Harrison's Neurology in Clinical Medicine, 3rd Edition

CHAPTER 40. MENINGITIS, ENCEPHALITIS, BRAIN ABSCESS, AND EMPYEMA

Karen L. Roos Image Kenneth L. Tyler

Acute infections of the nervous system are among the most important problems in medicine because early recognition, efficient decision-making, and rapid institution of therapy can be lifesaving. These distinct clinical syndromes include acute bacterial meningitis, viral meningitis, encephalitis, focal infections such as brain abscess and subdural empyema, and infectious thrombophlebitis. Each may present with a nonspecific prodrome of fever and headache, which in a previously healthy individual may initially be thought to be benign, until (with the exception of viral meningitis) altered consciousness, focal neurologic signs, or seizures appear. Key goals of early management are to emergently distinguish between these conditions, identify the responsible pathogen, and initiate appropriate antimicrobial therapy.


APPROACH TO THE

PATIENT Meningitis, Encephalitis, Brain Abscess, and Empyema

(Fig. 40-1) The first task is to identify whether an infection predominantly involves the subarachnoid space (meningitis) or whether there is evidence of either generalized or focal involvement of brain tissue in the cerebral hemispheres, cerebellum, or brainstem. When brain tissue is directly injured by a viral infection, the disease is referred to as encephalitis, whereas focal infections involving brain tissue are classified as either cerebritis or abscess, depending on the presence or absence of a capsule.

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FIGURE 40-1

The management of patients with suspected CNS infection. ADEM, acute disseminated encephalomyelitis; AFB, acid-fast bacillus; Ag, antigen; CSF, cerebrospinal fluid; CT, computed tomography; CTFV, Colorado tick fever virus; CXR, chest x-ray; DFA, direct fluorescent antibody; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis virus; MNCs, mononuclear cells; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PMNs, polymorphonuclear leukocytes; PPD, purified protein derivative; TB, tuberculosis; VDRL, Venereal Disease Research Laboratory; VZV, varicella-zoster virus; WNV, West Nile virus.

Nuchal rigidity (“stiff neck”) is the pathognomonic sign of meningeal irritation and is present when the neck resists passive flexion. Kernig’s and Brudzinski’s signs are also classic signs of meningeal irritation. Kernig’s sign is elicited with the patient in the supine position. The thigh is flexed on the abdomen, with the knee flexed; attempts to passively extend the knee elicit pain when meningeal irritation is present. Brudzinski’s sign is elicited with the patient in the supine position and is positive when passive flexion of the neck results in spontaneous flexion of the hips and knees. Although commonly tested on physical examinations, the sensitivity and specificity of Kernig’s and Brudzinski’s signs are uncertain. Both may be absent or reduced in very young or elderly patients, immunocompromised individuals, or patients with a severely depressed mental status. The high prevalence of cervical spine disease in older individuals may result in false-positive tests for nuchal rigidity.

Initial management can be guided by several considerations: (1) Empirical therapy should be initiated promptly whenever bacterial meningitis is a significant diagnostic consideration. (2) All patients who have had recent head trauma, are immunocompromised, have known malignant lesions or central nervous system (CNS) neoplasms, or have focal neurologic findings, papilledema, or a depressed level of consciousness should undergo CT or MRI of the brain prior to lumbar puncture (LP). In these cases empirical antibiotic therapy should not be delayed pending test results but should be administered prior to neuroimaging and LP. (3) A significantly depressed level of consciousness (e.g., somnolence, coma), seizures, or focal neurologic deficits do not occur in viral meningitis; patients with these symptoms should be hospitalized for further evaluation and treated empirically for bacterial and viral meningoencephalitis. (4) Immunocompetent patients with a normal level of consciousness, no prior antimicrobial treatment, and a cerebrospinal fluid (CSF) profile consistent with viral meningitis (lymphocytic pleocytosis and a normal glucose concentration) can often be treated as outpatients if appropriate contact and monitoring can be ensured. Failure of a patient with suspected viral meningitis to improve within 48 h should prompt a reevaluation including follow-up neurologic and general medical examination and repeat imaging and laboratory studies, often including a second LP.


ACUTE BACTERIAL MENINGITIS

DEFINITION

Bacterial meningitis is an acute purulent infection within the subarachnoid space. It is associated with a CNS inflammatory reaction that may result in decreased consciousness, seizures, raised intracranial pressure (ICP), and stroke. The meninges, the subarachnoid space, and the brain parenchyma are all frequently involved in the inflammatory reaction (meningoencephalitis).

EPIDEMIOLOGY

Bacterial meningitis is the most common form of suppurative CNS infection, with an annual incidence in the United States of >2.5 cases/100,000 population. The organisms most often responsible for community-acquired bacterial meningitis are Streptococcus pneumoniae (~50%), Neisseria meningitidis (~25%), group B streptococci (~15%), and Listeria monocytogenes (~10%). Haemophilus influenzaetype b accounts for <10% of cases of bacterial meningitis in most series. N. meningitidis is the causative organism of recurring epidemics of meningitis every 8 to 12 years.

ETIOLOGY

S. pneumoniae is the most common cause of meningitis in adults >20 years of age, accounting for nearly half the reported cases (1.1 per 100,000 persons per year). There are a number of predisposing conditions that increase the risk of pneumococcal meningitis, the most important of which is pneumococcal pneumonia. Additional risk factors include coexisting acute or chronic pneumococcal sinusitis or otitis media, alcoholism, diabetes, splenectomy, hypogammaglobulinemia, complement deficiency, and head trauma with basilar skull fracture and CSF rhinorrhea. The mortality rate remains ~20% despite antibiotic therapy.

The incidence of meningitis due to N. meningitidis has decreased with the routine immunization of 11- to 18-year-olds with the tetravalent (serogroups A, C, W-135, and Y) meningococcal glycoconjugate vaccine. The vaccine does not contain serogroup B, which is responsible for one-third of cases of meningococcal disease. The presence of petechial or purpuric skin lesions can provide an important clue to the diagnosis of meningococcal infection. In some patients the disease is fulminant, progressing to death within hours of symptom onset. Infection may be initiated by nasopharyngeal colonization, which can result in either an asymptomatic carrier state or invasive meningococcal disease. The risk of invasive disease following nasopharyngeal colonization depends on both bacterial virulence factors and host immune defense mechanisms, including the host’s capacity to produce antimeningococcal antibodies and to lyse meningococci by both classic and alternative complement pathways. Individuals with deficiencies of any of the complement components, including proper-din, are highly susceptible to meningococcal infections.

Enteric gram-negative bacilli cause meningitis in individuals with chronic and debilitating diseases such as diabetes, cirrhosis, or alcoholism and in those with chronic urinary tract infections. Gram-negative meningitis can also complicate neurosurgical procedures, particularly craniotomy.

Otitis, mastoiditis, and sinusitis are predisposing and associated conditions for meningitis due to Streptococci sp., gram-negative anaerobes, S. aureus, Haemophilus sp., and Enterobacteriaceae. Meningitis complicating endocarditis may be due to viridans streptococci, S. aureus, S. bovis, the HACEK group (Haemophilus sp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae), or enterococci.

Group B streptococcus, or S. agalactiae, was previously responsible for meningitis predominantly in neonates, but it has been reported with increasing frequency in individuals >50 years of age, particularly those with underlying diseases.

L. monocytogenes is an increasingly important cause of meningitis in neonates (<1 month of age), pregnant women, individuals >60 years, and immunocompromised individuals of all ages. Infection is acquired by ingesting foods contaminated by Listeria. Foodborne human listerial infection has been reported from contaminated coleslaw, milk, soft cheeses, and several types of “ready-to-eat” foods, including delicatessen meat and uncooked hotdogs.

The frequency of H. influenzae type b meningitis in children has declined dramatically since the introduction of the Hib conjugate vaccine, although rare cases of Hib meningitis in vaccinated children have been reported. More frequently, H. influenzae causes meningitis in unvaccinated children and older adults, and non-b H. influenzae is an emerging pathogen.

Staphylococcus aureus and coagulase-negative staphylococci are important causes of meningitis that occurs following invasive neurosurgical procedures, particularly shunting procedures for hydrocephalus, or as a complication of the use of subcutaneous Ommaya reservoirs for administration of intrathecal chemotherapy.

