Focal Infections of the Central Nervous System

Brain Abscess Etiology

Brain abscess is a focal infection of the brain parenchyma and is an uncommon pediatric infection. Predisposing conditions and infecting organisms differ according to the age of the patient (Table 1). In neonates, a brain abscess may occur as a sequela of Gram-negative or group B streptococcal meningitis. Seventy-five percent of cases of meningitis in neonates due to Citrobacter diversus have been associated with brain abscesses. In the school-aged child the peak incidence occurs in children ages 4 to 7 years old. In adolescence, brain abscesses occur as complications of sinusitis.

Bacteria may reach the brain parenchyma as a result of hematogenous spread from a remote site. However, bacteremia rarely results in a brain abscess because of the impermeable capillary-endothelial tight junctions of the blood-brain barrier. In children, hematogenous seeding of the brain occurs secondary to cyanotic heart disease with a hemodynamically significant left-to-right shunt. Tetralogy of Fallot and transposition of the great vessels have been associated with the greatest risk for subsequent brain abscess formation. Pyogenic lung infection, bronchiectasis, acute endocarditis with septic embolization, dental abscess and abdominal abscess represent less common potential sources for hematogenous spread.

Spread from a contiguous site of infection is another potential mechanism of brain abscess formation. In children, the middle ear and sinuses are the most common sites of the primary infection. Spread of infection to the brain occurs through

Table 1. Brain abscess formation in children according to age group

Age Group Predisposing Condition Location

Table 1. Brain abscess formation in children according to age group

Age Group Predisposing Condition Location

Neonates

meningitis

multiple abscesses

School age

chronic otitis media

temporal lobe

mastoiditis

cerebellum

congenital heart disease

multiple abscesses

Adolescence

sinusitis

frontal lobe

necrotic bone that is also infected, or via the valveless veins that drain the sinuses and middle ear and connect with the intracranial venous system. Less commonly, brain abscesses occur following neurosurgery, head trauma, or as a consequence of focal infections of the eye, face or scalp.

Clinical Features

The clinical presentation of a patient with a brain abscess depends on the location of the lesion and predisposing factors. Symptoms can be insidious until the abscess enlarges and increases intracranial pressure. Headache, fever and vomiting are the most common presenting clinical manifestations. Neurological abnormalities, such as focal signs, seizures and mental status changes, are present in less than half of pediatric patients.

Management

Computed tomography (CT) with contrast and magnetic resonance imaging (MRI) with intravenous gadolinium have improved the diagnosis of brain abscess and facilitated exact localization for surgical drainage. Early in the disease, CT may be normal or demonstrate nonspecific cerebral edema. A mature abscess appears as a well-demarcated, annular lesion with a hypodense center and a surrounding ring of enhancement. Cerebral edema also appears hypodense on CT and may surround the abscess. CT is not specific for brain abscess and does not distinguish it from tumor, granuloma, or infarct. MRI is the preferred imaging modality because it provides greater definition of the abscess components, distinguishes pyogenic material from CSF, and may detect small lesions not visualized on CT (Chapter 2, Fig. 10). Lumbar puncture is contraindicated until intracranial pressure is evaluated by CT or MRI.

Management includes surgical drainage of the abscess and antibiotic therapy. Patients who are clinically stable, have lesions less than 3 mm in diameter, and have been ill for less than 2 weeks duration may be considered for medical management. Additionally, patients with multiple abscesses or lesions not easily drained by surgery may be considered for a prolonged course of antibiotics without surgical drainage.

Surgical drainage is beneficial for treating increased intracranial pressure and for obtaining abscess specimens for Gram-stain, aerobic and anaerobic culture, and special stains and cultures as dictated by the clinical situation. Culture of pus from the abscess yields a pathogen in three-quarters of cases; in contrast, CSF culture is negative more than 90% of the time.

