Infection of the central nervous system (CNS)
It’s the most common cause of fever associated with signs and
symptoms of CNS disease in children.
In general, viral infections of the CNS are much more common than
bacterial infections, which, in turn, are more common than fungal and
parasitic infections; regardless of etiology, most patients with CNS
infection have similar clinical manifestations.
Infection of the CNS may be diffuse or focal. Meningitis and encephalitis
are examples of diffuse infection. Meningitis implies primary
involvement of the meninges, whereas encephalitis indicates brain
parenchymal involvement. Because these anatomic boundaries are often
not distinct, many patients have evidence of both meningeal and
parenchymal involvement and should be considered to have
meningoencephalitis. Brain abscess is the best example of a focal
infection of the CNS.
Acute Bacterial Meningitis beyond the Neonatal Period
Bacterial meningitis is one of the most potentially serious infections
occurring in infants and older children.
The most common causes of bacterial meningitis in children older than 1
mo. of age in the United States are Streptococcus pneumoniae and
Neisseria meningitidis. Bacterial meningitis caused by S. pneumonia and
Haemophilus influenzae type b has become much less common in
developed countries since the introduction of universal immunization
against these pathogens beginning at 2 mo of age.
A major risk factor for meningitis is the lack of immunity to specific
pathogens associated with young age. Additional risks include recent
colonization with pathogenic bacteria, close contact (household, daycare
centers, college dormitories, military barracks) with individuals having
invasive disease caused by N. meningitidis or H. influenza type b,
crowding, poverty, black or Native American race, and male gender. The
mode of transmission is probably person-to-person contact through
respiratory tract secretions or droplets.
Defects of the complement system
(C5-C8)
are associated with recurrent
meningococcal infection, and defects of the
properdin
system are
associated with a significant risk of lethal meningococcal disease.
A congenital or acquired CSF leak across a mucocutaneous barrier, such
as a lumbar dural sinus, or CSF leakage through a rupture of the
By Dr. R
RUSSUL
meninges as a result of a basal skull fracture, is associated with an
increased risk of pneumococcal meningitis.
PATHOLOGY AND PATHOPHYSIOLOGY
A meningeal purulent exudate of varying thickness may be distributed
around the cerebral veins, venous sinuses, convexity of the brain, and
cerebellum, and spinal cord. Ventriculitis with bacteria and inflammatory
cells in ventricular fluid may be present (more often in neonates), as may
subdural effusions and, rarely, empyema. Cerebral infarction, resulting
from vascular occlusion because of inflammation, vasospasm, and
thrombosis, is a frequent sequela. Inflammation of spinal nerves and roots
produces meningeal signs, and inflammation of the cranial nerves
produces cranial neuropathies of optic, oculomotor, facial, and auditory
nerves. Increased ICP is a result of cell death (cytotoxic cerebral
edema), cytokine-induced increased capillary vascular permeability
(vasogenic cerebral edema), and, possibly, increased hydrostatic pressure
(interstitial cerebral edema) after obstructed reabsorption of CSF in the
arachnoid villus or obstruction of the flow of fluid from the ventricles.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH)
may produce excessive water retention and potentially increase the risk of
elevated ICP.
Hydrocephalus can occur as an acute complication of bacterial
meningitis. It most often takes the form of a communicating
hydrocephalus caused by adhesive thickening of the arachnoid villi
around the cisterns at the base of the brain. Raised CSF protein levels are
partly a result of increased vascular permeability of the blood–brain
barrier and the loss of albumin-rich fluid from the capillaries and veins
traversing the subdural space. Continued transudation may result in
subdural effusions, usually found in the later phase of acute bacterial
meningitis. Hypoglycorrhachia (reduced CSF glucose levels) is
attributable to decreased glucose transport by the cerebral tissue.
