt-Koyanagi syndrome
Neoplastic disorders
Leukemia
Carcinomatous meningitis
secondary to primary or
secondary tumors of the brain
Inflammation of neighboring
structures
Brain abscess
Epidural abscess
Miscellaneous
Arachnoiditis
Migraine
Urinary tract infection
From Kumar R: Aseptic meningitis: Diagnosis and management. Indian J Pediatr
72:57-63, 2005.
Mycoplasma pneumoniae and idiopathic causes are becoming
more common in developed countries.
Central Nervous System Abscess
The causes of CNS abscess are multiple and reflect the primary
infective process and the immune state of the human host. A
variety of mixed pathogens may be responsible for intracranial
abscesses. Streptococci, particularly the Streptococcus milleri group,
have been identified in nearly 50% of brain abscesses.38 Anaerobic
Chapter 109 / Central Nervous System Infections 1449
increased permeability of the blood-brain barrier, cerebral vasculitis, edema, and increased intracranial pressure. A subsequent
decrease in cerebral blood flow leads to cerebral hypoxia. Glucose
transport into the CSF is decreased concomitantly with an
increased use of glucose by the brain, bacteria, and leukocytes,
which depresses CSF glucose concentrations. The increased permeability leads to increased CSF proteins.
Viral Meningitis and Encephalitis
Figure 109-1. Central nervous system abscess: computed tomography
scan of an intraparenchymal abscess (arrows).
bacteria, predominantly Bacteroides species, are commonly seen
when the primary infectious process is chronic otitis media or
pulmonary disease. S. aureus and Propionibacterium are often
identified, particularly after cranial penetration from surgery or
trauma.39 The Enterobacteriaceae are an additional common
isolate. Opportunistic fungal and parasitic agents, including
Nocardia species, are often seen in the immunosuppressed.40
Culture of epidural and subdural abscesses more often yields a
single organism; streptococci are most commonly seen in association with contiguous spread, and S. aureus and gram-negative rods
are most commonly encountered after neurologic trauma (Fig.
109-1).15 Etiologic agents in spinal abscess are similarly varied,
with S. aureus being the most commonly encountered.
Pathophysiology
Bacterial Meningitis
The pathogenetic sequence in bacterial meningitis has been well
characterized.14,15 The first step is nasopharyngeal colonization
and mucosal invasion. Although colonization rates vary, virulent
microbes use secretion of immunoglobulin A proteases and induce
ciliostasis of mucosal cells. After penetration occurs by a variety
of mechanisms, bacterial intravascular survival occurs because of
evasion of the complement pathway. The varying capsular properties of each organism protect the bacteria. The third step occurs
when the bacteria cross the blood-brain barrier to enter the CSF.
The dural venous sinuses, cribriform plate area, and choroid
plexus have all been implicated as potential sites of invasion.
Although the mechanism of invasion is not completely understood, host defense mechanisms within the CSF are often ineffective; there are low levels of complement, immunoglobulin, and
opsonic activity. Bacterial proliferation then occurs, which stimulates a convergence of leukocytes into the CSF.
Meningeal and subarachnoid space inflammation is also associated with the release of cytokines into the CSF, most notably
tumor necrosis factor and interleukins 1 and 6.41 This results in
Viruses enter the human host through the skin (i.e., insect vectors);
through the respiratory, gastrointestinal, or urogenital tract; or by
receipt of infected blood products or donor organs.42 Viral replication subsequently occurs outside the CNS, most often followed by
hematogenous spread to the CNS. Additional routes into the CNS
include retrograde transmission along neuronal axons and direct
invasion of the subarachnoid space after infection of the olfactory
submucosa.43,44
Fortunately, most systemic viral infections do not result in
meningitis or encephalitis. The development and subsequent
magnitude of viral infection depend on the virulence of the specific virus, the viral inoculum level, and the state of immunity
of the human host. The tropism of the virus for specific CNS
cell types also influences the focality of disease and its manifestations.43 Particular viruses may preferentially attack cortical,
limbic, or spinal neurons, oligodendroglia, or ependymal cells. An
example is the tropism of HSV for the temporal lobes and the
development of temporal lobe seizures and behavioral changes in
afflicted patients.
Fungal Meningitis
Fungal meningitis probably develops in much the same way as
bacterial meningitis does, although this has been incompletely
studied. Pulmonary exposure followed by hematogenous spread
is the primary pathogenic mechanism in most cases. Immune
system defects or immunosuppressive medications compromise
host defense mechanisms, with ensuing development of CNS
infection.
Central Nervous System Abscess
Intraparenchymal brain abscesses, subdural empyema, and intracranial or spinal epidural abscesses form by inoculation of the
CNS from contiguous spread of organisms from a sinus, middle
ear, or dental infection or metastatic seeding from a distant site,
usually from pulmonary infection, endocarditis, or osteomyelitis.45 The primary infection can be identified in 75 to 85% of cases.
These conditions may also follow surgery or penetrating cranial
trauma, particularly when bone fragments are retained in brain
tissue. Otogenic abscesses occur most commonly in the temporal
lobe in adults and the cerebellum in children, whereas sinogenic
abscesses typically occur in frontal areas.38 Multiple brain abscesses
suggest hematogenous spread of organisms, although solitary
lesions may also occur. The pulmonary system is the most common
source of hematogenous spread.15
CLINICAL FEATURES
Symptoms and Signs
Numerous host factors have been implicated in the acquisition of
meningitis (Box 109-2).46 Although these factors alone and in
combination increase the risk of meningitis, the disease often
occurs in patients with none of these factors.
Many patients with meningitis present with advanced disease;
in these patients, the diagnosis of acute meningitis is strongly
1450 PART III ◆ Medicine and Surgery / Section Seven • Neurology
BOX 109-2 Host Factors Predisposing to Meningitis
Age < 5 years
Age > 60 years
Male gender
Low socioeconomic status
Crowding (e.g., military recruits)
Splenectomy
Sickle cell disease
African American race
Alcoholism and cirrhosis
Diabetes
Immunologic defects
Recent colonization
Dural defect (e.g., traumatic, surgical, congenital)
Continuous infection (e.g., sinusitis)
Household contact with meningitis patient
Thalassemia major
Injection drug abuse
Bacterial endocarditis
Ventriculoperitoneal shunt
Malignant disease
suspected. The constellation of symptoms that may classically
occur in an acute CNS infection consists of fever, headache, photophobia, nuchal rigidity, lethargy, malaise, altered sensorium,
seizures, vomiting, and chills.13,46
Unfortunately, more subtle presentations are also common.
Immunosuppressed and geriatric patients present a diagnostic
challenge because the classic signs and symptoms of meningitis
may not be present. Although some degree of fever is present in
most patients, as are a headache and neck stiffness, meningitis
should be carefully considered in any immunosuppressed patient
with symptoms or signs of infectious disease. Often, the only
presenting sign of meningitis in elders is an alteration of mental
status. However, a meta-analysis suggested that the absence of
fever, stiff neck, and mental status change excludes meningitis in
immunocompetent adults.47 A systematic review of prospective
data in children found several clinical factors that were useful in
influencing the likelihood of bacterial meningitis within suspected
cases.48 There was no combination of factors that could rule in or
rule out the disease, which is not surprising given the diversity of
presentations in children.