Empiric antibiotic therapy is directed against the likely organisms causing the primary infection (Table 2). In a large series of pediatric brain abscesses, S. aureus was the most common pathogen and was isolated from 26% of bacterial isolates from 86 infants and children. Streptococci, Gram-negative aerobic bacilli, and anaerobes comprise the remainder of the pathogens isolated in this series. Thirty percent of abscesses are polymicrobial, therefore empiric regimens consist of several parenteral antibiotics. If a pathogen is isolated, antimicrobial therapy is changed accordingly. Intravenous therapy is continued for 6 to 8 weeks, but clinical response and evidence of radiographic improvement on serial imaging studies dictate length of therapy.

The use of corticosteroids is controversial because the decrease of central nervous system (CNS) inflammation as a result of steroid therapy may also act to

Table 2. Empiric antibiotic therapy for focal intracranial infection according to predisposing condition

Condition

Likely Organisms

Empiric Regimen

Meningitis

Neonates: group B streptococcus, E. coli, Listeria monocytogenes

Infants and children: S.

pneumoniae, Neisseria meningitidis, H. influenzae

Microaerophilic streptococci, Haemophilus spp S. aureus, anaerobes, streptococci, Enterobacteriaceae

S. aureus, anaerobes, streptococci, Enterobacteriaceae

S. aureus, streptococci, Enterobacteriaceae S. aureus, coagulase negative staphylococci

S. aureus, streptococci

Immunocompromised S. aureus, streptococci, host Enterobacteriaceae, unusual organisms (fungi, Toxoplasma gondii, Nocardia spp)

Unknown

Cyanotic congenital heart disease Sinusitis

Otitis media

Post-traumatic

Post-neurosurgical

Endocarditis

Ampicillin + gentamicin or cefotaxime

Vancomycin + ceftriaxone or cefotaxime

Ceftriaxone or cefotaxime +metronidazole

Nafcillina + ceftriaxone or cefotaxime11 + metronidazole

Nafcillina + ceftriaxone or cefotaxime1 + metronidazole

Nafcillina + ceftriaxone or cefotaxime

Vancomycin + ceftriaxone or cefotaxime Nafcillina + gentamicin

Nafcillina + ceftriaxone or cefotaximec + metronidazole + amphotericin

Nafcillina +ceftriaxone or cefotaxime+

metronidazole a Substitute vancomycin if rate of methicillin-resistant S. aureus is high. b Consider substitution of ceftazidime for Pseudomonas aeruginosa in chronic sinusitis or otitis media. c Consider substitution of ceftazidime for Pseudomonas aeruginosa

reduce antibiotic penetration of the meninges. Steroids are not recommended routinely, and should be reserved for the treatment of life-threatening cerebral edema that may accompany brain abscesses.

Brain abscesses in an immunocompromised host deserve special consideration. The inflammatory response to the infection is often diminished, and presentation may be indolent. CT or MRI are less likely to have the typical appearance of a ring-enhancing lesion. Unusual organisms, such as Nocardia species, fungi such as Candida species and Aspergillus species, and Toxoplasma gondii (particularly in patients infected with HIV), should be considered. Thus, surgical aspiration or biopsy of infected material is critical in making a definitive diagnosis and initiating appropriate therapy.

Subdural Empyema Etiology

A subdural empyema occurs when pus forms between the dura and arachnoid matter. In infants, this infection occurs as a complication of bacterial meningitis. Paranasal sinusitis is a common predisposing condition in older children and adolescents. The typical patient is a male teen or young adult with frontal sinusitis. Less common sources of infection include otitis media, mastoiditis, complications of neurosurgery or head trauma, and metastatic bacteremia from a distant focus.

Subdural empyema secondary to sinusitis develops when microorganisms enter the dural venous system through mucosal veins of the infected sinus. Meningitis-associated subdural empyema occurs when the organism seeds a sterile subdural effusion. Infection originating in the middle ear spreads through diseased bone or between sutures in the bone. Seventy-five percent of patients with subdural empyema will have involvement of both cerebral hemispheres.

