I. Central nervous system infections are usually life-threatening,
necessitating immediate diagnosis and treatment to prevent death or significant
residual brain damage.
Headache with fever and signs of meningeal irritation
(nuchal rigidity and Brudzinski's sign) strongly suggests infection
which must be ruled out without delay; however, neonates or elderly individuals
with central nervous system infection may not be able to report headache
and fever, and signs of meningeal irritation may be absent.
Predisposing factors for central nervous system infections include bacteremia
(such as in bacterial endocarditis), debilitating conditions (such
as chronic renal failure), immunologic compromise (such as
from AIDS, lymphoma or immunosuppressive drugs), disruption of protective
barrirers (such as following
basilar skull fracture with associated
cerebrospinal fluid rhinorrhea or following neurosurgical procedures
such as cerebrospinal fluid shunt placement).
II. Cerebrospinal fluid (CSF) examination
Most important test for identifying evidence of central nervous system
infeciton is examination of cerebrospinal fluid.
Cerebrospinal fluid study provides definitive evidence of infection
along with opportunity for culture and identification of infection organism;
must be performed
prior to instituting antibiotic therapy in order
to culture most organisms; culture of maternal obtained from sources other
than cerebrospinal fluid (such as blood culture, urine culture, or wound
culture) will usually either not yield organisms or yield organisms other
than that producing central nervous system infection.
Lumbar puncture (performed by attending physician) is preferred
method for obtaining cerebrospinal fluid in most cases; however, cerebrospinal
fluid can also be obtained by cisterna magna or lateral cervical puncture
(performed by neurosurgeons under fluoroscopy) or by ventricular puncture
(performed by neurosurgeons through cranial burr hole, except when cerebrospinal
fluid shunt tubing is already in place, or through open fontanelle in neonates).
Caution must be exercised in performing lumbar puncture in patient with
signs of increased intracranial pressure (such as papilledema),
since removal of cerebrospinal fluid from subarachnoid space may alter
intracranial pressure dynamics precipitating brain herniation (transtentorial
uncal herniation, central rostral-caudal herniation, or cerebellar tonsillar
herniation).
Since delay in diagnosis and treatment of central nervous system infection
is usually fatal, attending physician must balance potential risks of lumbar
puncture versus potential risk of delay in diagnosis.
Radiologic imaging studies (such as CT scans) can quickly identify
factors predisposing to herniation (such as mass effect or pre-existing
early herniation).
Inserting secure intravenous infusion apparatus prior to performing lumbar
puncture permits infusion of hyperosmolar agents (such as mannitol) to
reduce intracranial pressure if signs of herniation appear during lumbar
puncture; additionally, antiobiotic therapy can be immediately instituted
once appropriate cerebrospinal fluid samples have been obtained.
Lumbar puncture should be performed using meticulous sterile technique,
obtaining values for opening pressure and removing sufficient cerebrospinal
fluid for all necessary studies.
Normal opening pressure should be no more than 180 mm of water.
It is incorrect that removing only minimal (1 mL) cerebrospinal fluid will
prevent herniation; once arachnoid membrane is punctured, change in pressure
dynamics will occur, since after removal of spinal needs, at least 40 mL
or more of cerebrospinal fluid will continue to leak through puncture holes
in arachnoid and dura (filling subdural and epidural spaces).
Normal cerebrospinal fluid is thin, colorless, sparkling, crystal-clear
fluid that does not cagulate; abnormal cerebrospinal fluid can be turbid
(cloudy), colored, viscous, frankly purulent, or bloody; as few as 400
blood cells per cubic millimeter (microliter) result in turbidity.
Tests performed on cerebrospinal fluid include:
Glucose - normal cerebrospinal fluid glucose level is about 60%
of blood glucose level; values of less than 50% of simultaneous
blood glucose or values below 40 mg/dL are indicative of meningeal
inflammation (as occurs with central nervous system infection); very low
glucose values (less than 20 mg/dL) are indicative of granulomatous infections
such as tuberculous meningitis.
Protein - cerebrospinal fluid protein varies with central nervous
system site and with age; protein elevation is found with variety of central
nervous system disorders including inflammation, infection, tumor, or stroke.