The presentation of fungal meningitis can be obscure even in
the healthy adult population. Headache, low-grade fever, lassitude,
and weight loss may be present but often to such a mild degree
that the correct diagnosis is not initially considered.13 This is also
true of tuberculous meningitis, which often has a protracted
course and a vague nonspecific presentation consisting of fever,
weight loss, night sweats, and malaise, with or without headache
and meningismus.12
The physical findings in meningitis vary by the host, causative
organism, and severity of the illness. Nuchal rigidity or discomfort
on flexion of the neck is common. Kernig’s sign (the inability to
straighten the leg to a position of full knee extension when the
patient is lying supine with the hip flexed to a right angle) and
Brudzinski’s sign (attempts to flex the neck passively are accompanied by flexion of the hips) are present in approximately 50%
of adults.15 In the evaluation of patients with suspected meningitis,
the sensitivity of Kernig’s sign, Brudzinski’s sign, and nuchal
rigidity are 5%, 5%, and 30%, respectively, suggesting that these
physical examination findings have little diagnostic value.49 Deep
tendon reflexes may be increased, and ophthalmoplegia may be
present, especially of the lateral rectus muscles.
The systemic findings may include an obvious source of infection, such as sinusitis, otitis media, mastoiditis, pneumonia, or
urinary tract infection. Various manifestations of endocarditis
may be present. Arthritis may be seen with N. meningitidis and
occasionally with other bacteria.46 Petechiae and cutaneous hemorrhages are widely reported with meningococcemia but also
occur with H. influenzae type b, pneumococcal organisms, L.
monocytogenes, and ECHO virus infections in addition to staphylococcal endocarditis.46 Endotoxic shock with vascular collapse
often develops in severe meningococcal disease, but shock may be
present in the advanced stages of any bacterial meningitis. Any
determination of a serious systemic infection should encourage
rather than dissuade the clinician from considering the possibility
of a concomitant CNS infection.
Patients with encephalitis may also have symptoms of meningeal irritation. An alteration of consciousness occurs in virtually
all patients. Fever, headache, and a change of personality are also
usually present.44 Hallucinations and bizarre behavior may precede
motor, reflex, and other neurologic manifestations by several days,
occasionally prompting an initial diagnosis of a psychiatric disorder. Because focal neurologic deficits and seizures occur much
more commonly with encephalitis than with meningitis, there
may also be diagnostic confusion with a brain abscess. It is difficult
to distinguish the etiologic agent in encephalitis clinically, although
HSV encephalitis results in a higher incidence of dysphasia and
seizures.50 In some patients, WNV produces a myelitis that affects
the anterior horn cells of the spinal column, resulting in a flaccid
paralysis with a clear sensorium, similar to findings in poliomyelitis or Guillain-Barré syndrome.34
Patients with intracranial abscess may be indistinguishable
from those with meningitis or encephalitis. Most patients with
intraparenchymal abscess have a subacute course of illness, with
symptoms progressing during the course of 2 weeks or more.
However, nuchal rigidity and fever are present in less than 50% of
cases. Focal neurologic deficits are present in most of these
patients. A large number of patients exhibit papilledema, which is
a rare finding in meningitis. An abrupt neurologic deterioration
that results from uncal herniation or rupture into the ventricular
system may occur.
Patients with a subdural or epidural abscess most often have
headache, fever, and focal signs, although more subtle presentations are common. Most of the patients with spinal abscess typically present with spinal pain and other symptoms and signs of
cord compression but not necessarily with fever.51
Complications
Bacterial Meningitis
The immediate complications of bacterial meningitis include
coma (with loss of protective airway reflexes), seizures, cerebral
edema, vasomotor collapse, disseminated intravascular coagulation, respiratory arrest, dehydration, syndrome of inappropriate
secretion of antidiuretic hormone, pericardial effusion, and death
(Box 109-3).16 Various delayed complications include multiple
seizures, focal paralysis, subdural effusions, hydrocephalus, intellectual deficits, sensorineural hearing loss, ataxia, blindness, bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome),
peripheral gangrene, and death.46
The case fatality rate for pneumococcal meningitis averages 20
to 25%; higher fatality rates occur in patients with serious underlying or concomitant disease or advanced age.52 The prognosis is
related to the degree of neurologic impairment on presentation.
Overall, 20 to 30% of the survivors of pneumococcal meningitis
have some residual neurologic deficit.46 The case fatality rate for
Listeria meningitis may be as high as 40%.25
With the advent of antibiotic therapy, the mortality from
meningococcal meningitis has markedly decreased to less than
20%, but it remains substantially higher in elders and those who
Chapter 109 / Central Nervous System Infections 1451
BOX 109-3 Complications of Bacterial Meningitis
Immediate
Coma
Loss of airway reflexes
Seizures
Cerebral edema
Vasomotor collapse
Disseminated intravascular coagulation
Respiratory arrest
Dehydration
Pericardial effusion
Death
Delayed
Seizure disorder
Focal paralysis
Subdural effusion
Hydrocephalus
Intellectual deficits
Sensorineural hearing loss
Ataxia
Blindness
Bilateral adrenal hemorrhage
Cerebral venous thrombosis
Death
have meningococcemia.52 Although most of the complications
and sequelae are less common than with pneumococcal disease,
the incidence of Waterhouse-Friderichsen syndrome is dramatically higher when meningococcemia is present.46 The overall mortality rate in community-acquired gram-negative meningitis has
been less than 20% since the introduction of the third-generation
cephalosporins.14 Hydrocephalus may develop in as many as 5%
of patients with community-acquired meningitis; when this
is present on admission, the proportion dead or with an unfavorable outcome approaches 50 to 70%.53 A delayed cerebral venous
thrombosis was observed in several adults with an initially excellent recovery from pneumococcal meningitis, suggesting an
immunologic vasculopathy.54
approximately 30%.37 Common complications observed among
survivors include seizure disorders, motor deficits, and changes
in mentation.
Tuberculous Meningitis
Death from tuberculous meningitis in the adult age group ranges
from 10 to 50% of cases, with the incidence directly proportional
to the patient’s age and the duration of symptoms before presentation. Focal ischemic stroke may result from the associated cerebral
vasculitis. In advanced disease, up to 25% of patients may require
some neurosurgical procedure for obstruction (ventriculoperitoneal shunt or drainage).58 Some neurologic deficit develops in
most patients, but severe long-term sequelae among survivors
are unusual.12
Fungal Meningitis
Common CNS complications with fungal meningitis include
abscesses, papilledema, neurologic deficits, seizures, bone invasion, and fluid collections. Direct invasion of the optic nerve
results in ocular abnormalities in up to 40% of patients with
cryptococcal meningitis.13 The mortality rate is high but variable
and is related to the timeliness of diagnosis, underlying illness, and
therapeutic regimens.