Clinical Features

Subdural empyema in infants will result in a prolonged fever, bulging fontanelle, lethargy, increasing head circumference and vomiting during the course of antibiotic treatment for meningitis. Older children and adolescents may appear to have a toxic infection, with fever, headache, focal neurologic signs and meningismus following nonspecific symptoms of sinusitis or ear infection. Signs of increased intrac-ranial pressure (vomiting, mental status changes) may also be present.

Management

Neuroimaging by CT or MRI is used for diagnosis, but MRI with gadolinium is superior for localization and differentiation of fluid (e.g., blood, pus, or sterile effusion). Subdural empyema appears as a hypodense collection that displaces the dura and arachnoid. A shift of the midline may also be present. The imaging study should be examined to determine the primary source of infection, such as sinusitis, as well.

The management of subdural empyema is surgical drainage by burr hole or open craniotomy and intravenous antibiotics. Subdural taps can be performed in infants with an open anterior fontanelle. Repeat imaging by CT or MRI may identify remaining areas of undrained, loculated, or reaccumulated pus and multiple drainage procedures may be required.

Culture of operative fluid yields the infecting organism 90% of the time; CSF and blood cultures are rarely positive. Empiric antibiotics are dependent on the underlying condition giving rise to the empyema (Table 2). Infection arising from sinus disease often is polymicrobial. When the predisposing condition is meningitis, the same organism causes both infections. Streptococcus pneumoniae is the most common organism that causes meningitis and subsequent subdural empyema in children beyond the neonatal period. H. influenzae meningitis is rarely seen in children in most industrial countries because of widespread use of an effective conjugate vaccine. N. meningitidis meningitis has rarely been associated with the development of subdural empyema.

Sinus-associated subdural empyema is associated with a high rate of complications, such as simultaneous second site of infection (brain abscess, septic venous

Table 3. Clinical features associated with septic thrombosis of the dural venous sinuses

Location

Predisposing Symptoms

Clinical

Signs

Microbiology Presentation

Cavernous sinus

Superficial facial infection Paranasal sinusitis:

sphenoid Dental infection

Lateral sinus

Acute or chronic otitis media Mastoiditis

Superior Meningitis sagittal Paranasal sinusitis: sinus ethmoid, maxillary

Acute presentation Eye complaints: ptosis, proptosis, periorbital edema, papilledema Cranial nerve (CN)

lll-VI palsy Indolent presentation CN Vl palsy Subacute presentation

Temporal or occipital headache Nausea, vomiting, vertigo Abnormal ear exam Unilateral CN V, VI palsy

Acute presentation Headache, nausea, vomiting, seizure Obstruction of CSF resorption: increased intracranial pressure

S. aureus

Streptococci

Anaerobes

Streptococci Gram-negative bacilli

S. aureus Anaerobes

S. pneumoniae S. aureus Streptococci Anaerobes thrombosis, or epidural abscess), and reaccumulation of infection following drainage. A secondary source of infection should be considered if a patient does not respond to therapy or deteriorates during the course of treatment.

Septic Thrombosis of the Dural Venous Sinuses

Septic thrombosis is a consequence of extension of infection to an intracranial dural sinus. The primary infection spreads along emissary veins or via osteomyelitic bone to the adjacent dural sinus. Septic thrombosis most often involves the cavernous sinus, lateral sinus, or the superior sagittal sinus and the clinical features vary according to the site of involvement (Table 3).

MRI reveals increased signal in the area of the involvement and defines the intraparenchymal anatomy. Because the air sinuses, middle ear and mastoids are often the primary site of infection in pediatric patients, these locations should be included in the imaging study. MRI with angiography (MRA) is the diagnostic procedure of choice, and demonstrates decreased or absent blood flow in the affected sinus or vessel. CT is superior to MRI for defining bone disease, but will not detect thrombosis or decreased flow.