PATHOPHYSIOLOGY

The most common bacteria that cause meningitis, S. pneumoniae and N. meningitidis, initially colonize the nasopharynx by attaching to nasopharyngeal epithelial cells. Bacteria are transported across epithelial cells in membrane-bound vacuoles to the intravascular space or invade the intravascular space by creating separations in the apical tight junctions of columnar epithelial cells. Once in the bloodstream, bacteria are able to avoid phagocytosis by neutrophils and classic complement-mediated bactericidal activity because of the presence of a polysaccharide capsule. Bloodborne bacteria can reach the intraventricular choroid plexus, directly infect choroid plexus epithelial cells, and gain access to the CSF. Some bacteria, such as S. pneumoniae, can adhere to cerebral capillary endothelial cells and subsequently migrate through or between these cells to reach the CSF. Bacteria are able to multiply rapidly within CSF because of the absence of effective host immune defenses. Normal CSF contains few white blood cells (WBCs) and relatively small amounts of complement proteins and immunoglobulins. The paucity of the latter two prevents effective opsonization of bacteria, an essential prerequisite for bacterial phagocytosis by neutrophils. Phagocytosis of bacteria is further impaired by the fluid nature of CSF, which is less conducive to phagocytosis than a solid tissue substrate.

A critical event in the pathogenesis of bacterial meningitis is the inflammatory reaction induced by the invading bacteria. Many of the neurologic manifestations and complications of bacterial meningitis result from the immune response to the invading pathogen rather than from direct bacteria-induced tissue injury. As a result, neurologic injury can progress even after the CSF has been sterilized by antibiotic therapy.

The lysis of bacteria with the subsequent release of cell-wall components into the subarachnoid space is the initial step in the induction of the inflammatory response and the formation of a purulent exudate in the subarachnoid space (Fig. 40-2). Bacterial cell-wall components, such as the lipopolysaccharide (LPS) molecules of gram-negative bacteria and teichoic acid and peptidoglycans of S. pneumoniae, induce meningeal inflammation by stimulating the production of inflammatory cytokines and chemokines by microglia, astrocytes, monocytes, microvascular endothelial cells, and CSF leukocytes. In experimental models of meningitis, cytokines including tumor necrosis factor alpha (TNF-α) and interleukin 1 β (IL-1β) are present in CSF within 1–2 h of intracisternal inoculation of LPS. This cytokine response is quickly followed by an increase in CSF protein concentration and leukocytosis. Chemokines (cytokines that induce chemotactic migration in leukocytes) and a variety of other proinflammatory cytokines are also produced and secreted by leukocytes and tissue cells that are stimulated by IL-1β and TNF-α. In addition, bacteremia and the inflammatory cytokines induce the production of excitatory amino acids, reactive oxygen and nitrogen species (free oxygen radicals, nitric oxide, and peroxynitrite), and other mediators that can induce death of brain cells, especially in the dentate gyrus of the hippocampus.

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FIGURE 40-2

The pathophysiology of the neurologic complications of bacterial meningitis. CSF, cerebrospinal fluid; SAS, subarachnoid space.

Much of the pathophysiology of bacterial meningitis is a direct consequence of elevated levels of CSF cytokines and chemokines. TNF-α and IL-1β act synergistically to increase the permeability of the blood-brain barrier, resulting in induction of vasogenic edema and the leakage of serum proteins into the subarachnoid space (Fig. 40-2). The subarachnoid exudate of proteinaceous material and leukocytes obstructs the flow of CSF through the ventricular system and diminishes the resorptive capacity of the arachnoid granulations in the dural sinuses, leading to obstructive and communicating hydrocephalus and concomitant interstitial edema.

Inflammatory cytokines upregulate the expression of selectins on cerebral capillary endothelial cells and leukocytes, promoting leukocyte adherence to vascular endothelial cells and subsequent migration into the CSF. The adherence of leukocytes to capillary endothelial cells increases the permeability of blood vessels, allowing for the leakage of plasma proteins into the CSF, which adds to the inflammatory exudate. Neutrophil degranulation results in the release of toxic metabolites that contribute to cytotoxic edema, cell injury, and death. Contrary to previous beliefs, CSF leukocytes probably do little to contribute to the clearance of CSF bacterial infection.

During the very early stages of meningitis, there is an increase in cerebral blood flow, soon followed by a decrease in cerebral blood flow and a loss of cerebrovascular autoregulation (Chap. 28). Narrowing of the large arteries at the base of the brain due to encroachment by the purulent exudate in the subarachnoid space and infiltration of the arterial wall by inflammatory cells with intimal thickening (vasculitis) also occur and may result in ischemia and infarction, obstruction of branches of the middle cerebral artery by thrombosis, thrombosis of the major cerebral venous sinuses, and thrombophlebitis of the cerebral cortical veins. The combination of interstitial, vasogenic, and cytotoxic edema leads to raised ICP and coma. Cerebral herniation usually results from the effects of cerebral edema, either focal or generalized; hydrocephalus and dural sinus or cortical vein thrombosis may also play a role.

CLINICAL PRESENTATION

Meningitis can present as either an acute fulminant illness that progresses rapidly in a few hours or as a subacute infection that progressively worsens over several days. The classic clinical triad of meningitis is fever, headache, and nuchal rigidity, but the classic triad may not be present. A decreased level of consciousness occurs in >75% of patients and can vary from lethargy to coma. Fever and either headache, stiff neck, or an altered level of consciousness will be present in nearly every patient with bacterial meningitis. Nausea, vomiting, and photophobia are also common complaints.

Seizures occur as part of the initial presentation of bacterial meningitis or during the course of the illness in 20–40% of patients. Focal seizures are usually due to focal arterial ischemia or infarction, cortical venous thrombosis with hemorrhage, or focal edema. Generalized seizure activity and status epilepticus may be due to hyponatremia, cerebral anoxia, or, less commonly, the toxic effects of antimicrobial agents such as high-dose penicillin.

Raised ICP is an expected complication of bacterial meningitis and the major cause of obtundation and coma in this disease. More than 90% of patients will have a CSF opening pressure >180 mmH2O, and 20% have opening pressures >400 mmH2O. Signs of increased ICP include a deteriorating or reduced level of consciousness, papilledema, dilated poorly reactive pupils, sixth nerve palsies, decerebrate posturing, and the Cushing reflex (bradycardia, hypertension, and irregular respirations). The most disastrous complication of increased ICP is cerebral herniation. The incidence of herniation in patients with bacterial meningitis has been reported to occur in as few as 1% to as many as 8% of cases.

Attention to clinical features that are hallmarks of infection with certain pathogens may provide invaluable clues to the diagnosis of individual organisms. The most important of these clues is the rash of meningococcemia, which begins as a diffuse erythematous maculopapular rash resembling a viral exanthem; however, the skin lesions of meningococcemia rapidly become petechial. Petechiae are found on the trunk and lower extremities, in the mucous membranes and conjunctiva, and occasionally on the palms and soles.

DIAGNOSIS

When bacterial meningitis is suspected, blood cultures should be immediately obtained and empirical antimicrobial and adjunctive dexamethasone therapy initiated without delay (Table 40-1). The diagnosis of bacterial meningitis is made by examination of the CSF (Table 40-2). The need to obtain neuroimaging studies (CT or MRI) prior to LP requires clinical judgment. In an immunocompetent patient with no known history of recent head trauma, a normal level of consciousness, and no evidence of papilledema or focal neurologic deficits, it is considered safe to perform LP without prior neuroimaging studies. If LP is delayed in order to obtain neuroimaging studies, empirical antibiotic therapy should be initiated after blood cultures are obtained. Antibiotic therapy initiated a few hours prior to LP will not significantly alter the CSF WBC count or glucose concentration, nor is it likely to prevent visualization of organisms by Gram’s stain or detection of bacterial nucleic acid by polymerase chain reaction (PCR) assay.

TABLE 40-1

ANTIBIOTICS USED IN EMPIRICAL THERAPY OF BACTERIAL MENINGITIS AND FOCAL CNS INFECTIONSa

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TABLE 40-2

CEREBROSPINAL FLUID (CSF) ABNORMALITIES IN BACTERIAL MENINGITIS

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The classic CSF abnormalities in bacterial meningitis (Table 40-2) are (1) polymorphonuclear (PMN) leukocytosis (>100 cells/μL in 90%), (2) decreased glucose concentration (<2.2 mmol/L [<40 mg/dL] and/or CSF/serum glucose ratio of <0.4 in ~60%), (3) increased protein concentration (>0.45 g/L [>45 mg/dL] in 90%), and (4) increased opening pressure (>180 mmH2O in 90%). CSF bacterial cultures are positive in >80% of patients, and CSF Gram’s stain demonstrates organisms in >60%.