Cell count - cerebrospinal fluid normally contains no neutrophils
or
polymorphonuclear leukocytes and no more than five lymphocytes per
cubic millimeter (microliter); more cells (cerebrospinal fluid pleocytosis)
are abnormal; neutrophils are associated with infection, hemmorrhage, infarction
(stroke), and tumor; eosinophils occur in small numbers in same circumstances
as neutrophils, while large numbers are found with central nervous system
parasitic infections, foreign bodies, allergies processes, malignant lymphomas,
and post-myelography; plasma cells are found in viral disease, multiple
sclerosis, in recovery phase of bacterial meningitis, and in luetic (syphilis)
infection.
Microbiology
Light microscopy - if cerebrospinal fluid contains more than 100 organisms
per milliliter, microscopic slide made from sediment obtained by centrifugation
will reveal bacteria or fungi after Gram stain; tuberculous bacilli
can be visualized in slides stained with
acid-fast methods (Ziehl-Neelsen
or fluorescent rhodamine stains); identification of Cryptococcus neoformans
is
possible in India ink preparations; amoeba can be detected as mobile
trophozoites in wet mounts examined by phase interference microscopy; neutrophils
containing keratin fragments can be identified using polarized light in
chemical meningitis secondary to spillage of contents of epidermoid tumor,
craniopharyngioma, or dermoid cyst.
Elevated IgM levels can be detected in herpes simplex encephalitis
Countercurrent immunoelectrophoresis (CIE) can rapidly detect polysaccharide
antigens associated with meningococcal, pneumococcal, and Hameophilus influenzae
(type B) meningitis
Syphilis serology - VDRL procedure can identify up to 50% and fluorescent
treponemal antibody absorption test (FTA-ABS)will identify
over 90% of patients with neurosyphilis
IgG and measles antibody titers are elevated in subacute sclerosing panencephalitis
Culture
Final identification and verification of organism type requires culture;
however, contamination can lead to false positive results and negative
culture results do not exclude organisms, since technical problems may
prevent culture; false negative cultures result from antimicrobial drug
treatment prior to cerebrospinal fluid collection (partially-treated
meningitis).
Culture of some organisms requires special media or collection techniques
(for example, large quantities of cerebrospinal fluid are necessary for
successful culturing of tuberculous bacilli and special transport media
are necessary to preserve many viruses).
III Bacterial (suppurative; purulent) meningitis
Organisms typically causing bacterial meningitis vary with age:
Neonates (up to age 3 months)
Lack of sufficient immunologic maturity to mount adequate immune response
allows local infections to become disseminated to central nervous system;
presenting signs and symptoms are non-specific (such as irritability,
poor feeding, cyanosis, jitteriness, or lethargy); nuchal rigidity
does not occur; fever is uncommon, and infected infant often is hypothermic.
Infection by organisms of femal genital tract is acquired during passage
through birth canal; such organisms include: enteric gram-negative rods
(particularly Escherichia coli), group B B-hemolytic streptococci,
and Listeria monocytogenes; such infections usually present during
first week of life.
Infections with Staphylococcus aureus, Pseudomonas, Proteus,
andSalmonella
are usually acquired after birth due to environmental contamination ( contact
with contaminated articles or handling by infected individuals).
Infants
Immunologic system is mature enough by age 3 months to protect against
most environmental pathogens, except those organisms surrounded by polysaccharide
capsule: Haemophilus influenzae (particularly group B) and Streptococcus
pneumoniae(pneumococcus); loss of protective maternal immunoglobulins
(acquired through transplacental passage) against these organisms permits
nasopharyngeal colonization to progress to localized infection (including
otitis media), bacteremia, and in some infants, meningitis.
Peak incidence at age 1 year; after age 4 years meningitis is uncommon
(due to further maturation of immune system)
Children and adolescents
Because of large number of type specific capsular antigens and lack of
cross immunity between types, Streptococcus pneumoniae(pneumococcus)
remains common as cause of meningitis in all age groups after 3 years.
Neisseria meningitidis (meningococcus) produces epidemic
meningitis with rapid revolution of symptoms and associated petechial or
purpuric skin rash.
Adults
Meningitis is rare and most often is associated with some underlying predisposing
condition such as immunologic compromise, alcoholism, trauma,
surgery, or systemic illness (such as pneumonia, septicemia, or endocarditis);
recurrent
meningitis (particularly pneumococcal) suggests abnormal communication
between subarachnoid space and skin or nasopharynx; splenectomy or sickle
cell anemia (with its associated auto-splenectomy) predisposes to pneumococcal
sepsis and meningitis.