Central Nervous System Abscess
With the early diagnosis afforded by the use of cranial computed
tomography (CT), appropriate antimicrobial therapy, and combined management approaches with surgery, aspiration, and
medical therapy, the mortality rate from brain abscess has declined
dramatically from approximately 50% to less than 20%.45,59 A
seizure disorder is the most common complication of an intracranial abscess, occurring in 80% of patients.14 Other neurologic
findings of intracranial abscesses, including focal motor or sensory
deficits and changes in mentation, are common. Complications of
spinal abscess primarily result from cord compression, including
paralysis, motor and sensory deficits, and bowel and bladder
dysfunction. Generalized spread of CNS infection and death may
also occur.51
Viral Meningitis
With rare exceptions, the overall prognosis for complete recovery
from viral meningitis is excellent. Various complications related to
the systemic effects of the particular virus include orchitis, parotitis, pancreatitis, and various dermatoses. Usually, all of these complications resolve without sequelae.31 Interestingly, HSV meningitis
is often associated with the initial outbreak of genital herpes.33
Viral Encephalitis
The outcomes in viral encephalitis are dependent on the infecting
agent. Encephalitis caused by Japanese encephalitis virus, Eastern
equine virus, and St. Louis encephalitis virus is severe, with
high mortality rates and virtually universal neurologic sequelae
among survivors.55 WNV produces encephalitis in only 0.5% of
those infected, yet it resulted in 120 deaths in 2003.22 Western
equine virus and California encephalitis virus cause milder infections, and death is rare. The incidence of neurologic sequelae is
highly variable and appears to depend on both the host and the
infecting agent.56 Reports have emerged of influenza A H1N1
encephalitis that bears striking resemblance to “encephalitis
lethargica,” reported as a complication of influenza-like illnesses
in the 1920s.57
The mortality from HSV encephalitis before the use of acyclovir
was 60 to 70%. Acyclovir treatment has reduced the mortality to
DIAGNOSTIC STRATEGIES
Lumbar Puncture
General Considerations
The possibility of the diagnosis of meningitis mandates lumbar
puncture (LP) unless the procedure is contraindicated by the presence of infection in the skin or soft tissues at the puncture site or
the likelihood of brain herniation.37 Adherence to this principle
prevents a delay in diagnosis, which substantially increases the
morbidity and mortality of the disease. Some patients have clinically obvious bacterial meningitis, and CSF examination serves
primarily to help identify the organism, thereby facilitating the
appropriate treatment. Most patients, however, present more of a
diagnostic problem, and analysis of the CSF constitutes the critical
step in confirming the presence of CNS infection.
Increased Intracranial Pressure
In most patients with bacterial meningitis, LP may be safely performed without antecedent neuroimaging studies. As this may not
be the case in other brain diseases, in many circumstances it is
advisable to obtain a CT scan of the head before LP is performed.60
1452 PART III ◆ Medicine and Surgery / Section Seven • Neurology
Suspicion for bacterial meningitis
Typical signs may be absent, prior antibiotics may mask severity of illness
Assess severity
Start investigations
Ventilation
Circulation
Neurologic examination
Blood cultures
Blood gases
Serum laboratory investigations
Chest x-ray
Rash: skin biopsy
Shock and/or coagulopathy?
Anticoagulant use
Disseminated intravascula coagulation
Yes
No
Shock: low dose
steroids
No shock: DXM
Empiric antimicrobials
therapy
Indications for imaging before
lumbar puncture?
Yes
No
Lumbar puncture
Stabilization and/or
correction
coagulopathy
DXM and empiric
antimicrobial
therapy
Cloudy CSF or
apparent progress
of disease?
Yes
Indications for imaging
before lumbar
puncture?
Yes
CT/MRI
scan
brain
No
DXM and
empiric
antimicrobial
therapy
Cerebrospinal Fluid Analysis
No
No
Lumbar puncture
Significant
spaceoccupying
lesion?
CSF consistent with
bacterial meningitis?
No
Yes
Yes
Bacterial
meningitis
No lumbar
puncture
CSF consistent
with bacterial
meningitis?
Yes
exacerbated by LP. If the presentation is an acute, fulminating,
febrile illness and bacterial meningitis is the concerning diagnosis,
early initiation of antimicrobial therapy is mandatory because of
the association of prognosis and time to treatment.66 The algorithmic alternatives are therefore (1) immediate LP followed by initiation of antibiotic treatment before the results are obtained and (2)
initiation of antibiotic treatment followed by a cranial CT scan
and then LP. The latter choice of empirical treatment with antibiotics is now the routine in many institutions, although in some
cases a third option could be considered: antibiotics and no LP
despite an unremarkable CT scan.65 This reflects the efficacy of
current methods of identification of causative organisms in CSF
by means other than bacteriologic cultures that are less likely to
be affected by antibiotic administration. The controversy emerging about not performing LP despite a lack of CT findings is based
on some reviews and case reports. These describe a fulminant
herniation syndrome temporally related to LP in patients with
normal CT scans.63 Raised intracranial pressure may not be reliably detected by CT. Clinical signs of increased intracranial pressure, rapid change in consciousness, and recent seizures were
identified as risk factors predicting deterioration despite a normal
CT scan.65 The risks of ongoing empirical treatment with antibiotics without additional information from CSF analysis appears to
be low as the yield from blood cultures and other diagnostic techniques such as PCR is relatively high. Therefore, this risk may be
less than the risks of performing LP in certain very high-risk
patients. In patients who have rapid neurologic deterioration,
seizures, or signs of herniation, antibiotics should be given, a
CT scan ordered, and the patient moved to intensive care. In this
situation, LP may be deferred.
No
Bacterial
meningitis:
DXM and
empiric
therapy
Reconsider diagnosis
Figure 109-2. Algorithm for diagnostic and therapeutic decisionmaking when bacterial meningitis is clinically suspected. CSF,
cerebrospinal fluid; CT, computed tomography; DXM,
dextromethorphan; MRI, magnetic resonance imaging.
An algorithm for diagnostic and therapeutic decision-making is
presented in Figure 109-2.61
It has been conventionally asserted that LP in the presence
of increased intracranial pressure may be harmful or fatal to the
patient. Although data to address this concern are limited, the
presence of focal neurologic signs does appear to be associated
with a dramatic increase in complications associated with LP.
These patients may deteriorate precipitously during or after
the procedure.62-65
Patients with a markedly depressed sensorium that precludes
careful neurologic examination or those with a focal neurologic
deficit, papilledema, seizures, or evidence of head trauma must be
considered to be at risk for a herniation syndrome that may be
Opening Pressure
The normal CSF pressure in an adult varies from 5 to 20 cm H2O.
This value applies only to patients in the lateral recumbent position and may increase substantially when the patient is in the
sitting position. The pressure is often elevated in bacterial, tuberculous, and fungal meningitides and a variety of noninfectious
processes.44 Pressure may be falsely elevated when the patient is
tense or obese or has marked muscle contraction.
Collection of Fluid
At least three sterile tubes each containing at least 1 to 1.5 mL of
CSF are obtained and numbered in sequence. A fourth tube may
be desirable should later studies, such as viral cultures or a Venereal Disease Research Laboratory (VDRL) test for syphilis, become
necessary. The fluid is sent to the laboratory for immediate analysis of turbidity, xanthochromia, glucose, protein, cell count and
differential, Gram’s stain, bacterial culture, and antigen testing
(Table 109-1). In certain cases an India ink stain, a bacteriologic
stain for acid-fast bacilli, or a VDRL test should be obtained. When
only a small amount of fluid can be obtained, the most important
studies are the cell count with differential, Gram’s stain, and bacterial cultures. Ideally, the cell count should be performed on both
the first and third or fourth tubes to help differentiate true
CSF pleocytosis from contamination of the specimen by a
traumatic LP.