CSF glucose concentrations <2.2 mmol/L (<40 mg/dL) are abnormal, and a CSF glucose concentration of zero can be seen in bacterial meningitis. Use of the CSF/serum glucose ratio corrects for hyperglycemia that may mask a relative decrease in the CSF glucose concentration. The CSF glucose concentration is low when the CSF/serum glucose ratio is <0.6. A CSF/serum glucose ratio <0.4 is highly suggestive of bacterial meningitis but may also be seen in other conditions, including fungal, tuberculous, and carcinomatous meningitis. It takes from 30 min to several hours for the concentration of CSF glucose to reach equilibrium with blood glucose levels; therefore, administration of 50 mL of 50% glucose (D50) prior to LP, as commonly occurs in emergency room settings, is unlikely to alter CSF glucose concentration significantly unless more than a few hours have elapsed between glucose administration and LP.

A 16S rRNA conserved sequence broad-based bacterial PCR can detect small numbers of viable and nonviable organisms in CSF and is expected to be useful for making a diagnosis of bacterial meningitis in patients who have been pretreated with oral or parenteral antibiotics and in whom Gram’s stain and CSF culture are negative. When the broad-range PCR is positive, a PCR that uses specific bacterial primers to detect the nucleic acid of S. pneumoniae, N. meningitidis, Escherichia coli, L. monocytogenes, H. influenzae, and S. agalactiae can be obtained based on the clinical suspicion of the meningeal pathogen. The latex agglutination (LA) test for the detection of bacterial antigens of S. pneumoniaeN. meningitidisH. influenzae type b, group B streptococcus, and E. coli K1 strains in the CSF has been useful for making a diagnosis of bacterial meningitis but is being replaced by the CSF bacterial PCR assay. The CSF LA test has a specificity of 95–100% for S. pneumoniae and N. meningitidis, so a positive test is virtually diagnostic of bacterial meningitis caused by these organisms. However, the sensitivity of the CSF LA test is only 70–100% for detection of S. pneumoniae and 33–70% for detection of N. meningitidisantigens, so a negative test does not exclude infection by these organisms. The Limulus amebocyte lysate assay is a rapid diagnostic test for the detection of gram-negative endotoxin in CSF and thus for making a diagnosis of gram-negative bacterial meningitis. The test has a specificity of 85–100% and a sensitivity approaching 100%. Thus, a positive Limulus amebocyte lysate assay occurs in virtually all patients with gram-negative bacterial meningitis, but false positives may occur.

Almost all patients with bacterial meningitis will have neuroimaging studies performed during the course of their illness. MRI is preferred over CT because of its superiority in demonstrating areas of cerebral edema and ischemia. In patients with bacterial meningitis, diffuse meningeal enhancement is often seen after the administration of gadolinium. Meningeal enhancement is not diagnostic of meningitis but occurs in any CNS disease associated with increased blood-brain barrier permeability.

Petechial skin lesions, if present, should be biopsied. The rash of meningococcemia results from the dermal seeding of organisms with vascular endothelial damage, and biopsy may reveal the organism on Gram’s stain.

DIFFERENTIAL DIAGNOSIS

Viral meningoencephalitis, and particularly herpes simplex virus (HSV) encephalitis, can mimic the clinical presentation of bacterial meningitis (see “Viral Encephalitis,” later in the chapter). HSV encephalitis typically presents with headache, fever, altered consciousness, focal neurologic deficits (e.g., dysphasia, hemiparesis), and focal or generalized seizures. The findings on CSF studies, neuroimaging, and electroencephalogram (EEG) distinguish HSV encephalitis from bacterial meningitis. The typical CSF profile with viral CNS infections is a lymphocytic pleocytosis with a normal glucose concentration, in contrast to PMN pleocytosis and hypoglycorrhachia characteristic of bacterial meningitis. MRI abnormalities (other than meningeal enhancement) are not seen in uncomplicated bacterial meningitis. By contrast, in HSV encephalitis, on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI images, high signal intensity lesions are seen in the orbitofrontal, anterior, and medial temporal lobes in the majority of patients within 48 h of symptom onset. Some patients with HSV encephalitis have a distinctive periodic pattern on EEG (discussed later).

Rickettsial disease can resemble bacterial meningitis. Rocky Mountain spotted fever (RMSF) is transmitted by a tick bite and caused by the bacteria Rickettsia rickettsii. The disease may present acutely with high fever, prostration, myalgia, headache, nausea, and vomiting. Most patients develop a characteristic rash within 96 h of the onset of symptoms. The rash is initially a diffuse erythematous maculopapular rash that may be difficult to distinguish from that of meningococcemia. It progresses to a petechial rash, then to a purpuric rash and, if untreated, to skin necrosis or gangrene. The color of the lesions changes from bright red to very dark red, then yellowish-green to black. The rash typically begins in the wrist and ankles and then spreads distally and proximally within a matter of a few hours, involving the palms and soles. Diagnosis is made by immunofluorescent staining of skin biopsy specimens. Ehrlichioses are also transmitted by a tick bite. These are small gram-negative coccobacilli of which two species cause human disease. Anaplasma phagocytophilum causes human granulocytic ehrlichiosis (anaplasmosis), and Ehrlichia chaffeensis causes human monocytic ehrlichiosis. The clinical and laboratory manifestations of the infections are similar. Patients present with fever, headache, nausea, and vomiting. Twenty percent of patients have a maculopapular or petechial rash. There is laboratory evidence of leukopenia, thrombocytopenia, and anemia, and mild to moderate elevations in alanine aminotransferases, alkaline phosphatase, and lactate dehydrogenase. Patients with RMSF and those with ehrlichial infections may have an altered level of consciousness ranging from mild lethargy to coma, confusion, focal neurologic signs, cranial nerve palsies, hyperreflexia, and seizures.

Focal suppurative CNS infections (discussed later), including subdural and epidural empyema and brain abscess, should also be considered, especially when focal neurologic findings are present. MRI should be performed promptly in all patients with suspected meningitis who have focal features, both to detect the intracranial infection and to search for associated areas of infection in the sinuses or mastoid bones.

A number of noninfectious CNS disorders can mimic bacterial meningitis. Subarachnoid hemorrhage (SAH; Chap. 28) is generally the major consideration. Other possibilities include chemical meningitis due to rupture of tumor contents into the CSF (e.g., from a cystic glioma or craniopharyngioma epidermoid or dermoid cyst); drug-induced hypersensitivity meningitis; carcinomatous or lymphomatous meningitis; meningitis associated with inflammatory disorders such as sarcoid, systemic lupus erythematosus (SLE), and Behçet’s syndrome; pituitary apoplexy; and uveomeningitic syndromes (Vogt-Koyanagi-Harada syndrome).

On occasion, subacutely evolving meningitis (Chap. 41) may be considered in the differential diagnosis of acute meningitis. The principal causes include Mycobacterium tuberculosisCryptococcus neoformansHistoplasma capsulatumCoccidioides immitis, and Treponema pallidum.