Elderly individuals seem to be particularly susceptible to meningitis caused
by same organisms as in neonates or infants.
Complications
Increased intracranial pressure
Obstruction of normal subarachnoid cerebrospinal fluid circulation due
to inflammation produces increased pressure that resolves as inflammation
subsides with treatment.
Cerebral edema may result from inflammation and bacterial toxins.
Cortical venous thrombophlebitis or arteritis involving subarachnoid
vessels can produce brain ischemia or infarction with resultant
edema
Syndrome of inappropriate antidiuretic hormone (ADH; vasopressin) secretion
(cerebral salt wasting)
Derangement (due to subarachnoid inflammation or cerebral edema) of hypothalamic
mechanisms regulating blood volume and osmolality resulting in water
retention with consequent dilutional hyponatremia
Persistent ADH secretion despite fall in serum osmolality below normal
values; diagnosis based upon finding hyponatremia with concomitant
serum
hypo-osmolality and urinary hyperosmolality
Hyponatremia is usually not associated with clinical symptoms until serum
sodium level falls below 120 meq/L and seizures and coma may occur with
values approaching 100 meq/L levels
Treatment involves fluid restriction; treatment with combination
hypertonic saline infusion and diuretics can rapidly correct serum sodium
level but also causes central pontine myelinolysis
Brain infarction
Thrombophlebitis - cortical venins encased in purulent exudate within
subarachnoid space can become thrombosed resulting in venous infarction
Arteritis - subarachnoid arteries encased in purulent exudate become
inflamed (vasculitis) with consequent thrombosis and infarction
Abscess - dead tissue in areas of infarction can become nidus for
development of brain abscess
Identified by radiologic imaging studies
Must be differentiated from primary brain abscess which leaks organisms
into subarachnoid space producing secondary meningitis
Subdural fluid collection
Subdural effusion - infants with meningitis are particularly susceptible
to development of subdural fluid collections: differentiated from subarachnoid
(cerebrospinal) fluid by high protein content of subdural fluid;
signs of subdural fluid collection include increased irritability,
lethargy, seizures, persistent fever, fullness of fontanelle, or
increasing head circumference; small effusions resolve spontaneously, but
large effusions require repeated percutaneous subdural taps to remove fluid
utnil it no longer accumulate
Subdural empyema - extremely rare complications of meningitis in
which subdural effusion fluid becomes infected; treatment involves immediate
neurosurgical drainage
Seizures
Frequent in infants and children presumably related to effects of subarachnoid
inflammation and bacterial toxins on adjacent cerebral cortex; can also
occur with subdural effusion or empyema (local pressure effect) or with
metabolic derangements (such as hyponatremia from syndrome of inappropriate
ADH section); seizures usually stop with successful treatment of meningitis
and do not lead to epilepsy
Can also occur due to cortical infarction or brain abscess; subsequent
epilepsy is likely due to permanent cerebral damage
Persistent fever - indicates inadequate antibiotic therapy, subdural
effusion or empyema, brain abscess, or systemic infectious
focus (such as abscess elsewhere in body or osteomyelitis)
Hydrocephalus
Acute - purulent material can obstruct cerebrospinal fluid pathways
leading to ventricular enlargement; diagnosed by radiology imaging studies;
usually resolves with treatment of infection
Communicating hydrocephalus - long-term complication due to subarachnoid
fibrosis as reparative reaction following meningitis; fibrosis obstructs
normal cerebrospinal flow toward arachnoid granulations (site of absorption
into venous sinuses); diagnosed by radiologic imaging studies; necessitates
cerebrospinal fluid shunt insertion after complete cure of infection.