Turbidity
The CSF is assessed immediately for turbidity or cloudiness by the
person performing the LP. Because normal CSF is completely clear
and colorless and is indistinguishable from water, any degree of
turbidity is pathologic. Leukocytosis is the most common cause
Chapter 109 / Central Nervous System Infections 1453
Table 109-1 Analysis of Cerebrospinal Fluid
TEST
NORMAL VALUE
Cell count
≤5 WBC/mm3
≤1 PMN/mm3
≤1 eosinophil/mm3
SIGNIFICANCE OF
ABNORMALITY
Increased WBC counts are
seen in all types of meningitis
and encephalitis; increased
PMN count suggests bacterial
pathogen
Gram’s Stain Characteristics of Selected
Table 109-2 Meningeal Pathogens
PATHOGEN
TYPICAL CHARACTERISTICS
Staphylococci
Gram-positive cocci: singles, doubles,
tetrads, clusters
Streptococcus pneumoniae
Gram-positive cocci: paired diplococci
Other streptococci
Gram-positive cocci: pairs and chains
Listeria monocytogenes
Gram-positive rods: single or chains
Neisseria meningitidis
Gram-negative cocci: negative paired
diplococci; kidney or coffee bean
appearance
Gram’s stain
No organism
Offending organism identified
80% of the time in bacterial
meningitis, 60% if patient has
been pretreated
Turbidity
Clear
Increased turbidity with
leukocytosis, blood, or
high concentration of
microorganisms
Haemophilus influenzae
Gram-negative coccobacilli: “pleomorphic”
bacilli
Enterobacteriaceae
(including Escherichia coli)
Gram-negative rods
Presence of RBCs in spinal
fluid for 4 hr before lumbar
puncture; occasionally
caused by traumatic tap
(if protein ≥150 mg/dL) or
hypercarotenemia
Pseudomonas aeruginosa
Gram-negative rods
Xanthochromia
None
CSF-to-serum
glucose ratio
0.6 : 1
Depressed in pyogenic
meningitis or hyperglycemia;
lag time if glucose given
intravenously
Protein
15-45 mg/dL
Elevated with acute bacterial
or fungal meningitis; also
elevated with vasculitis,
syphilis, encephalitis,
neoplasms, and demyelination
syndromes
India ink stain
Negative
Positive in one third of cases
of cryptococcal meningitis
Cryptococcal
antigen
Negative
90% accuracy for cryptococcal
disease
Lactic acid
≤35 mg/dL
Elevated in bacterial and
tubercular meningitis
Bacterial
antigen tests
Negative
≥95% specific for organism
tested; up to 50% falsenegative rate
Acid-fast stain
Negative
Positive in 80% of cases of
tuberculous meningitis if
≥10 mL of fluid
CSF, cerebrospinal fluid; PMN, polymorphonuclear leukocyte; RBC, red blood cell;
WBC, white blood cell.
of CSF turbidity; counts greater than 200 cells/mm3 usually cause
clinically detectable changes in CSF clarity.67
Cell Count and Differential
Normal adult CSF contains no more than 5 leukocytes/mm3 with
at most one granulocyte (polymorphonuclear [PMN] leukocyte)46,67,68; therefore, the presence of more than one PMN or a
total cell count of more than 5 cells/mm3 should be considered
evidence of CNS infection. In addition, the presence of any eosinophil in the CSF is abnormal, although basophils may occasionally
be seen in the absence of disease.67 Pretreatment with a few doses
of antibiotics, although possibly diminishing the yield of Gram’s
staining and cultures, should not affect the CSF cell counts in
meningitis.14,69,70
The cell counts in bacterial meningitis are usually markedly
elevated, sometimes exceeding 10,000 cells/mm3, and demonstrate
a dramatic granulocytic shift.46 In general, counts exceed 500 cells/
mm3, with a preponderance of PMN leukocytes. However, the
initial CSF analysis exhibits lymphocytosis (lymphocyte count
greater than 50%) in 6 to 13% of all cases of bacterial meningitis.
When only the patients with bacterial meningitis with fewer than
1000 cells/mm3 are considered, 24 to 32% have a predominance
of lymphocytes.71,72 In addition, the same population of patients
often has only a mild disturbance of CSF glucose and protein
levels. In well-established viral meningitis and encephalitis, counts
are usually less than 500 cells/mm3, with nearly 100% of the cells
being mononuclear.32 Early (48 hours) presentations may reveal
significant PMN pleocytosis and hence be indistinguishable from
presentations in early bacterial meningitis.73
Similarly, normal cell counts and differentials, although reassuring, do not absolutely exclude bacterial meningitis.68 Any
patient thought to have a clinical syndrome compatible with meningitis requires hospital admission with frequent reevaluation,
repeated LP, and antimicrobial therapy. In some patients who
have symptoms or signs of meningitis and have a normal initial
CSF analysis, CSF pleocytosis may develop within 24 hours;
the causative organism may be cultured from the original
“normal” CSF.
Brain abscess and parameningeal infections, such as subdural
empyema and epidural abscess, usually display CSF cell counts
and differentials similar to those of viral meningitis and encephalitis, although the CSF may also be normal.
A traumatic LP is suggested by the presence of a clot in one of
the tubes or the clearing of the CSF and a decreasing red blood
cell (RBC) count from tubes one to three. In the presence of a
traumatic LP, one may estimate the true degree of CSF white blood
cell (WBC) pleocytosis with the following formula67:
True CSF WBC = (measured CSF WBC )
(CSF RBC ) × (blood WBC )
×
blood RBC
Alternatively, when peripheral cell counts are normal, the CSF
from a traumatic LP should contain about 1 WBC per 700 RBCs.
Gram’s Stain
A properly performed Gram’s stain of a centrifuged specimen of
CSF identifies the causative organism approximately 80% of the
time in cases of bacterial meningitis.70 Gram’s stain characteristics
of the most commonly encountered organisms are described in
Table 109-2. The yield from this procedure is diminished by 20 to
30% when there has been prior treatment with antibiotics.14
1454 PART III ◆ Medicine and Surgery / Section Seven • Neurology
Misidentification of gram-positive organisms as gram negative is
also known to occur more commonly among pretreated patients
because organisms with damaged walls stain unpredictably.
Xanthochromia
Xanthochromia refers to the yellowish discoloration of the supernatant of a centrifuged CSF specimen. Xanthochromia is abnormal and results from the lysis of RBCs and release of the breakdown
pigments oxyhemoglobin, bilirubin, and methemoglobin into the
CSF. This process normally begins within 2 hours, and pigments
may persist up to 30 days; therefore, early analysis of the LP specimen is essential. If a traumatic tap has introduced enough plasma
to raise the CSF protein level to 150 mg/dL or more, blood pigments may cause xanthochromia. If the CSF protein level is less
than 150 mg/dL, however, and systemic hypercarotenemia does
not exist, xanthochromia of a centrifuged CSF specimen should
suggest that subarachnoid hemorrhage has occurred.67
Glucose
When the serum glucose concentration is normal, the CSF glucose
concentration is usually between 50 and 80 mg/dL. The CSF
glucose concentration is normally in a ratio of 0.6 : 1 to the serum
glucose concentration, except with marked systemic hyperglycemia, when the ratio is closer to 0.4 : 1. Therefore, a CSF-to-serum
glucose ratio of less than 0.5 in normoglycemic subjects or 0.3
in hyperglycemic subjects is abnormal and may represent the
impaired glucose transport mechanisms and increased CNS
glucose use associated with pyogenic meningitis.46,67 Mild decreases
in the CSF glucose level may occur with certain viral and parameningeal processes. However, bacterial or fungal meningitis should
be presumed to be the cause of low CSF glucose concentration,
termed hypoglycorrhachia, until each is clearly excluded.74 If the
serum glucose level has increased rapidly (e.g., after intravenous
administration of 50% dextrose in water), equilibration in the CSF
may take up to 4 hours, and therefore the interpretation of CSFto-serum glucose ratios may be unreliable.