Clinical features
The signs and symptoms of meningitis are related to the nonspecific
findings associated with a systemic infection and to manifestations of
meningeal irritation. Nonspecific findings include fever, anorexia and
poor feeding, headache, symptoms of upper respiratory tract infection,
myalgias, arthralgias, tachycardia, hypotension, and various cutaneous
signs, such as petechiae, or an erythematous macular rash.
Meningeal irritation is manifested as nuchal rigidity, back pain, Kernig
sign (flexion of the hip 90 degrees with subsequent pain with extension of
the leg), and Brudzinski sign (involuntary flexion of the knees and hips
after passive flexion of the neck while supine).
In children, particularly in those younger than 12-18 mo, Kernig and
Brudzinski signs are not consistently present. Increased ICP is suggested
by headache, emesis, bulging fontanel or diastasis (widening) of the
sutures, oculomotor (anisocoria, ptosis) or abducens nerve paralysis,
hypertension with bradycardia, apnea or hyperventilation, decorticate or
decerebrate posturing, stupor, coma, or signs of herniation. Papilledema
is uncommon in uncomplicated meningitis and should suggest a more
chronic process, such as the presence of an intracranial abscess, subdural
empyema, or occlusion of a dural venous sinus. Focal neurologic signs
usually are a result of vascular occlusion.
Cranial neuropathies of the ocular, oculomotor, abducens, facial, and
auditory nerves may also be the result of focal inflammation. Overall,
approximately 10-20% of children with bacterial meningitis have focal
neurologic signs.
Seizures (focal or generalized) caused by cerebritis, infarction, or
electrolyte disturbances occur in 20-30% of patients with meningitis.
Seizures that occur on presentation or within the 1st 4 days of onset are
usually of no prognostic significance. Seizures that persist after the 4th
day of illness and those that are difficult to treat may be associated with a
poor prognosis.
Alterations of mental status are common among patients with
meningitis and may be the consequence of increased ICP, cerebritis, or
hypotension; manifestations include irritability, lethargy, stupor,
obtundation, and coma. Comatose patients have a poor prognosis.
Additional manifestations of meningitis include photophobia.
Diagnosis
The diagnosis of acute pyogenic meningitis is confirmed by analysis of
the CSF, which typically reveals microorganisms on Gram stain and
culture, a neutrophilic pleocytosis, elevated protein, and reduced glucose
concentrations. LP should be performed when bacterial meningitis is
suspected. Contraindications for an mimmediate LP include (1) evidence
of increased ICP (other than a bulging fontanel), such as 3rd or 6th
cranial nerve palsy with a depressed level of consciousness, or
hypertension and bradycardia with respiratory abnormalities (2) severe
cardiopulmonary compromise requiring prompt resuscitative measures
for shock or in patients in whom positioning for the LP would further
compromise cardiopulmonary function; and (3) infection of the skin
overlying the site of the LP. Thrombocytopenia is a relative
contraindication for LP.
LP may be performed after increased ICP has been treated or a brain
abscess has been excluded. Normal healthy neonates may have as many
as 30 leukocytes/mm3 (usually <10), but older children without viral or
bacterial meningitis have <5 leukocytes/mm3 in the CSF; in both age
groups there is a predominance of lymphocytes or monocytes. Pleocytosis
with a lymphocyte predominance may be present during the early stage of
acute bacterial meningitis; conversely, neutrophilic pleocytosis may be
present in patients in the early stages of acute viral meningitis. The
Gram stain is positive in 70-90% of patients with untreated bacterial
meningitis.
Latex agglutination
:
Helpful in partially treated meningitis
Specific but not that sensitive
Strep pneumo – 96% specific, 70 -100 %
sensitive.
PCRs are available for neisseria and pneumococcus
Both are sensitive and specific
,
DNA load correlates with mortality for
Neisseria.
Blood cultures should be performed in all patients with suspected
meningitis. Blood cultures reveal the responsible bacteria in up to 80-
90% of cases of meningitis.