Persistent neurologic deficits
Cranial nerve palsies - palsies related to increased intracranial
pressure (involving oculomotor, abducens, and facial nerve) usually resolve
with treatment of infection; persistent damage to vestibuloacoustic
nerve (cranial nerve VIII), particularly manifested as hearing loss,
is common complication of meningitis in infants and children; visual disturbances
are also common
Infarction or abscess results in permanent brain destruction with consequent
neurologic deficits
Other long-term sequelae in children include mental retardation, behavioral
disorders, and learning disabilities
Recurrent meningitis - suggests communication between subarachnoid space
and skin or mucous membranes, parameningeal focus of infection (such as
cranial osteomyelitis), or inadequate antibiotic treatment
Waterhouse-Friderichsen syndrome - fulminant meningococcemia can
produce septic shock and vasomotor collapse associated with
hemorrhagic
infarction of adrenal glands; often rapidly fatal
Ventriculitis - infection of intraventricular cerebrospinal fluid;
uncommon except associated with abscess that ruptures into ventricle or
with neurosurgical opening to ventricles (as with cerebrospinal shunt tubing);
often rapidly fatal except when caused by low virulence organisms such
as Staphylococcus epidermidis or enterococcus (group D streptococci)
Antibiotic therapy must be administered intravenously and at high doses;
minimum treatment is for 10 days (or 7 days after becoming afebrile), but
for relatively resistant organisms (such as gram-negative bacteria) treatment
for 3 weeks or longer often is necessary
Cerebrospinal fluid is examined from lumbar punctures performed 24-48 hours
after initiating antibiotic therapy and 24-48 hours after cessation of
antibiotics;
Cerebrospinal fluid should be sterile by 48 hours after beginning therapy
for relatively sensitive infection organisms (such as
Neisseria meningitidis,
Haemophilus influenzae, or Streptococcus pneumoniae)
Positive culture at 48 hours can sometimes still be obtained in relatively
resistant organisms (such as gram-negative enteric bacteria), necessitating
repeat lumbar puncture at 72-96 hours after antibiotic initiation, at which
time cerebrospinal fluid should be sterile
With successful antibiotic therapy, cerebrospinal fluid differential cell
count changes to predominantly lymphocytes
Persistence of organisms identifiable by culture or persistent neurophilic
predominance in cell count signifies inadequate antibiotic therapy
or parameningeal focus with continue seeding of cerebrospinal fluid
Antibiotic choice
Initial therapy (prior to culture results) should be based upon assumptions
concerning likely organism based upon patient age, environmental exposure,
and risk factors; combinations of antibiotics covering a wide-range of
potential pathogens is preferred
Combination therapy with ampicillin/gentamycin or ampicillin/cefotaxime
for neonates
Combination therapy with ampicillin/ceftriaxone or ampicillin/chloramphenicol
for infants, children, adolescents, and adults
Once culture results are available, therapy should be changed to antibiotic
to which organism is sensitive
Prophylaxis
All infants should receive immunization against Haemophilus influenzae
type B
Immunization against many serotypes of pneumococcus is available for elderly
and immunocompromised individuals
During epidemics of meningococcal meningitis, contacts should receive prophylactic
antibiotics
IV. Tuberculous (Mycobacterium tuberculosis) infection
Since organism culture takes as long as four weeks, diagnosis must be based
upon finding evidence of central nervous system infection (such as elevated
cerebrospinal fluid cell count) along with active pulmonary tuberculosis,
positive purified protein derivative (PPD) skin test, and microscopically
identifiable acid-fast organisms in cerebrospinal fluid sediment or brain
tissue biopsy
Tuberculous meningitis
Gradual onset of nonspecific symptoms of malaise, low-grade fever,
and anorexia followed later by lethargy, seizures, cranial nerve
palsies focal (often brain stem) neurologic signs, and evidence of
increased intracranial pressure (papilledema); meningeal signs (such as
nuchal rigidity) are uncommon
Cerebrospinal fluid obtained by lumbar puncture usually shows increased
numbers of lymphocytes, low glucose (often less than 20 mg/dL),
and elevated protein (sometimes fluid will form clot or pellicle)
Tuberculoma - granuloma involving brain parenchyma (can be
single or multiple); must be differentiated from tumor or abscess, necessitating
neurosurgical biopsy with culture and histologic identification of tuberculous
organisms
Treatment requires long course of combination antituberculous medications;
initial medication regimen must be modified when culture results establish
sensitivity
Complications
Medication-induced neurologic sequelae include:
Isoniazid-induced neuropathy - can be avoided by pyridoxine supplementation
Streptomycin-induced damage to cranial nerve VIII (with consequent deafness
and vestibular dysfunction