Protein
The normal CSF protein level in adults ranges from 15 to 45 mg/
dL. An elevated CSF protein level, usually higher than 150 mg/dL,
commonly occurs with acute bacterial meningitis.46 When a traumatic LP has occurred, the CSF protein level can be corrected for
the presence of blood by subtracting 1 mg/dL of protein for each
1000 RBCs.67 Elevated CSF protein concentrations can result from
any cause of meningitis, subarachnoid hemorrhage, CNS vasculitis, syphilis, viral encephalitis, neoplasms, and demyelination syndromes.67 A greatly elevated CSF protein level (>1000 mg/dL) in
the presence of a relatively benign clinical presentation should
suggest fungal disease.13
India Ink Preparation
India ink staining of the CSF should be performed when a diagnosis of cryptococcal meningitis is being considered. The demonstration of budding organisms (Fig. 109-3) is virtually diagnostic
for cryptococcal disease but occurs in only one third of the cases.13
A more definitive diagnostic test is the cryptococcal antigen, which
appears to have a similar sensitivity when it is measured in serum,
CSF, or urine.75
Lactic Acid
Although nonspecific, elevations in CSF lactic acid concentrations
(>35 mg/dL) are potentially indicative of bacterial meningitis,
Figure 109-3. India ink staining of cerebrospinal fluid showing
cryptococcal meningitis.
and lactate may rise before the decline in glucose.76,77 Normal
lactate levels (<35 mg/dL) are usually seen in patients with viral
meningitides. A systematic review suggested that with respect to
efficacy, CSF lactate outperforms other commonly used laboratory
findings (glucose, protein, leukocyte count).78 The authors did
observe that the CSF lactate level is less helpful if it is low but that
higher values are highly associated with bacterial meningitis.
Antigen Detection
Counterimmunoelectrophoresis (CIE), latex agglutination, and
coagglutination are methods of detecting specific antigens. These
tests are particularly useful in patients receiving antibiotic treatment before CSF sampling because the tests depend on the presence of only an antigen and not viable organisms.
The CIE techniques that are performed for the most common
bacterial pathogens demonstrate high sensitivity and specificity
for bacterial antigens, particularly when they are performed on
CSF, blood, and urine simultaneously. Latex agglutination techniques are, however, more rapid and sensitive and are replacing
CIE in many facilities. Although reported results vary, the sensitivities of antigen tests are 50 to 90% for Neisseria organisms, 50
to 100% for S. pneumoniae, and approximately 80% for H. influenzae. A specific agglutination test for cryptococcal antigen is also
highly sensitive (90%) and specific. Cultures are always indicated
because a negative antigen test result does not exclude the possibility of any particular bacterial or fungal etiology.
Antigen and antibody testing is also being used to identify viral
and atypical pathogens. These tests have particular utility in HSV
encephalitis. Enzyme-linked immunosorbent assays can detect
HSV antibody production.79 Unfortunately, the appearance of
antibody in CSF occurs too late to aid in any therapeutic decision
analysis. PCR amplification and the identification of HSV DNA
have demonstrated a sensitivity of 95 to 100% and a specificity of
100% early in the disease and have markedly decreased the need
for diagnostic brain biopsy in this disorder.80 PCR has improved
the diagnosis of tuberculous meningitis, with a sensitivity of 80 to
85% and a specificity of 97 to 100%, and is superior to standard
techniques.81,82 PCR has additionally been shown to be superior in
identifying bacteria, enteroviruses, and other viral etiologic agents
in both immunocompromised and immunocompetent patients.83,84
Reported sensitivities of detection in CSF by PCR for N. meningitidis, H. influenzae, and S. pneumoniae are 88%, 100%, and 92%,
with nearly 100% specificity.85,86 The sensitivities of bacteriologic
culture are much lower, especially for N. meningitidis at 37 to 55%
and H. influenzae at 50%.87,88
In addition, PCR assays have nearly tripled the yield of viral
culture in identifying the etiologic agent.89 In studies of enteroviral
Chapter 109 / Central Nervous System Infections 1455
meningitis, sensitivities and specificities for PCR ranged from
86 to 100% and 92 to 100%, respectively.90 PCR has been
shown to be at least as sensitive as culture technique in detecting
cryptococcal meningitis. Quantitative PCR may be of benefit in
monitoring response to therapy in some forms of severe disease.35
The growing availability of these molecular techniques does
not, however, suggest that they should be routinely used as initial
diagnostic tests. Most cases of acute bacterial meningitis are
readily diagnosed and treated on the basis of the standard Gram’s
stain and culture. PCR should be reserved for less clear presentations, patients pretreated with antibiotics, and cases in which
concern exists for tuberculous, cryptococcal, and treatable viral
CNS infections.91 A reasonable approach is to save the CSF and
to consider ordering PCR when acute infection is strongly suspected on the basis of the initial results from the cell count and
Gram’s stain.
Bacteriologic Cultures
Although results are not available for emergency management,
bacteriologic cultures of CSF should be performed. Bacterial
culture yields are significantly decreased in patients pretreated
with antibiotics. Viral cultures may also be indicated.
Other Tests
A variety of additional, nonspecific tests of CSF have been advocated. These include measurement of CSF lactate dehydrogenase,
C-reactive protein, and the limulus lysate test; however, none of
these has demonstrated a high degree of clinical usefulness. Likewise, the evaluation of CSF chloride as a diagnostic aid for tuberculous meningitis is no longer clinically relevant.
Neuroimaging Techniques
Cranial CT or magnetic resonance imaging (MRI) is indicated in
the evaluation of any patient with presumed CNS infection in
whom there is the possibility of an intracranial abscess, intracranial hemorrhage, or mass lesion. In the diagnostic evaluation of
acute meningitis, however, a CT scan should not unnecessarily
delay LP or antimicrobial therapy. The CT scan may also show
hypodense lesions in the temporal lobes in patients with HSV
encephalitis, although MRI reveals this abnormality much earlier
in the disease process. A contrast-enhanced cranial CT scan or
MRI scan is invaluable in the diagnosis of a CNS abscess.45 MRI
is also helpful in the evaluation of other infectious and noninfectious encephalitides.
Additional Investigations
As with other infectious diseases, the complete blood count with
differential is a nonspecific adjunct in the diagnostic evaluation of
a patient thought to have a CNS infection. The peripheral cell
counts are often normal in the presence of significant disease and
may even be depressed, particularly in elders or immunosuppressed persons. A “normal” leukocyte count and differential
should not dissuade one from performing a diagnostic LP, obtaining a CT scan, or otherwise pursuing the diagnosis of a CNS
infection. Serum C-reactive protein is nonspecific, but a negative
test result is potentially helpful.92 Procalcitonin is emerging as a
promising serum marker in infectious disease; however, there is
not convincing evidence at this point to advocate its use to attempt
to rule out bacterial meningitis.93
Even when antimicrobial therapy has already been administered, two or three blood culture specimens should be obtained
for all patients who are being evaluated for a CNS infection. The
blood cultures can improve the identification of the causative
organisms, especially with pneumococcus and, to a lesser degree,
meningococcus. Although blood cultures are not immediately
useful in the initial diagnosis of meningitis, they may be of considerable clinical importance later in management of the disease.
The cultures are helpful in identifying a causative organism in only
a small minority of cases of brain abscess.