CSF abnormalities vary. Over 90% of patients with cavernous sinus thrombosis have an abnormal CSF profile that is consistent with meningitis or a parameningeal

focus (pleocytosis, normal glucose, elevated protein and sterile culture). Seventy-five percent of patients with lateral venous thrombosis have an elevated opening pressure.

Empiric antibiotics are directed toward the likely organisms causing the underlying infection (Table 2). Surgical drainage of the source or associated abscesses may be required. Anticoagulation therapy with heparin is generally accepted as adjunc-tive therapy for cavernous sinus and lateral sinus thrombosis.

Epidural Abscess Cranial Epidural Abscess

Epidural abscess is a focal collection of pus outside the dura matter in the cranial or spinal epidural space. Cranial epidural abscess can be a complication of sinusitis, otitis media, mastoiditis, or head trauma, and is rare in children younger than 12 years of age. When the abscess develops secondary to frontal sinusitis and surrounding osteomyelitis, the infection is called Pott's puffy tumor. The dura adheres tightly to the skull. Purulent material collects slowly in the epidural space so symptoms often develop over weeks to months. When the abscess reaches sufficient size, increased intracranial pressure may develop. Clinical presentation commonly includes fever, headache, nausea, vomiting, change in mental status, or focal neurological signs.

MRI is the imaging procedure of choice. Management consists of a combination of neurosurgical drainage and prolonged antibiotic therapy. Empiric antibiotic therapy is guided by the underlying predisposing condition, as with the other focal intracra-nial infections (Table 2).

Spinal Epidural Abscess

Epidural abscess occurs more frequently in the spine than the cranium, and is caused by hematogenous spread from a distant site of infection or contiguous spread following penetrating back trauma or vertebral osteomyelitis. In children, the lumbar and cervical spine are the most common sites of involvement.

Clinical presentation may include fever, back pain, headache and meningismus. As the infection progresses, nerve root and spinal cord compression develops with focal motor and sensory deficits specific to the involved spinal cord level. Further progression leads to total paralysis.

MRI with gadolinium is the preferred imaging modality for diagnosis and identifies abnormalities in the bone (vertebral osteomyelitis) and intramedullary spinal cord lesions as well as the abscess. Myelography may also be used for diagnosis if MRI is not available.

Management consists of immediate surgical drainage of the abscess by laminec-tomy or CT-guided aspiration. The abscess fluid should be sent for Gram-stain and culture. S. aureus is the most frequently isolated pathogen, so an antistaphylococcal penicillin, such as nafcillin, is appropriate empiric therapy. In penicillin-allergic patients, or in institutions with a high rate of infection with methicillin-resistant S. aureus, vancomycin is indicated. Antimicrobial therapy is changed according to the susceptibility of the isolated pathogen and continued parenterally for 3 to 4 weeks. When vertebral osteomyelitis accompanies the epidural abscess, 6 to 8 weeks of intravenous antibiotics is recommended.

Vertebral Osteomyelitis Etiology

Involvement of the vertebral bodies occurs in 1% to 2% of children with osteomyelitis. Bacteria reach the vertebral body via hematogenous seeding but a source is seldom identified. S. aureus is isolated in about 65% of cases of pediatric vertebral osteomyelitis, followed by Salmonella species (particularly in patients with hemoglo-binopathies). Other Gram-negative bacilli, such as E. coli and Psuedomonas aeruginosa, are rarely seen in children. Blood cultures are positive in 30% to 50% of cases. CT-guided vertebral biopsy for culture is indicated if the blood cultures are negative.

Clinical Features

Clinical presentation varies. Infants less than 3 months of age may appear septic whereas older children have an indolent presentation and nonspecific symptoms. About 50% will present with fever and localizing pain in the back or chest. About 20% of patients have a preceding history of back trauma. Neurological deficits are present in about 20% of patients at the time of presentation.