TREATMENT Acute Bacterial Meningitis

EMPIRICAL ANTIMICROBIAL THERAPY (Table 40-1) Bacterial meningitis is a medical emergency. The goal is to begin antibiotic therapy within 60 min of a patient’s arrival in the emergency room. Empirical antimicrobial therapy is initiated in patients with suspected bacterial meningitis before the results of CSF Gram’s stain and culture are known. S. pneumoniae and N. meningitidis are the most common etiologic organisms of community-acquired bacterial meningitis. Due to the emergence of penicillin- and cephalosporin-resistant S. pneumoniae, empirical therapy of community-acquired suspected bacterial meningitis in children and adults should include a combination of dexamethasone, a third- or fourth-generation cephalosporin (e.g., ceftriaxone, cefotaxime, or cefepime), and vancomycin, plus acyclovir, as HSV encephalitis is the leading disease in the differential diagnosis, and doxycycline during tick season to treat tick-borne bacterial infections. Ceftriaxone or cefotaxime provide good coverage for susceptible S. pneumoniae, group B streptococci, and H. influenzae and adequate coverage for N. meningitidis. Cefepime is a broad-spectrum fourth-generation cephalosporin with in vitro activity similar to that of cefotaxime or ceftriaxone against S. pneumoniae and N. meningitidis and greater activity against Enterobacter species and Pseudomonas aeruginosa. In clinical trials, cefepime has been demonstrated to be equivalent to cefotaxime in the treatment of penicillin-sensitive pneumococcal and meningococcal meningitis, and it has been used successfully in some patients with meningitis due to Enterobacter species and P. aeruginosa. Ampicillin should be added to the empirical regimen for coverage of L. monocytogenes in individuals <3 months of age, those >55, or those with suspected impaired cell-mediated immunity because of chronic illness, organ transplantation, pregnancy, malignancy, or immunosuppressive therapy. Metronidazole is added to the empirical regimen to cover gram-negative anaerobes in patients with otitis, sinusitis, or mastoiditis. In hospital-acquired meningitis, and particularly meningitis following neuro-surgical procedures, staphylococci and gram-negative organisms including P. aeruginosa are the most common etiologic organisms. In these patients, empirical therapy should include a combination of vancomycin and ceftazidime, cefepime, or meropenem. Ceftazidime, cefepime, or meropenem should be substituted for ceftriaxone or cefotaxime in neurosurgical patients and in neutropenic patients, as ceftriaxone and cefotaxime do not provide adequate activity against CNS infection with P. aeruginosa. Meropenem is a carbapenem antibiotic that is highly active in vitro against L. monocytogenes, has been demonstrated to be effective in cases of meningitis caused by P. aeruginosa, and shows good activity against penicillin-resistant pneumococci. In experimental pneumococcal meningitis, meropenem was comparable to ceftriaxone and inferior to vancomycin in sterilizing CSF cultures. The number of patients with bacterial meningitis enrolled in clinical trials of meropenem has not been sufficient to definitively assess the efficacy of this antibiotic.

SPECIFIC ANTIMICROBIAL THERAPY

Meningococcal Meningitis (Table 40-3) Although ceftriaxone and cefotaxime provide adequate empirical coverage for N. meningitidis, penicillin G remains the antibiotic of choice for meningococcal meningitis caused by susceptible strains. Isolates of N. meningitidis with moderate resistance to penicillin have been identified, but patients infected with these strains have still been successfully treated with penicillin. CSF isolates of N. meningitidisshould be tested for penicillin and ampicillin susceptibility, and if resistance is found, cefotaxime or ceftriaxone should be substituted for penicillin. A 7-day course of intravenous antibiotic therapy is adequate for uncomplicated meningococcal meningitis. The index case and all close contacts should receive chemoprophylaxis with a 2-day regimen of rifampin (600 mg every 12 h for 2 days in adults and 10 mg/kg every 12 h for 2 days in children >1 year). Rifampin is not recommended in pregnant women. Alternatively, adults can be treated with one dose of azithromycin (500 mg), or one intramuscular dose of ceftriaxone (250 mg). Close contacts are defined as those individuals who have had contact with oropharyngeal secretions, either through kissing or by sharing toys, beverages, or cigarettes.

TABLE 40-3

ANTIMICROBIAL THERAPY OF CNS BACTERIAL INFECTIONS BASED ON PATHOGENa

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Pneumococcal Meningitis Antimicrobial therapy of pneumococcal meningitis is initiated with a cephalosporin (ceftriaxone, cefotaxime, or cefepime) and vancomycin. All CSF isolates of S. pneumoniae should be tested for sensitivity to penicillin and the cephalosporins. Once the results of antimicrobial susceptibility tests are known, therapy can be modified accordingly (Table 40-3). For S. pneumoniae meningitis, an isolate of S. pneumoniae is considered to be susceptible to penicillin with a minimal inhibitory concentration (MIC) <0.06 μg/mL, to have intermediate resistance when the MIC is 0.1–1.0 μg/mL, and to be highly resistant when the MIC >1.0 μg/mL. Isolates of S. pneumoniae that have cephalosporin MICs <0.5 μg/mL are considered sensitive to the cephalosporins (cefotaxime, ceftriaxone, cefepime). Those with MICs of 1 μg/mL are considered to have intermediate resistance, and those with MICs ≥2 μg/mL are considered resistant. For meningitis due to pneumococci, with cefotaxime or ceftriaxone MICs <0.5 μg/mL, treatment with cefotaxime or ceftriaxone is usually adequate. For MIC >1 μg/mL, vancomycin is the antibiotic of choice. Rifampin can be added to vancomycin for its synergistic effect but is inadequate as monotherapy because resistance develops rapidly when it is used alone.

A 2-week course of intravenous antimicrobial therapy is recommended for pneumococcal meningitis.

Patients with S. pneumoniae meningitis should have a repeat LP performed 24–36 h after the initiation of antimicrobial therapy to document sterilization of the CSF. Failure to sterilize the CSF after 24–36 h of antibiotic therapy should be considered presumptive evidence of antibiotic resistance. Patients with penicillin- and cephalosporin-resistant strains of S. pneumoniae who do not respond to intravenous vancomycin alone may benefit from the addition of intraventricular vancomycin. The intraventricular route of administration is preferred over the intrathecal route because adequate concentrations of vancomycin in the cerebral ventricles are not always achieved with intrathecal administration.

Listeria Meningitis Meningitis due to L. monocytogenes is treated with ampicillin for at least 3 weeks (Table 40-3). Gentamicin is added in critically ill patients (2 mg/kg loading dose, then 7.5 mg/kg per day given every 8 h and adjusted for serum levels and renal function). The combination of trimethoprim (10–20 mg/kg per day) and sulfamethoxazole (50–100 mg/kg per day) given every 6 h may provide an alternative in penicillin-allergic patients.

Staphylococcal Meningitis Meningitis due to susceptible strains of S. aureus or coagulase-negative staphylococci is treated with nafcillin (Table 40-3). Vancomycin is the drug of choice for methicillin-resistant staphylococci and for patients allergic to penicillin. In these patients, the CSF should be monitored during therapy. If the CSF is not sterilized after 48 h of intravenous vancomycin therapy, then either intraventricular or intrathecal vancomycin, 20 mg once daily, can be added.

Gram-Negative Bacillary Meningitis The third-generation cephalosporins—cefotaxime, ceftriaxone, and ceftazidime—are equally efficacious for the treatment of gram-negative bacillary meningitis, with the exception of meningitis due to P. aeruginosa, which should be treated with ceftazidime, cefepime, or meropenem (Table 40-3). A 3-week course of intravenous antibiotic therapy is recommended for meningitis due to gram-negative bacilli.

ADJUNCTIVE THERAPY The release of bacterial cell-wall components by bactericidal antibiotics leads to the production of the inflammatory cytokines IL-1β and TNF-α in the subarachnoid space. Dexamethasone exerts its beneficial effect by inhibiting the synthesis of IL-1β and TNF-α at the level of mRNA, decreasing CSF outflow resistance, and stabilizing the blood-brain barrier. The rationale for giving dexamethasone 20 min before antibiotic therapy is that dexamethasone inhibits the production of TNF-α by macrophages and microglia only if it is administered before these cells are activated by endotoxin. Dexamethasone does not alter TNF-α production once it has been induced. The results of clinical trials of dexamethasone therapy in children, predominantly with meningitis due to H. influenzaeand S. pneumoniae, have demonstrated its efficacy in decreasing meningeal inflammation and neurologic sequelae such as the incidence of sensorineural hearing loss.

A prospective European trial of adjunctive therapy for acute bacterial meningitis in 301 adults found that dexamethasone reduced the number of unfavorable outcomes (15 vs. 25%, Image) including death (7 vs. 15%, Image). The benefits were most striking in patients with pneumococcal meningitis. Dexamethasone (10 mg intravenously) was administered 15–20 min before the first dose of an antimicrobial agent, and the same dose was repeated every 6 h for 4 days. These results were confirmed in a second trial of dexamethasone in adults with pneumococcal meningitis. Therapy with dexamethasone should ideally be started 20 min before, or not later than concurrent with, the first dose of antibiotics. It is unlikely to be of significant benefit if started >6 h after antimicrobial therapy has been initiated. Dexamethasone may decrease the penetration of vancomycin into CSF, and it delays the sterilization of CSF in experimental models of S. pneumoniae meningitis. As a result, its potential benefit should be carefully weighed when vancomycin is the antibiotic of choice. Alternatively, vancomycin can be administered by the intraventricular route.