Ethambutol-induced optic nerve damage
Cycloserine-induced seizures
Hydrocephalus - very common due to dense subarachnoid fibrosis
surrounding brain stem and interfering with normal cerebrospinal fluid
flow
Arteritis - involves vessels at base of the brain, producing infarctions
V. Brain abscess
Slowly progressive onset of symptoms suggesting intracranial mass lesion,
including headache, focal neurologic signs, lethargy, and increased
intracranial pressure; seizures are frequent, but fever and leukocytosis
often are absent; predisposing conditions include sinusitis, mastoiditis,
bacterial
endocarditis, or lung abscess
Diagnosis suggested by radiologic imaging studies (particularly "doughnut"
lesion consisting of low density area with encircling higher density
capsule and marked surrounding cerebral edema); confirmation requires neurosurgical
exploration and drainage (with biopsy and culture to determine organism)
Lumbar puncture can be dangerous due to potential for inducing herniation,
and cerebrospinal fluid study generally is not helpful (culture is usually
negative, cell count normal, and protein only slightly elevated)
Evolution of brain abscess - initial phase is cerebritis (poorly
marginated area of infection and edema); followed by central necrosis
and liquefaction which is then walled off by margin of dense fibrosis and
gliosis (evident as "doughnut" lesion on radiologic imaging studies)
Treatment involves neurosurgical drainage and high dose intravenous
antibiotics
VI Fungal infection
Can present either as chronic meningitis (mimicking tuberculous
meningitis) or as parenchymal infection (mimicking brain abscess)
Most often affects ummunocompromised individuals (although cryptococcal
meningitis can occur in otherwise healthy individuals and candidal meningitis
can affect neonates)
Selected common pathogenic organisms
Cryptococcus neoformans - symptoms of meningitis can be rapidly
progressive and fatal or indolent over many months; large volumes of cerebrospinal
fluid (40 mL or more) are often necessary to establish diagnosis by culture,
microscopic examination (Gram stain and India ink preparation), or antigen
assay
Candida albicans - usually produces both meningitis and multiple
parenchymal abscesses (granulomas) in patients with candidal sepsis;
antecedent predisposing illnesses include severe burns, anatomic disruptions
of urinary tract (such as hydronephrosis), peritonitis, or following prolonged
broad spectrum antibiotic treatment
Rhinocerebral phycomycosis (zygomycosis; mucormycosis) - vasoinvasive
organisms spreading from paranasal sinuses into retroorbital tissues
and brain to cause fatal multifocal hemorrhagic brain infarction; usually
associated with poorly controlled diabetic hyperglycemia and acidosis
Aspergillosis - increasingly common infection found in
immunocompromised
individuals (particularly in AIDS); due to embolization of vasoinvasive
fungal hyphae from lung infection; fungal
emboli obstruct brain
vesses resulting in infarcts which then serve as culture media for
organism proliferation
Treatment consists of antifungal medication: amphotericin B, 5-fluorocytosine,
or ketoconazole depending on specific organism sensitivity; however, in
most cases unless underlying disease or immunologic compromise can be reversed,
antifungal therapy is not successful
VII. Neurosyphilis
Neurologic disease from infection by spirochete Treponema pallidum
can occur in all patients with inadequately treated syphilis, producing
various types neurologic damage over many years; this complication is completely
avoidable by adequate early antibiotic treatment
Diagnosis based upon examination of cerebrospinal fluid
VIII. Cysticercosis
Multiple brain cysts produced by larval (embryo) form of pork tapeworm
Taenia
solium; larva migrate from intestine into circulation to be transported
to muscle, eye, and brain; associated with intense in inflammatory reaction
and calcification
Often asymptomatic; most common clinical symptom is seizures; radiologic
imaging studies demonstrate multiple intracranial calcifications and ring-enhancing
lesions; treatment with praziquantel (broad-spectrum antinematode drug)
kills surviving organisms
IX. Rickettsial infection
brupt onset of fever, headache, myalgias, stiff neck, confusion.
seizures,
lethargy and subsequent coma; associated with maculopapular rash development
two to four days after onset of fever; death results from pneumonia, renal
failure, or circulatory collapse
Pathology consists of generalized necrotizing vasculitis resulting
in petechial hemorrhages and focal necrosis scattered throughout brain
Causative agent include Rickettsia prowazekii (typhus;
transmitted by body lice); Rickettsia tsutsugamushi (scrub
typhus; transmitted by chiggers)
Diagnosis is based upon signs of neurologic disturbance associated with
characteristics skin rash and history of insect bite: Weil-Felix reaction
(antibody
test) positive during second week of illness
Treatment involves prompt administration of antibiotics, either intravenous
chloramphenicol or oral tetracycline