Peripheral WBC, CSF lactate, procalcitonin, and various cytokines are
used to differentiate bacterial (usually elevated) from viral causes of
meningitis.
TREATMENT
The therapeutic approach to patients with presumed bacterial meningitis
depends on the nature of the initial manifestations of the illness.
A child with 1)rapidly progressing disease of less than 24 hr duration, or
2) have a more protracted subacute course and become ill over a 4-7 day
period; in the absence of increased ICP, should receive antibiotics as
soon as possible after an LP is performed. If there are signs of increased
ICP or focal neurologic findings, antibiotics should be given without
performing an LP and before obtaining a CT scan. Increased ICP should
be treated simultaneously.
Initial Antibiotic Therapy
The initial (empirical) choice of therapy for meningitis in
immunocompetent infants and children is primarily influenced by the
antibiotic susceptibilities of S. pneumonia . In the United States, 25-50%
of strains of S. pneumoniae are currently resistant to penicillin;
vancomycin (60 mg/kg/24 hr), given every 6 hr plus cefotaxime (300
mg/kg/24 hr, given every 6 hr) or ceftriaxone (100 mg/kg/24 hr
administered once per day or 50 mg/kg/dose, given every 12 hr) for 10-14
days.
Most strains of N. meningitidis are sensitive to penicillin and
cephalosporins for 5-7 days.
For H. influenzae type b, Approximately 30-40% of isolates of H.
influenzae type b produce β-lactamases and, therefore, are resistant to
ampicillin. These β-lactamase–producing strains are sensitive to the
extended-spectrum cephalosporins.
cefotaxime (300 mg/kg/24 hr, given every 6 hr) or ceftriaxone (100
mg/kg/24 hr administered once per day or 50 mg/kg/dose, given every 12
hr) for 7-10 days should also be used in initial empirical therapy.
If L. monocytogenes infection is suspected, as in young infants or those
with a T-lymphocyte deficiency, ampicillin (200 mg/kg/24 hr, given
every 6 hr) also should also be given because cephalosporins are inactive
against L. monocytogenes.
If patient immunecompromised and Gram negative bacterial meningitis
are suspected, initial therapy might include ceftazedime and an
aminoglycoside ore meropenem.
Repeat examination of CSF is indicated in some neonates, in all patients
with Gram-negative bacillary meningitis, or in infection caused by a β-
lactam–resistant S. pneumoniae. The CSF should be sterile within 24-48
hr of initiation of appropriate antibiotic therapy.
Corticosteroids
Rapid killing of bacteria in the CSF effectively sterilizes the meningeal
infection but releases toxic cell products after cell lysis (cell wall
endotoxin) that precipitate the cytokine-mediated inflammatory cascade
may produce additional neurologic injury with worsening of CNS signs
and symptoms. Among children with meningitis caused by H. influenza
type b, corticosteroid recipients have a shorter duration of fever, lower
CSF protein and lactate levels, and a reduction in sensorineural hearing
loss.
Supportive Care
Pulse rate, blood pressure, and
respiratory rate should be monitored
frequently. Neurologic assessment, including pupillary reflexes, level of
consciousness, motor strength, cranial nerve signs, and evaluation for
seizures, should be made frequently in the 1st 72 hr, when the risk of
neurologic complications is greatest. Important laboratory studies include
an assessment of blood urea nitrogen; serum sodium, chloride, potassium,
and bicarbonate levels; urine output and specific gravity; complete blood
and platelet counts.
Seizures are common during the course of bacterial meningitis.
Immediate therapy for seizures includes intravenous diazepam (0.1- 0.2
mg/kg/dose), and careful attention paid to the risk of respiratory
suppression. Serum glucose, calcium, and sodium levels should be
monitored. After immediate management of seizures, patients should
receive phenytoin (15-20 mg/
kg loading dose, 5 mg/kg/24 hr
maintenance) to reduce the likelihood of recurrence. Phenytoin is
preferred to phenobarbital because it produces less CNS depression and
permits assessment of a patient’s level of consciousness.