One of the concerns for using dexamethasone in adults with bacterial meningitis is that in experimental models of meningitis, dexamethasone therapy increased hippocampal cell injury and reduced learning capacity. This has not been the case in clinical series. The efficacy of dexamethasone therapy in preventing neurologic sequelae is different between high- and low-income countries. Three large randomized trials in low-income countries (sub-Saharan Africa, Southeast Asia) failed to show benefit in subgroups of patients. The lack of efficacy of dexamethasone in these trials has been attributed to late presentation to the hospital with more advanced disease, antibiotic pretreatment, malnutrition, infection with HIV, and treatment of patients with probable, but not microbiologically proven, bacterial meningitis. The results of these clinical trials suggest that patients in sub-Saharan Africa and those in low-income countries with negative CSF Gram’s stain and culture should not be treated with dexamethasone.

INCREASED INTRACRANIAL PRESSURE Emergency treatment of increased ICP includes elevation of the patient’s head to 30–45°, intubation and hyperventilation (Paco2 25–30 mmHg), and mannitol. Patients with increased ICP should be managed in an intensive care unit; accurate ICP measurements are best obtained with an ICP monitoring device.

Treatment of increased intracranial pressure is discussed in detail in Chap. 28.


PROGNOSIS

Mortality rate is 3–7% for meningitis caused by H. influenzaeN. meningitidis, or group B streptococci; 15% for that due to L. monocytogenes; and 20% for S. pneumoniae. In general, the risk of death from bacterial meningitis increases with (1) decreased level of consciousness on admission, (2) onset of seizures within 24 h of admission, (3) signs of increased ICP, (4) young age (infancy) and age >50, (5) the presence of comorbid conditions including shock and/or the need for mechanical ventilation, and (6) delay in the initiation of treatment. Decreased CSF glucose concentratio (<2.2 mmol/L [<40 mg/dL]) and markedly increased CSF protein concentration (>3 g/L [>300 mg/dL]) have been predictive of increased mortality and poorer outcomes in some series. Moderate or severe sequelae occur in ~25% of survivors, although the exact incidence varies with the infecting organism. Common sequelae include decreased intellectual function, memory impairment, seizures, hearing loss and dizziness, and gait disturbances.

ACUTE VIRAL MENINGITIS

CLINICAL MANIFESTATIONS

Immunocompetent adult patients with viral meningitis usually present with headache, fever, and signs of meningeal irritation coupled with an inflammatory CSF profile (discussed later). Headache is almost invariably present and often characterized as frontal or retroorbital and frequently associated with photophobia and pain on moving the eyes. Nuchal rigidity is present in most cases but may be mild and present only near the limit of neck anteflexion. Constitutional signs can include malaise, myalgia, anorexia, nausea and vomiting, abdominal pain, and/or diarrhea. Patients often have mild lethargy or drowsiness; however, profound alterations in consciousness, such as stupor, coma, or marked confusion do not occur in viral meningitis and suggest the presence of encephalitis or other alternative diagnoses. Similarly, seizures or focal neurologic signs or symptoms or neuroimaging abnormalities indicative of brain parenchymal involvement are not typical of viral meningitis and suggest the presence of encephalitis or another CNS infectious or inflammatory process.

ETIOLOGY

Using a variety of diagnostic techniques, including CSF PCR, culture, and serology, a specific viral cause can be found in 75–90% of cases of viral meningitis. The most important agents are enteroviruses (including echoviruses and coxsackieviruses in addition to numbered enteroviruses), HSV type 2 (HSV-2), HIV, and arboviruses (Table 40-4). CSF cultures are positive in 30–70% of patients, the frequency of isolation depending on the specific viral agent. Approximately two-thirds of culture-negative cases of “aseptic” meningitis have a specific viral etiology identified by CSF PCR testing (discussed later).

TABLE 40-4

VIRUSES CAUSING ACUTE MENINGITIS AND ENCEPHALITIS IN NORTH AMERICA

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EPIDEMIOLOGY

Viral meningitis is not a nationally reportable disease; however, it has been estimated that the incidence is ~75,000 cases per year. In temperate climates, there is a substantial increase in cases during the summer and early fall months, reflecting the seasonal predominance of enterovirus and arthropod-borne virus (arbovirus) infections, with a peak monthly incidence of about 1 reported case per 100,000 population.

LABORATORY DIAGNOSIS

CSF examination

The most important laboratory test in the diagnosis of viral meningitis is examination of the CSF. The typical profile is a lymphocytic pleocytosis (25–500 cells/μL), a normal or slightly elevated protein concentration (0.2–0.8 g/L [20–80 mg/dL]), a normal glucose concentration, and a normal or mildly elevated opening pressure (100–350 mmH2O). Organisms are not seen on Gram’s stain of CSF. Rarely, PMNs may predominate in the first 48 h of illness, especially with infections due to echovirus 9, West Nile virus, eastern equine encephalitis (EEE) virus, or mumps. A pleocytosis of polymorpho-nuclear neutrophils occurs in 45% of patients with West Nile virus (WNV) meningitis and can persist for a week or longer before shifting to a lymphocytic pleocytosis. Despite these exceptions, the presence of a CSF PMN pleocytosis in a patient with suspected viral meningitis in whom a specific diagnosis has not been established should prompt consideration of alternative diagnoses, including bacterial meningitis or parameningeal infections. The total CSF cell count in viral meningitis is typically 25–500/μL, although cell counts of several thousand/μL are occasionally seen, especially with infections due to lymphocytic choriomeningitis virus (LCMV) and mumps virus. The CSF glucose concentration is typically normal in viral infections, although it may be decreased in 10–30% of cases due to mumps or LCMV. Rare instances of decreased CSF glucose concentration occur in cases of meningitis due to echoviruses and other enteroviruses, HSV-2, and varicella-zoster virus (VZV). As a rule, a lymphocytic pleocytosis with a low glucose concentration should suggest fungal or tuberculous meningitis, Listeria meningoencephalitis, or noninfectious disorders (e.g., sarcoid, neoplastic meningitis).

A number of tests measuring levels of various CSF proteins, enzymes, and mediators—including C-reactive protein, lactic acid, lactate dehydrogenase, neopterin, quinolinate, IL-1β, IL-6, soluble IL-2 receptor, β2-microglobulin, and TNF—have been proposed as potential discriminators between viral and bacterial meningitis or as markers of specific types of viral infection (e.g., infection with HIV), but they remain of uncertain sensitivity and specificity and are not widely used for diagnostic purposes.

Polymerase chain reaction amplification of viral nucleic acid

Amplification of viral-specific DNA or RNA from CSF using PCR amplification has become the single most important method for diagnosing CNS viral infections. In both enteroviral and HSV infections of the CNS, PCR has become the diagnostic procedure of choice and is substantially more sensitive than viral cultures. HSV PCR is also an important diagnostic test in patients with recurrent episodes of “aseptic” meningitis, many of whom have amplifiable HSV DNA in CSF despite negative viral cultures. CSF PCR is also used routinely to diagnose CNS viral infections caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV), VZV, and human herpesvirus 6 (HHV-6). CSF PCR tests are available for WNV but are not as sensitive as detection of WNV-specific CSF IgM. PCR is also useful in the diagnosis of CNS infection caused by Mycoplasma pneumoniae, which can mimic viral meningitis and encephalitis.

Viral culture

The sensitivity of CSF cultures for the diagnosis of viral meningitis and encephalitis, in contrast to its utility in bacterial infections, is generally poor. In addition to CSF, specific viruses may also be isolated from throat swabs, stool, blood, and urine. Enteroviruses and adenoviruses may be found in feces; arboviruses, some enteroviruses, and LCMV in blood; mumps and CMV in urine; and enteroviruses, mumps, and adenoviruses in throat washings. During enteroviral infections, viral shedding in stool may persist for several weeks. The presence of enterovirus in stool is not diagnostic and may result from residual shedding from a previous enteroviral infection; it also occurs in some asymptomatic individuals during enteroviral epidemics.