As many as 50% of patients with pneumococcal meningitis also
have evidence of pneumonia on an initial chest radiographic
study. This association occurs in less than 10% of the cases of
meningitis caused by H. influenzae type b and N. meningitidis and
in approximately 20% of cases of meningitis caused by other
organisms. The identification of a pulmonary infection on chest
radiography may assist in identification of causative organisms
and appropriate antimicrobial therapy in approximately 10% of
cases of brain abscess.45
Other ancillary investigations, such as echocardiography, cultures of other body fluids, and bone scans, may be undertaken as
necessary to evaluate coexistent or complicated disease. Serum
electrolyte, glucose, urea nitrogen, and creatinine levels should
be measured to facilitate the interpretation of the CSF glucose
level and to establish the level of renal function and the state
of electrolyte balance. Although organism-specific abnormalities
are uncommon, hyponatremia has been associated with tuberculous meningitis.
A number of characteristic but not pathognomonic electroencephalographic abnormalities have been associated with HSV type
1 encephalitis. Focal or lateralized electroencephalographic abnormalities in the presence of an encephalitis syndrome should
be considered strong evidence supporting a diagnosis of HSV
encephalitis.94
DIFFERENTIAL CONSIDERATIONS
Patients with meningitis may have symptoms and signs ranging
from mild headache with fever to frank coma and shock. To facilitate the discussion of diagnosis and treatment, meningitis may be
divided into three clinical syndromes: acute meningitis, subacute
meningitis, and chronic meningitis.
Acute meningitis encompasses patients with obvious signs and
symptoms of meningitis who are evaluated in less than 24 hours
after the onset of their symptoms and who rapidly deteriorate. In
many of these patients the diagnosis of meningitis is not in doubt,
and the crucial step is to initiate antimicrobial therapy immediately. The most likely pathogens in this syndrome are S. pneumoniae and N. meningitidis. Although H. influenzae has been
reported in this context, it is not commonly implicated in the adult
population.16,69
In the syndrome of subacute meningitis, the symptoms and
signs causing the patient to seek care have developed during a
period of 1 to 7 days. This syndrome includes virtually all cases
of viral meningitis along with most of the bacterial and some
of the fungal causes.14,15 The differential diagnosis depends on
the symptoms and signs at presentation. Among elders and immunosuppressed individuals, a change in the patient’s mental status
may be the only presenting sign in meningitis. Even when a fever
is present, the patient’s change in mental status may be misattributed to another disease outside the CNS, such as pneumonia or
urinary tract infection; neck stiffness may be misattributed to
degenerative joint disease. Elders are at high risk for meningitis,
and rather than constituting a diagnostic endpoint, the identification of an infection outside the CNS in elders is a clear indication
for LP because of the risk of bacteremic seeding by the involved
organisms.
The differential diagnosis of encephalitis and brain abscess
occurs in the context of the subacute meningitis syndrome. Brain
abscess should be considered, especially if fever is minimal or
absent or if there are focal neurologic findings. The presence of
1456 PART III ◆ Medicine and Surgery / Section Seven • Neurology
fever, altered sensorium, headache, seizures, and personality
change is consistent with encephalitis. In addition, diagnoses such
as subdural empyema, brain tumor, subarachnoid hemorrhage,
subdural hematoma, and traumatic intracranial hemorrhage
should be considered. In these circumstances, a cranial CT scan
should be obtained before LP is performed.
The spectrum of chronic meningitis includes some of the viral
meningitides as well as meningitis caused by tubercle bacilli, syphilis, and fungi. Many of the patients in this group have had symptoms for at least 1 week before presentation and generally have a
prolonged indolent course marked by difficult and changing diagnoses and multiple therapies.12,13 Prediction rules have been both
derived and validated and have not yet diffused into widespread
practice, probably because of limitations in the models, shifts in
the epidemiology of the causative organisms, and relatively small
sample sizes.95
MANAGEMENT
However, in children, once fluid volume and vital signs are
normalized through resuscitation, there does not appear to be
evidence to restrict fluids, and appropriate maintenance fluids
should be instituted.96
Active airway management with endotracheal intubation may
be required in severely ill patients with meningitis, particularly in
cases of coma, recurrent seizures, or severe accompanying pulmonary infection. Cardiac monitoring may also be necessary, particularly in elderly patients, those with known coronary disease, and
those with an altered mental status. Seizures are a particularly
prominent component of the clinical presentation in patients with
a brain abscess but may also occur with any CNS infection, especially when an underlying seizure disorder is present.
If acute cerebral edema or an elevated intracranial pressure is
present, it is managed by immediate intubation and adequate
ventilation. Osmotic agents such as mannitol or diuretics such as
furosemide may be used, but caution should be exercised if shock
or uncontrolled hypotension is present. If diuretics or osmotic
agents are administered, one must ensure that the patient does not
become volume depleted and hypotensive.
Assessment and Stabilization
Septic shock, hypoxemia, seizures, cerebral edema, and hypo­
tension resulting from dehydration require aggressive management. When possible, a thorough history should be obtained
from the patient, family members, or ambulance personnel with
particular emphasis on preexisting conditions that may com­
plicate the patient’s disease. Examples include recent neurosurgery, trauma, history of leukopenia, immune suppression, and
diabetes mellitus.
Hypotension or shock is treated with isotonic crystalloid infusion, high-flow oxygen, and pressors. Intravenous administration
of dextrose may be required for hypoglycemia secondary to depletion of glycogen stores. Alcoholic or nutritionally compromised
patients should also receive 50 to 100 mg of thiamine intravenously (IV). In cases of moderate to severe hypotension, central
venous pressure monitoring should be initiated on the basis of
sepsis guidelines and used to determine additional intravenous
fluids or vasopressors. Concern has been raised about brain edema
with large amounts of crystalloid fluid in patients with meningitis.
Definitive Therapy
Bacterial Meningitis
Therapy for bacterial meningitis requires antibiotics that penetrate the blood-brain barrier and achieve adequate CSF con­
centrations, are bactericidal against the offending organism in
vivo, and maintain adequate tissue levels to treat the infection
effectively.
Until the pathogenetic organism is identified, broad-spectrum
coverage of the most common pathogens is necessary (Table
109-3). Many authorities recommend cefotaxime or ceftriaxone,
plus vancomycin to cover potentially resistant organisms.97 Highdose ampicillin is also added if concern exists about Listeria.97 In
patients allergic to penicillin and cephalosporins, meropenem or
chloramphenicol plus vancomycin may be effective while the
outcome of desensitization techniques is awaited.97
After the pathogen is identified, more targeted therapy can
be instituted. It is prudent to refer to a current antimicrobial
Recommendations for Empirical Antimicrobial Therapy for Purulent Meningitis Based on Patient Age
Table 109-3 and Specific Predisposing Condition
PREDISPOSING FACTOR
COMMON BACTERIAL PATHOGENS
ANTIMICROBIAL THERAPY
Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes,
Klebsiella species
Streptococcus pneumoniae, Neisseria meningitidis, S. agalactiae,
Haemophilus influenzae, E. coli
N. meningitidis, S. pneumoniae
S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gramnegative bacilli
Ampicillin plus cefotaxime or ampicillin plus an
aminoglycoside
Vancomycin plus a third-generation cephalosporin*,†
S. pneumoniae, H. influenzae, group A β-hemolytic streptococci
Staphylococcus aureus, coagulase-negative staphylococci
(especially Staphylococcus epidermidis), aerobic gram-negative
bacilli (including Pseudomonas aeruginosa)
Vancomycin plus a third-generation cephalosporin*,†
Vancomycin plus cefepime, vancomycin plus ceftazidime,
or vancomycin plus meropenem
Postneurosurgery
Aerobic gram-negative bacilli (including P. aeruginosa), S. aureus,
coagulase-negative staphylococci (especially S. epidermidis)
Vancomycin plus cefepime, vancomycin plus ceftazidime,
or vancomycin plus meropenem
CSF shunt
Coagulase-negative staphylococci (especially S. epidermidis), S.