Fever associated with bacterial meningitis usually resolves within 5-7
days of the onset of therapy. Prolonged fever (>10 days) is noted in
approximately 10% of patients. Prolonged fever is usually caused by
intercurrent viral infection, nosocomial or secondary bacterial infection,
thrombophlebitis, or drug reaction. Secondary fever refers to the
recrudescence of elevated temperature after an afebrile interval.
Nosocomial infections are especially important to consider in the
evaluation of these patients. Pericarditis or arthritis may occur in patients
being treated for meningitis, especially that caused by N. meningitidis.
Involvement of these sites may result either from bacterial dissemination
or from immune complex deposition.
Thrombocytosis, eosinophilia, and anemia may develop during therapy
for meningitis. Anemia may be a result of hemolysis or bone marrow
suppression. Disseminated intravascular coagulation is most often
associated with the rapidly progressive pattern of presentation and is
noted most commonly in patients with shock and purpura.
Encephalopathy describes a diffuse brain disorder, in which two of the
followings are present:
1. Altered state of consciousness, 2. Altered cognition or personality.
3. Seizures. Encephalitis: encephalopathy plus CSF pleocytosis.
Viral Meningoencephalitis (ME)
Viral ME is an acute inflammatory process involving the meninges and,
to a variable degree, brain tissue. These infections are relatively common
and may be caused by a number of different agents. The CSF is
characterized by pleocytosis and the absence of microorganisms on Gram
stain and routine bacterial culture. In most instances, the infections are
self-limited. In some cases, substantial morbidity and mortality occur.
Enteroviruses are the most common cause of viral ME. Several members
of the herpes family of viruses can cause ME. Herpes simplex virus
(HSV) type 1 is an important cause of severe, sporadic encephalitis in
children and adults. Brain involvement usually is focal; progression to
coma and death occurs in 70% of cases without antiviral therapy.
Varicella-zoster virus may cause CNS infection in close temporal
relationship with chickenpox. Mumps is a common pathogen in regions
where mumps vaccine is not widely used.
Mumps ME is mild, but deafness from damage of the 8th cranial nerve
may be a sequela.
ME is caused occasionally by respiratory viruses (adenovirus, influenza
virus, parainfluenza virus), rubeola, rubella, or rabies; it may follow live
virus vaccinations against polio, measles, mumps, or rubella.
The progression and severity of disease are determined by the relative
degree of meningeal and parenchymal involvement, which, in part, is
determined by the specific etiology. The clinical course resulting from
infection with the same pathogen varies widely.
The onset of illness is generally acute, although CNS signs and symptoms
are often preceded by a nonspecific febrile illness of a few days’ duration.
The presenting manifestations in older children are headache and
hyperesthesia, and in infants, irritability and lethargy. Headache is most
often frontal or generalized. Fever, nausea and vomiting, photophobia,
and pain in the neck, back, and legs are common. As body temperature
increases, there may be mental dullness, progressing to stupor in
combination with bizarre movements and convulsions. Focal neurologic
signs may be stationary, progressive, or fluctuating. Loss of bowel and
bladder control may occur. Examination often reveals nuchal rigidity
without significant localizing neurologic changes, at least at the onset.
The diagnosis of viral encephalitis is usually made on the basis of the
clinical presentation of nonspecific prodrome followed by progressive
CNS symptoms. The diagnosis is supported by examination of the CSF,
which usually shows a mild mononuclear predominance. Other tests of
potential value in the evaluation of patients with suspected viral ME
include an electroencephalogram (EEG) and neuroimaging studies.
With the exception of the use of acyclovir for HSV encephalitis,
treatment of viral meningoencephalitis is supportive.