Serologic studies

For some viruses, including many arboviruses such as WNV, serologic studies remain a crucial diagnostic tool. Serum antibody determination is less useful for viruses with high seroprevalence rates in the general population such as HSV, VZV, CMV, and EBV. For viruses with low seroprevalence rates, diagnosis of acute viral infection can be made by documenting seroconversion between acute-phase and convalescent sera (typically obtained after 2–4 weeks) or by demonstrating the presence of virus-specific IgM antibodies. Documentation of synthesis of virus-specific antibodies in CSF, as shown by an increased IgG index or the presence of CSF IgM antibodies, is more useful than serum serology alone and can provide presumptive evidence of CNS infection. Although serum and CSF IgM antibodies generally persist for only a few months after acute infection, there are exceptions to this rule. For example, WNV IgM has been shown to persist in some patients for >1 year following acute infection. Unfortunately, the delay between onset of infection and the host’s generation of a virus-specific antibody response often means that serologic data are useful mainly for the retrospective establishment of a specific diagnosis, rather than in aiding acute diagnosis or management.

CSF oligoclonal gamma globulin bands occur in association with a number of viral infections. The associated antibodies are often directed against viral proteins. Oligoclonal bands also occur commonly in certain non-infectious neurologic diseases (e.g., multiple sclerosis) and may be found in nonviral infections (e.g., neurosyphilis, Lyme neuroborreliosis).

Other laboratory studies

All patients with suspected viral meningitis should have a complete blood count and differential, liver and renal function tests, erythrocyte sedimentation rate (ESR), and C-reactive protein, electrolytes, glucose, creatine kinase, aldolase, amylase, and lipase. Neuroimaging studies (MRI, CT) are not necessary in patients with uncomplicated viral meningitis but should be performed in patients with altered consciousness, seizures, focal neurologic signs or symptoms, or atypical CSF profiles.

DIFFERENTIAL DIAGNOSIS

The most important issue in the differential diagnosis of viral meningitis is to consider diseases that can mimic viral meningitis, including (1) untreated or partially treated bacterial meningitis; (2) early stages of meningitis caused by fungi, mycobacteria, or Treponema pallidum (neurosyphilis), in which a lymphocytic pleocytosis is common, cultures may be slow growing or negative, and hypoglycorrhachia may not be present early; (3) meningitis caused by agents such as MycoplasmaListeria spp., Brucella spp., Coxiella spp., Leptospira spp., and Rickettsia spp.; (4) parameningeal infections; (5) neoplastic meningitis; and (6) meningitis secondary to noninfectious inflammatory diseases, including hypersensitivity meningitis, SLE and other rheumatologic diseases, sarcoidosis, Behçet’s syndrome, and the uveomeningitic syndromes. Studies in children >28 days of age suggest that the presence of CSF protein >0.5 g/L (sensitivity 89%, specificity 78%), and elevated serum procalcitonin levels >0.5 ng/mL (sensitivity 89%, specificity 89%) were clues to the presence of bacterial as opposed to “aseptic” meningitis. A variety of clinical algorithms for differentiating bacterial from aseptic meningitis have been promulgated, although none have been widely validated. One such prospectively validated system, the bacterial meningitis score, suggests that the probability of bacterial meningitis is 0.1% or less (negative predictive value 99.9%, 95% CI 99.6–100%) in children with CSF pleocytosis who have: (1) a negative CSF Gram’s stain, (2) CSF neutrophil count <1000 cells/μL, (3) CSF protein <80 mg/dL, (4) peripheral absolute neutrophil count of <10,000 cells/μL, and (5) no prior history or current presence of seizures.

SPECIFIC VIRAL ETIOLOGIES

Enteroviruses (EV) are the most common cause of viral meningitis, accounting for >85% of cases in which a specific etiology can be identified. Cases may either be sporadic or occur in clusters. Recent outbreaks of EV meningitis in the United States have been associated with coxsackievirus B5 and echovirus strains 6, 9, and 30. Coxsackievirus strains A9, B3, and B4 are more commonly associated with individual cases. EV71 has produced large epidemics of neurologic disease outside the United States, especially in Southeast Asia, but most recently reported cases in the United States have been sporadic. Enteroviruses are the most likely cause of viral meningitis in the summer and fall months, especially in children (<15 years), although cases occur at reduced frequency year round. Although the incidence of enteroviral meningitis declines with increasing age, some outbreaks have preferentially affected older children and adults. Meningitis outside the neonatal period is usually benign. Patients present with sudden onset of fever; headache; nuchal rigidity; and often constitutional signs, including vomiting, anorexia, diarrhea, cough, pharyngitis, and myalgias. The physical examination should include a careful search for stigmata of enterovirus infection, including exanthems, hand-foot-mouth disease, herpangina, pleurodynia, myopericarditis, and hemorrhagic conjunctivitis. The CSF profile is typically a lymphocytic pleocytosis (100–1000 cells/μL) with normal glucose and normal or mildly elevated protein concentration. However, up to 15% of patients, most commonly young infants rather than older children or adults, have a normal CSF leukocyte count. In rare cases, PMNs may predominate during the first 48 h of illness. CSF reverse transcriptase PCR (RT-PCR) is the diagnostic procedure of choice and is both sensitive (>95%) and specific (>100%). CSF PCR has the highest sensitivity if performed within 48 h of symptom onset, with sensitivity declining rapidly after day 5 of symptoms. Treatment is supportive, and patients usually recover without sequelae. Chronic and severe infections can occur in neonates and in individuals with hypo- or agammaglobulinemia.

Arbovirus infections occur predominantly in the summer and early fall. Arboviral meningitis should be considered when clusters of meningitis and encephalitis cases occur in a restricted geographic region during the summer or early fall. In the United States the most important causes of arboviral meningitis and encephalitis are West Nile virus, St. Louis encephalitis virus, and the California encephalitis group of viruses. In WNV epidemics, avian deaths may serve as sentinel infections for subsequent human disease. A history of tick exposure or travel or residence in the appropriate geographic area should suggest the possibility of Colorado tick fever virus or Powassan virus infection, although nonviral tick-borne diseases, including RMSF and Lyme neuroborreliosis, may present similarly. Arbovirus meningoencephalitis is typically associated with a CSF lymphocytic pleocytosis, normal glucose concentration, and normal or mildly elevated protein concentration. However, 40–45% of patients with WNV meningoencephalitis have CSF neutrophilia, which can persist for a week or more. The rarity of hypoglycorrhachia in WNV infection as well as the absence of positive Gram’s stains and the negative cultures helps distinguish these patients from those with bacterial meningitis. The presence of increased numbers of plasmacytoid cells or Mollaret-like large mononuclear cells in the CSF may be a clue to the diagnosis of WNV infection. Definitive diagnosis of arboviral meningoencephalitis is based on demonstration of viral-specific IgM in CSF or seroconversion. CSF PCR tests are available for some viruses in selected diagnostic laboratories and at the Centers for Disease Control and Prevention (CDC), but in the case of WNV, sensitivity (~70%) of CSF PCR is less than that of CSF serology.

HSV-2 meningitis has been increasingly recognized as a major cause of viral meningitis in adults, and overall it is probably second in importance to enteroviruses as a cause of viral meningitis, accounting for 5% of total cases overall and undoubtedly a higher frequency of those cases occurring in adults and/or outside of the summer-fall period when enterovirus infections are increasingly common. HSV meningitis occurs in ~25-35% of women and ~10-15% of men at the time of an initial (primary) episode of genital herpes. Of these patients, 20% go on to have recurrent attacks of meningitis. Diagnosis of HSV meningitis is usually by HSV CSF PCR as cultures may be negative, especially in patients with recurrent meningitis. Demonstration of intrathecal synthesis of HSV-specific antibody may also be useful in diagnosis, although antibody tests are less sensitive and less specific than PCR and may not become positive until after the first week of infection. In contrast to HSV encephalitis in adults in which >90% of cases are due to HSV-1, the overwhelming majority of HSV meningitis is due to HSV-2. Although a history of or the presence of HSV genital lesions is an important diagnostic clue, many patients with HSV meningitis give no history and have no evidence of active genital herpes at the time of presentation. Most cases of recurrent viral or “aseptic” meningitis, including cases previously diagnosed as Mollaret’s meningitis, are likely due to HSV.