aureus, aerobic gram-negative bacilli (including P. aeruginosa),
Propionibacterium acnes
Vancomycin plus cefepime,‡ vancomycin plus
ceftazidime,‡ or vancomycin plus meropenem‡
Age
<1 month
1-23 months
2-50 years
>50 years
Head trauma
Basilar skull fracture
Penetrating trauma
Vancomycin plus a third-generation cephalosporin*,†
Vancomycin plus ampicillin plus a third-generation
cephalosporin*,†
From Tunkel AR, et al: Practice guidelines for bacterial meningitis. Clin Infect Dis 39:1267-1284, 2004.
* Ceftriaxone or cefotaxime.
† Some experts would add rifampin if dexamethasone is also given.
‡ In infants and children, vancomycin alone is reasonable unless Gram stains reveal the presence of gram-negative bacilli.
Chapter 109 / Central Nervous System Infections 1457
reference to guide therapy in all instances, given rapid changes in
etiologic spectrum, drug resistance, and available agents. Duration
of treatment varies, and in certain situations (namely, epidemics
in sub-Saharan African), long-acting chloramphenicol or ceftriaxone is effective.98
Corticosteroid treatment is additionally recommended in adult
acute bacterial meningitis, although the evidence of efficacy is
becoming less compelling over time. Animal studies demonstrate
the salutary effects of the administration of corticosteroids in
experimental pneumococcal meningitis, including reduced brain
edema, CSF pressure, and CSF lactate levels.99 Earlier resolution
of the clinical and CSF stigmata of meningitis and a decrease in
long-term hearing loss are observed in infants and children given
dexamethasone with cefuroxime or ceftriaxone compared with
those receiving the antibiotic alone, particularly when H. influenzae is the offending agent.100 In adult bacterial meningitis, an
absolute risk reduction of 10% for unfavorable outcome is seen
when dexamethasone is given either 15 minutes before or concomitantly with antibiotics and continued for 4 days at 6-hour
intervals.101 This benefit is greatest in those with S. pneumoniae.
Subgroup analyses for different causative organisms did not establish a benefit; however, the study was not designed with adequate
power to detect improved outcomes. In addition, amoxicillin and
penicillin were the most commonly used initial therapy at the time
of that study because of the process of health care delivery in
Europe, in which nearly all patients were seen initially in an officebased practice. A randomized controlled trial did not demonstrate
a benefit of adjuvant dexamethasone in adult patients, even when
only those with S. pneumoniae were included in a secondary analysis.102 In the current era of initial empirical parenteral therapy,
rising β-lactam resistance, the possibility of the decreased CSF
penetration of vancomycin after dexamethasone treatment, and
shifts in the likely causative organisms secondary to vaccination
campaigns, the true effectiveness of dexamethasone is unclear. The
most recent meta-analysis suggests a benefit for patients in the
developed (but not developing) world, but the included studies
suffer from one or more of the aforementioned limitations.103 A
pooled analysis of patient-level data was less conclusive, suggesting
that the benefit of adjunctive dexamethasone for any “subgroup
of patients with bacterial meningitis remains unproven.”104 Despite
uncertainty from conflicting trials, an initial dose of dexamethasone 10 mg IV is recommended before or concurrent with empirical antibiotics in patients with suspected community-acquired
meningitis and without signs of septic shock. Given the potential
adverse effects of high-dose corticosteroids in patients with septic
shock, the use of low-dose hydrocortisone at 50 mg IV instead of
high-dose dexamethasone is a reasonable approach, although it
has not been proved in randomized controlled trials of patients
with both septic shock and meningitis.105,106
In pediatric meningitis, the evidence that adjunctive dexamethasone is helpful is less compelling. Invasive H. influenzae type b
and pneumococcal infections have drastically been reduced by
vaccination.19 A randomized trial of dexamethasone in childhood
meningitis in sub-Saharan Africa did not demonstrate a benefit.107
A retrospective analysis from U.S. administrative data did not
demonstrate any mortality benefit to adjunctive dexamethasone.108 Current recommendations are organism specific, which
presents a major limitation as recommendations are to begin
empirical therapy before laboratory results in suspicious cases. For
H. influenzae type b (Hib): “dexamethasone may be beneficial for
treatment of infants and children with Hib meningitis to diminish
the risk of neurological sequelae, including hearing loss, if given
before or concurrently with the first dose of antimicrobial agent(s).
There probably is no benefit if dexamethasone is given more than
1 hour after antimicrobial agent(s).”109 For S. pneumoniae: “for
infants and children 6 weeks of age and older, adjunctive therapy
with dexamethasone may be considered after weighing the
potential benefits and possible risks. Experts do not agree on a
recommendation to use corticosteroids in pneumococcal meningitis; data are not sufficient to demonstrate a clear benefit in
children. If used, dexamethasone should be given before or concurrently with the first dose of the antimicrobial agent.”110 The
implication for frontline physicians caring for children is that
unless the causative organism is known before antibiotic treatment, there is probably little role for adjunctive dexamethasone
in children.
Viral Meningitis
No specific agents are available to treat most types of viral meningitis. Investigational agents in development may reduce symptoms in enterovirus meningitis111; however, with the exception of
HSV meningitis, the viral meningitides contracted in the United
States are generally characterized by a short, benign, self-limited
course followed by a complete recovery. The primary therapeutic
consideration in cases of viral meningitis is therefore the validity
of the diagnosis. Early cases of viral meningitis may be indistinguishable from bacterial meningitis, and this confusion may not
be resolved by CSF analysis; therefore, when any doubt exists
about the veracity of the diagnosis, appropriate culture specimens
should be obtained and the patient admitted to the hospital. Antimicrobial therapy for presumed bacterial meningitis may be initiated on the basis of the clinical presentation or may be withheld
pending the outcome of close clinical observation and repeated
LP in 8 to 12 hours.
Viral Encephalitis
Specific therapy for meningoencephalitis from HHV is available.
Acyclovir remains the current choice and is capable of substantially improving the patient’s outcome. When the diagnosis of
herpes meningoencephalitis is suspected or established, acyclovir
should be administered in a dose of 10 mg/kg IV every 8 hours.81
Ganciclovir, foscarnet, and cidofovir are also effective in HHV
infections, and pleconaril has been effective in enteroviral disease.
Additional antiviral treatments are in development.34,35,111
Tuberculous Meningitis
Early chemotherapeutic intervention in acute tuberculous
meningitis improves the patient’s prognosis. A strong clinical suggestion of this disease is an adequate indication to begin anti­
tuberculous therapy. A standard treatment regimen consists of
isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin.97 Corticosteroids have also been shown to decrease secondary
complications.97
Fungal Meningitis
The treatment of fungal meningitis is complex.13 Four agents are
commonly used: amphotericin B, flucytosine, miconazole, and
fluconazole. Of these, amphotericin B, either alone or in combination with flucytosine, is the most commonly recommended initial
therapeutic regimen.97 These diseases are rarely acutely lifethreatening but rather are slowly progressive. Prolonged therapy,
often with multiple agents, is necessary. The initiation of antifungal therapy is rarely indicated in the emergency department.