Management

Plain films of the spine may be normal if taken early in the course of disease, or may demonstrate erosion of the bone or disc space collapse if the infection has progressed. MRI is highly sensitive and specific and demonstrates increased signal in the disc space and adjacent vertebral bodies, and neural compression by bone or soft tissue. CT is superior to MRI for the demonstration of the extent of bony involvement.

Most children without neurological deficits respond to medical management alone. Surgery is indicated for patients with spinal cord compression, worsening symptoms despite optimal medical management, associated paraspinous abscess, or necrotic bone. Empiric antibiotic therapy consists of nafcillin or vancomycin (reserved for use in patients with penicillin allergy or hospitals with a high-rate of methicillin-resistant S. aureus). Antibiotics are continued for 6 to 8 weeks, with intravenous therapy for at least 4 weeks.

It may be difficult to differentiate discitis, which refers to disc space inflammation involving the intervertebral discs and the end plates of the vertebral bodies, from vertebral osteomyelitis. Both conditions have a gradual onset with localized back pain as a presenting symptom. However, compared to patients with osteomyelitis, those with discitis appear well, are afebrile or have low grade fever, and respond to bed rest or immobilization. Blood cultures are rarely positive. However, antibiotic therapy is indicated if a pathogen (usually S. aureus) is isolated from blood culture. If blood cultures are sterile but the patient does not respond to bed rest or clinically worsens, empiric treatment with nafcillin is recommended.

Post-Traumatic Meningitis

Etiology

Disruption of the dural barrier secondary to trauma creates an entryway for organisms into the CNS and increases the risk of meningitis by 10 to 20 fold. Dural

tears are likely to occur in association with fractures of the base of the cranium and the thin bone of the roof of the paranasal sinuses.

Meningitis develops acutely in the first week following trauma or several years following the primary event. Clinical presentation may include fever, headache, seizure, or a change in mental status. CSF rhinorrhea or otorrhea may be present. In the acute setting, fever, seizure and altered mental status may be present already as a result of the trauma, so a high index of suspicion should be maintained.

Management

Diagnosis is made by high-resolution CT or MRI. Thin coronal cuts or intrath-ecal contrast may be necessary to identify the defect. Plain radiography is insensitive for diagnosis unless a large defect is present. The presence of glucose or p-transferrin in otorrhea or rhinorrhea confirms the presence of a CSF leak.

CSF should be obtained for gram stain and culture. S. pneumoniae is isolated in 50% of cases. Organisms that normally reside in the upper respiratory tract, such as H. influenzae, N. meningititis and streptococci, cause the remainder of cases. S. aureus and Gram-negative bacilli rarely cause post-traumatic meningitis except in patients with prolonged hospitalization or penetrating wounds.

Treatment consists of antibiotic therapy and repair of the dural tear. Empiric antibiotics are directed against pneumococcus and consist of ceftriaxone and vanco-mycin. Ceftriaxone or high-dose penicillin should not be used alone because of intermediate and high-level resistance of S. pneumonia to beta-lactam antibiotics. Vancomycin is given at high doses (15mg/kg/dose every 6 hours) to maximize CNS penetration. For late-onset disease, nafcillin plus ceftriaxone or ceftazidime are given empirically to target S. aureus and Gram-negative bacilli. Vancomycin should be used in place of nafcillin in patients with severe beta-lactam allergy, or when infection with methicillin-resistant staphylococci is likely. The antibiotic regimen is altered according to the susceptibility profile once the pathogen is known.

Prophylactic antibiotics have been used following basilar skull fracture because 25% of patients with this fracture develop meningitis. However, the efficacy of prophylaxis in this setting is unproven, and exposure to antibiotics may alter normal flora and increase the likelihood of developing colonization or infection with resistant organisms. Therefore, prophylactic antibiotics are not recommended, but patients with basilar skull fractures should be diligently monitored for signs of infection. Empiric antibiotics are initiated if meningitis is suspected.

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