VZV meningitis should be suspected in the presence of concurrent chickenpox or shingles. However, it is important to recognize that in some series, up to 40% of VZV meningitis cases have been reported to occur in the absence of rash. The frequency of VZV as a cause of meningitis is extremely variable, ranging from as low as 3% to as high as 20% in different series. Diagnosis is usually based on CSF PCR, although the sensitivity of this test may not be as high as for the other herpesviruses. In patients with negative CSF PCR results, the diagnosis of VZV CNS infection can be made by the demonstration of VZV-specific intrathecal antibody synthesis and/or the presence of VZV CSF IgM antibodies, or by positive CSF cultures.

EBV infections may also produce aseptic meningitis, with or without associated infectious mononucleosis. The presence of atypical lymphocytes in the CSF or peripheral blood is suggestive of EBV infection but may occasionally be seen with other viral infections. EBV is almost never cultured from CSF. Serum and CSF serology can help establish the presence of acute infection, which is characterized by IgM viral capsid antibodies (VCAs), antibodies to early antigens (EAs), and the absence of antibodies to EBV-associated nuclear antigen (EBNA). CSF PCR is another important diagnostic test, although positive results may reflect viral reactivation associated with other infectious or inflammatory processes.

HIV meningitis should be suspected in any patient presenting with a viral meningitis with known or suspected risk factors for HIV infection. Meningitis may occur following primary infection with HIV in 5–10% of cases and less commonly at later stages of illness. Cranial nerve palsies, most commonly involving cranial nerves V, VII, or VIII, are more common in HIV meningitis than in other viral infections. Diagnosis can be confirmed by detection of HIV genome in blood or CSF. Seroconversion may be delayed, and patients with negative HIV serologies who are suspected of having HIV meningitis should be monitored for delayed sero-conversion. For further discussion of HIV infection, see Chap. 42.

Mumps should be considered when meningitis occurs in the late winter or early spring, especially in males (male/female ratio 3:1). With the widespread use of the live attenuated mumps vaccine in the United States since 1967, the incidence of mumps meningitis has fallen by >95%; however, mumps remains a potential source of infection in nonimmunized individuals and populations. Rare cases (10–100:100,000 vaccinated individuals) of vaccine-associated mumps meningitis have been described, with onset typically 2–4 weeks after vaccination. The presence of parotitis, orchitis, oophoritis, pancreatitis, or elevations in serum lipase and amylase is suggestive of mumps meningitis; however, their absence does not exclude the diagnosis. Clinical meningitis was previously estimated to occur in 10–30% of patients with mumps parotitis; however, in a recent U.S. outbreak of nearly 2600 cases of mumps, only 11 cases of meningitis were identified, suggesting the incidence may be lower than previously suspected. Mumps infection confers lifelong immunity, so a documented history of previous infection excludes this diagnosis. Patients with meningitis have a CSF pleocytosis that can exceed 1000 cells/μL in 25%. Lymphocytes predominate in 75%, although CSF neutrophilia occurs in 25%. Hypoglycorrhachia occurs in 10–30% of patients and may be a clue to the diagnosis when present. Diagnosis is typically made by culture of virus from CSF or by detecting IgM antibodies or seroconversion. CSF PCR is available in some diagnostic and research laboratories.

LCMV infection should be considered when aseptic meningitis occurs in the late fall or winter and in individuals with a history of exposure to house mice (Mus musculus), pet or laboratory rodents (e.g., hamsters, rats, mice), or their excreta. Some patients have an associated rash, pulmonary infiltrates, alopecia, parotitis, orchitis, or myopericarditis. Laboratory clues to the diagnosis of LCMV, in addition to the clinical findings noted earlier, may include the presence of leukopenia, thrombocytopenia, or abnormal liver function tests. Some cases present with a marked CSF pleocytosis (>1000 cells/μL) and hypoglycorrhachia (<30%). Diagnosis is based on serology and/or culture of virus from CSF.


TREATMENT Acute Viral Meningitis

Treatment of almost all cases of viral meningitis is primarily symptomatic and includes use of analgesics, antipyretics, and antiemetics. Fluid and electrolyte status should be monitored. Patients with suspected bacterial meningitis should receive appropriate empirical therapy pending culture results (discussed earlier). Hospitalization may not be required in immunocompetent patients with presumed viral meningitis and no focal signs or symptoms, no significant alteration in consciousness, and a classic CSF profile (lymphocytic pleocytosis, normal glucose, negative Gram’s stain) if adequate provision for monitoring at home and medical follow-up can be ensured. Immunocompromised patients; patients with significant alteration in consciousness, seizures, or the presence of focal signs and symptoms suggesting the possibility of encephalitis or parenchymal brain involvement; and those patients who have an atypical CSF profile should be hospitalized. Oral or intravenous acyclovir may be of benefit in patients with meningitis caused by HSV-1 or -2 and in cases of severe EBV or VZV infection. Data concerning treatment of HSV, EBV, and VZV meningitis are extremely limited. Seriously ill patients should probably receive intravenous acyclovir (15–30 mg/kg per day in three divided doses), which can be followed by an oral drug such as acyclovir (800 mg, five times daily), famciclovir (500 mg tid), or valacyclovir (1000 mg tid) for a total course of 7–14 days. Patients who are less ill can be treated with oral drugs alone. Patients with HIV meningitis should receive highly active antiretroviral therapy (Chap. 42).

Patients with viral meningitis who are known to have deficient humoral immunity (e.g., X-linked agammaglobulinemia) and who are not already receiving either intramuscular gamma globulin or intravenous immunoglobulin (IVIg) should be treated with these agents. Intraventricular administration of immunoglobulin through an Ommaya reservoir has been tried in some patients with chronic enteroviral meningitis who have not responded to intramuscular or intravenous immunoglobulin.

An investigational drug, pleconaril, has shown efficacy against a variety of enteroviral infections and has good oral bioavailability and excellent CNS penetration. Clinical trials in patients with enteroviral meningitis indicated that pleconaril decreased the duration of symptoms compared to placebo; however, the drug is not likely to be marketed and is not generally available, due to its modest benefit in trials of non-CNS EV infections.

Vaccination is an effective method of preventing the development of meningitis and other neurologic complications associated with poliovirus, mumps, and measles infection. A live attenuated VZV vaccine (Varivax) is available in the United States. Clinical studies indicate an effectiveness rate of 70–90% for this vaccine, but a booster may be required to maintain immunity. An inactivated varicella vaccine is available for transplant recipients.


PROGNOSIS

In adults, the prognosis for full recovery from viral meningitis is excellent. Rare patients complain of persisting headache, mild mental impairment, incoordination, or generalized asthenia for weeks to months. The outcome in infants and neonates (<1 year) is less certain; intellectual impairment, learning disabilities, hearing loss, and other lasting sequelae have been reported in some studies.

VIRAL ENCEPHALITIS

DEFINITION

In contrast to viral meningitis, where the infectious process and associated inflammatory response are limited largely to the meninges, in encephalitis the brain parenchyma is also involved. Many patients with encephalitis also have evidence of associated meningitis (meningoencephalitis) and, in some cases, involvement of the spinal cord or nerve roots (encephalomyelitis, encephalomyeloradiculitis).

CLINICAL MANIFESTATIONS

In addition to the acute febrile illness with evidence of meningeal involvement characteristic of meningitis, the patient with encephalitis commonly has an altered level of consciousness (confusion, behavioral abnormalities), or a depressed level of consciousness ranging from mild lethargy to coma, and evidence of either focal or diffuse neurologic signs and symptoms. Patients with encephalitis may have hallucinations, agitation, personality change, behavioral disorders, and, at times, a frankly psychotic state. Focal or generalized seizures occur in many patients with encephalitis. Virtually every possible type of focal neurologic disturbance has been reported in viral encephalitis; the signs and symptoms reflect the sites of infection and inflammation. The most commonly encountered focal findings are aphasia, ataxia, upper or lower motor neuron patterns of weakness, involuntary movements (e.g., myoclonic jerks, tremor), and cranial nerve deficits (e.g., ocular palsies, facial weakness). Involvement of the hypothalamic-pituitary axis may result in temperature dysregulation, diabetes insipidus, or the development of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Even though neurotropic viruses typically cause pathologic injury in distinct regions of the CNS, variations in clinical presentations make it impossible to reliably establish the etiology of a specific case of encephalitis on clinical grounds alone (see “Differential Diagnosis,” later in the chapter).