Central Nervous System Abscess
The treatment of cerebral abscess is complex, and neurosurgical
consultation is indicated. The location, size, and number of
abscesses influence the choice of medical management, surgical
excision, aspiration, or a combination of these modalities.38 In
1458 PART III ◆ Medicine and Surgery / Section Seven • Neurology
general, small multiple abscesses are more appropriately treated
medically, whereas large, surgically accessible lesions should be
excised. Empirical antimicrobial therapy before identification of
specific organisms by aspiration or surgical excision should be
guided by the principles of CSF penetration and the coverage of
likely pathogens.
Otogenic and sinogenic abscesses are often treated with cefotaxime or ceftriaxone plus metronidazole.97 Abscesses with traumatic or neurosurgical causes should have antimicrobial coverage
for S. aureus or methicillin-resistant S. aureus. Patients at high risk
for tuberculous, fungal, or parasitic abscess should also receive
coverage for the suspected etiologic agent. Corticosteroids should
be reserved specifically for management of any attendant cerebral
edema; in other circumstances, steroid use is associated with
increased mortality. In cases in which the etiology is bacterial
endocarditis, valve replacement is often required.112
Chemoprophylaxis
Among household contacts, the incidence of transmission of
meningococcus is approximately 5%; therefore, it is recommended
that household contacts of bacteriologically confirmed cases
receive rifampin (adults, 600 mg; children older than 1 month,
10 mg/kg; children younger than 1 month, 5 mg/kg) orally every
12 hours for a total of four doses.97 In addition, these contacts
should be advised to watch for fever, sore throat, rash, or any
symptoms of meningitis. They should be hospitalized with appropriate intravenous antimicrobial therapy if there are signs that
active meningococcal disease is developing because rifampin
is ineffective against invasive meningococcal disease. Intimate,
nonhousehold contacts who have had mucosal exposure to the
patient’s oral secretions should also receive rifampin prophylaxis.
Health care workers are not at increased risk for the disease and
do not require prophylaxis unless they have had direct mucosal
contact with the patient’s secretions, as might occur during
mouth-to-mouth resuscitation, endotracheal intubation, or nasotracheal suctioning. Ciprofloxacin 500 mg by mouth (adults
only) and ceftriaxone 250 mg intramuscularly (125 mg intramuscularly for children younger than 15 years) provide single-dose
alternatives.97
There is no indication for chemoprophylaxis in pneumococcal
meningitis. Rifampin prophylaxis for the contacts of patients with
H. influenzae type b meningitis is recommended for nonpregnant
household contacts when there are children younger than 4 years
in the household97 (adults, 600 mg by mouth; children, 20 mg/kg
by mouth daily for 4 days).
Immunoprophylaxis
A quadrivalent vaccine based on the polysaccharide capsule and
conferring protection against group A, C, Y, and W-135 meningococci has been in routine use by the U.S. military since the 1980s.113
However, the capsular polysaccharide vaccines used to immunize
adults are neither immunogenic nor protective in children younger
than 2 years because of poor antibody response. In addition, no
licensed vaccine is currently available against the serogroup B
meningococcus.47 The serogroup B capsular polysaccharide has
proved to be poorly immunogenic in both adults and children.114
The sequence variation of the surface proteins and cross-reactivity
of the group B polysaccharide with human tissues have further
impeded efforts to develop a successful vaccine. Efforts to enhance
the immunogenicity and protective efficacy of meningococcal vaccines have focused on use of conjugate methods that link polysaccharides and carrier proteins. Serogroup C and serogroup C + Y
conjugate vaccines have been developed and used effectively.115
Current recommendations for the quadrivalent vaccine are evolving. The vaccine is recommended in established meningococcal
epidemics and for travelers to countries where meningococcal
disease is currently epidemic. Elective vaccination of college freshmen has been recommended by the Advisory Committee on
Immunization Practices (ACIP) in the United States and public
health authorities in the United Kingdom.116,117 The United
Kingdom has also implemented universal childhood immunization with a group C conjugate vaccine.115
The development of effective pneumococcal vaccines has been
hampered by the large number of serotypes of the organism. A
small number of serotypes, however, are responsible for most
clinical pneumococcal disease, and a 23-valent vaccine effective
against many of these principal serotypes has been developed.118
The recommendations for this polyvalent pneumococcal vaccine
are targeted primarily at prevention of pneumonia, despite a
potential beneficial effect for meningitis. A single dose of the
vaccine should be considered for elderly or debilitated patients,
especially those with pulmonary disease, and for patients with
impaired splenic function, splenectomy, or sickle cell anemia.18 A
heptavalent conjugated pneumococcal vaccine has also been
developed and is recommended for universal childhood immunization by the ACIP.119
A conjugate vaccine effective against H. influenzae type b
has been developed for use in the pediatric but not the adult
population. It appears to be approximately 90% protective and
has a very low incidence of adverse reactions.120 Modern childhood immunization against H. influenzae type b has raised the
average age of patients afflicted with Haemophilus meningitis to
25 years and decreased the incidence of meningitis of any etiology
by 55%.91
Vaccination is also available to confer immune protection
against Japanese encephalitis virus, and it is recommended for
people performing extensive outdoor activities or spending more
than 30 days in endemic areas during transmission seasons.121 The
reported protective efficacy of the vaccine is approximately 90%.
Although there is no current human vaccine for WNV, vaccines
for nonhuman mammals have been developed.34
DISPOSITION
With the exception of viral meningitis, all but the most chronic
CNS infections require initial inpatient evaluation and treatment.
Bed rest, analgesics, and the institution of appropriate intravenous
antimicrobials are indicated.
Some patients with suspected viral meningitides merit hospitalization. These include patients with more severe disease,
immunocompromise, suspicion of HSV meningitis, and potential
nonviral causes. Some authorities manage patients with classic
presentations of viral meningitis as outpatients and ensure close
follow-up within 24 hours. Others admit all patients until the
more serious causes, such as early bacterial meningitis and
encephalitis, can be excluded with certainty.
Chapter 109 / Central Nervous System Infections 1459
KEY CONCEPTS
■ CNS infection should be considered in all patients with
headache, neck stiffness, fever, altered sensorium, or diffuse
or focal neurologic findings.
■ Lumbar puncture with sampling of CSF is the only reliable
method of assessing the presence or absence of meningitis.
In the absence of contraindications, any suspicion of
meningitis mandates performance of lumbar puncture.
■ Early initiation of antimicrobial therapy is mandatory in any
case of suspected acute CNS infection. Antibiotic
administration must not be delayed for CSF analysis or
performance of neuroimaging studies.
■ Antibiotic chemoprophylaxis should be ensured for close
contacts of patients with meningitis resulting from Neisseria
meningitidis or Haemophilus influenzae. Single-dose and
multiple-dose regimens are available.
■ Vaccination against N. meningitidis is recommended for
certain at-risk populations but does not afford protection
against serogroup B infection.
■ Concomitant CNS infection should be strongly considered in
any patient with another severe systemic infection, such as
urinary tract infection or pneumonia.
The references for this chapter can be found online by
accessing the accompanying Expert Consult website.
Chapter 109 / Central Nervous System Infections 1459.e1
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