Guillain-Barre Syndrome
Guillain-Barre syndrome is a postinfectious polyneuropathy involving
mainly motor but sometimes also sensory and autonomic nerves. This
syndrome affects people of all ages and is not hereditary.
Clinical Manifestations
The paralysis usually follows a nonspecific viral infection by about 10
days. The original infection might have caused only gastrointestinal or
respiratory tract symptoms.
Weakness usually begins in the lower extremities and progressively
involves the trunk, the upper limbs, and finally the bulbar muscles, a
pattern known as Landry ascending paralysis. Proximal and distal
muscles are involved relatively symmetrically, but asymmetry is found in
9% of patients. The onset is gradual and progresses over days or weeks.
Particularly in cases with an abrupt onset, tenderness on palpation and
pain in muscles is common in the initial stages. Affected children are
irritable. Weakness can progress to inability or refusal to walk and later to
flaccid tetraplegia.
Bulbar involvement occurs in about half of cases. Respiratory
insufficiency can result. Dysphagia and facial weakness are often
impending signs of respiratory failure. They interfere with eating and
increase the risk of aspiration. The facial nerves may be involved. Some
young patients exhibit symptoms of viral meningitis or
meningoencephalitis. Extraocular muscle involvement is rare, but in an
uncommon variant, oculomotor and other cranial neuropathies are severe
early in the course. Miller-Fisher syndrome consists of acute external
ophthalmoplegia, ataxia, and areflexia. Papilledema is found in some
cases, although visual impairment is not clinically evident. Urinary
incontinence or retention of urine is a complication in about 20% of cases
but is usually transient.
Tendon reflexes are lost, usually early in the course. The autonomic
nervous system is also involved in some cases. Lability of blood pressure
and cardiac rate, postural hypotension, episodes of profound bradycardia,
and occasional asystole occur.
Laboratory Findings and Diagnosis
CSF studies are essential for diagnosis. The CSF protein is elevated to
more than twice the upper limit of normal, glucose level is normal, and
there is no pleocytosis. Fewer than 10 white blood cells/mm
3
are found.
The results of bacterial cultures are negative, and viral cultures rarely
isolate specific viruses. The dissociation between high CSF protein and a
lack of cellular response in a patient with an acute or subacute
polyneuropathy
is
diagnostic
of
Guillain-Barre
syndrome.
Motor NCVs are greatly reduced, and sensory nerve conduction time is
often slow. Electromyography (EMG) shows evidence of acute
denervation of muscle. Serum creatine kinase (CK) level may be mildly
elevated or normal.
Treatment
Patients in early stages of this acute disease should be admitted to the
hospital for observation because the ascending paralysis can rapidly
involve respiratory muscles during the next 24 hr. Respiratory effort
(negative inspiratory force, spirometry) must be monitored to prevent
respiratory failure and respiratory arrest. Patients with slow progression
might simply be observed for stabilization and spontaneous remission
without treatment. Rapidly progressive ascending paralysis is treated with
intravenous immunoglobulin (IVIG), administered for 5 days.
Plasmapheresis and/or immunosuppressive drugs are alternatives if IVIG
is ineffective. Steroids are not effective. Combined administration of
immunoglobulin and interferon is effective in some patients. Supportive
care, such as respiratory support, prevention of decubiti in children with
flaccid tetraplegia, and treatment of secondary bacterial infections, is
important.
Prognosis
The clinical course is usually benign, and spontaneous recovery begins
within 2-3 wk. Most patients regain full muscular strength, although some
are left with residual weakness. The tendon reflexes are usually the last
function to recover. Improvement usually follows a gradient opposite the
direction of involvement: bulbar function recovering first, and lower
extremity weakness resolving last. Bulbar and respiratory muscle
involvement can lead to death if the syndrome is not recognized and
treated. Although prognosis is generally good and the majority of
children recover completely, 3 clinical features are predictive of poor
outcome with sequelae: cranial nerve involvement, intubation, and
maximum disability at the time of presentation.