ETIOLOGY

In the United States, there are ~20,000 reported cases of encephalitis per year, although the actual number of cases is likely to be significantly larger. Despite comprehensive diagnostic efforts, the majority of cases of acute encephalitis of suspected viral etiology remain of unknown cause. Hundreds of viruses are capable of causing encephalitis, although only a limited subset is responsible for most cases in which a specific cause is identified (Table 40-4). The most commonly identified viruses causing sporadic cases of acute encephalitis in immunocompetent adults are herpesviruses (HSV, VZV, EBV). Epidemics of encephalitis are caused by arboviruses, which belong to several different viral taxonomic groups including Alphaviruses (e.g., EEE virus, western equine encephalitis virus), Flaviviruses (e.g., WNV, St. Louis encephalitis virus, Japanese encephalitis virus, Powassan virus), and Bunyaviruses (e.g., California encephalitis virus serogroup, LaCrosse virus). Historically, the largest number of cases of arbovirus encephalitis in the United States has been due to St. Louis encephalitis virus and the California encephalitis virus serogroup. However, since 2002, WNV has been responsible for the majority of arbovirus meningitis and encephalitis cases in the United States. The 2003 epidemic was the largest epidemic of arboviral neuroinvasive disease (encephalitis + meningitis) ever recorded in the United States, with 2866 cases and 264 deaths. In 2004–2007, WNV has accounted for between 1142 and 1459 confirmed cases of neuroinvasive disease per year in the United States and 100–177 deaths. In 2008 and 2009 there was an unexpected and dramatic decline in both the number of WNV neuroinvasive cases (ImageImage) and the number of deaths (ImageImage). New causes of viral CNS infections are constantly appearing, as evidenced by the recent outbreak of cases of encephalitis in Southeast Asia caused by Nipah virus, a newly identified member of the Paramyxoviridae family; of meningitis in Europe caused by Toscana virus, an arbovirus belonging to the Bunyavirus family; and of neurologic disorders associated with major epidemics of Chikungunya virus, a togavirus, in Africa, India, and Southeast Asia.

LABORATORY DIAGNOSIS

CSF examination

CSF examination should be performed in all patients with suspected viral encephalitis unless contraindicated by the presence of severely increased ICP. The characteristic CSF profile is indistinguishable from that of viral meningitis and typically consists of a lymphocytic pleocytosis, a mildly elevated protein concentration, and a normal glucose concentration. A CSF pleocytosis (>5 cells/μL) occurs in >95% of immunocompetent patients with documented viral encephalitis. In rare cases, a pleocytosis may be absent on the initial LP but present on subsequent LPs. Patients who are severely immunocompromised by HIV infection, glucocorticoid or other immunosuppressant drugs, chemotherapy, or lymphoreticular malignancies may fail to mount a CSF inflammatory response. CSF cell counts exceed 500/μL in only about 10% of patients with encephalitis. Infections with certain arboviruses (e.g., EEE virus or California encephalitis virus), mumps, and LCMV may occasionally result in cell counts >1000/μL, but this degree of pleocytosis should suggest the possibility of nonviral infections or other inflammatory processes. Atypical lymphocytes in the CSF may be seen in EBV infection and less commonly with other viruses, including CMV, HSV, and enteroviruses. Increased numbers of plasmacytoid or Mollaret-like large mononuclear cells have been reported in WNV encephalitis. Polymorphonuclear pleocytosis occurs in ~45% of patients with WNV encephalitis and is also a common feature in CMV myeloradiculitis in immunocompromised patients. Large numbers of CSF PMNs may be present in patients with encephalitis due to EEE virus, echovirus 9, and, more rarely, other enteroviruses. However, persisting CSF neutrophilia should prompt consideration of bacterial infection, leptospirosis, amebic infection, and noninfectious processes such as acute hemorrhagic leukoencephalitis. About 20% of patients with encephalitis will have a significant number of red blood cells (>500/μL) in the CSF in a nontraumatic tap. The pathologic correlate of this finding may be a hemorrhagic encephalitis of the type seen with HSV; however, CSF red blood cells occur with similar frequency and in similar numbers in patients with nonherpetic focal encephalitides. A decreased CSF glucose concentration is distinctly unusual in viral encephalitis and should suggest the possibility of bacterial, fungal, tuberculous, parasitic, leptospiral, syphilitic, sarcoid, or neoplastic meningitis. Rare patients with mumps, LCMV, or advanced HSV encephalitis and many patients with CMV myeloradiculitis have low CSF glucose concentrations.

CSF PCR

CSF PCR has become the primary diagnostic test for CNS infections caused by CMV, EBV, HHV-6, and enteroviruses (see “Viral Meningitis,” earlier in the chapter). In the case of VZV CNS infection, CSF PCR and detection of virus-specific IgM or intrathecal antibody synthesis both provide important aids to diagnosis. The sensitivity and specificity of CSF PCRs varies with the virus being tested. The sensitivity (~96%) and specificity (~99%) of HSV CSF PCR is equivalent to or exceeds that of brain biopsy. It is important to recognize that HSV CSF PCR results need to be interpreted after considering the likelihood of disease in the patient being tested, the timing of the test in relationship to onset of symptoms, and the prior use of antiviral therapy. A negative HSV CSF PCR test performed by a qualified laboratory at the appropriate time during illness in a patient with a high likelihood of HSV encephalitis based on clinical and laboratory abnormalities significantly reduces the likelihood of HSV encephalitis but does not exclude it. For example, in a patient with a pretest probability of 35% of having HSV encephalitis, a negative HSV CSF PCR reduces the posttest probability to ~2%, and for a patient with a pretest probability of 60%, a negative test reduces the posttest probability to ~6%. In both situations a positive test makes the diagnosis almost certain (98–99%). There have been several recent reports of initially negative HSV CSF PCR tests that were obtained early (<72 h) following symptom onset and that became positive when repeated 1–3 days later. The frequency of positive HSV CSF PCRs in patients with herpes encephalitis also decreases as a function of the duration of illness, with only ~20% of cases remaining positive after >14 days. PCR results are generally not affected by <1 week of antiviral therapy. In one study, 98% of CSF specimens remained PCR-positive during the first week of initiation of antiviral therapy, but the numbers fell to ~50% by 8–14 days and to ~21% by >15 days after initiation of antiviral therapy.

The sensitivity and specificity of CSF PCR tests for viruses other than herpes simplex have not been definitively characterized. Enteroviral CSF PCR appears to have a sensitivity and specificity of >95%. The specificity of EBV CSF PCR has not been established. Positive EBV CSF PCRs associated with positive tests for other pathogens have been reported and may reflect reactivation of EBV latent in lymphocytes that enter the CNS as a result of an unrelated infectious or inflammatory process. In patients with CNS infection due to VZV, CSF antibody and PCR studies should be considered complementary, as patients may have evidence of intrathecal synthesis of VZV-specific antibodies and negative CSF PCRs. In the case of WNV infection, CSF PCR appears to be less sensitive (~70% sensitivity) than detection of WNV-specific CSF IgM, although PCR testing remains useful in immunocompromised patients who may not mount an effective anti-WNV antibody response.

CSF culture

CSF culture is generally of limited utility in the diagnosis of acute viral encephalitis. Culture may be insensitive (e.g., >95% of patients with HSV encephalitis have negative CSF cultures as do virtually all patients with EBV-associated CNS disease) and often takes too long to significantly affect immediate therapy.

Serologic studies and antigen detection

The basic approach to the serodiagnosis of viral encephalitis is identical to that discussed earlier for viral meningitis. Demonstration of WNV IgM antibodies is diagnostic of WNV encephalitis as IgM antibodies do not cross the blood-brain barrier, and their presence in CSF is therefore indicative of intrathecal synthesis. Timing of antibody collection may be important as the rate of CSF WNV IgM seropositivity increases by ~10% per day during the first week after illness onset, reaching 80% or higher on day 7 after symptom onset. In patients with HSV encephalitis, both antibodies to HSV-1 glycoproteins and glycoprotein antigens have been detected in the CSF. Optimal detection of both HSV antibodies and antigen typically occurs after the first week of illness, limiting the utility of these tests in acute diagnosis. Nonetheless, HSV CSF antibody testing is of value in selected patients whose illness is >1 week in duration and who are CSF PCR–negative for HSV. In the case of VZV infection, CSF antibody tests may be positive when PCR fails to detect viral DNA, and both tests should be considered complementary rather than mutually exclusive.

MRI, CT, EEG

Patients with suspected encephalitis almost invariably undergo neuroimaging studies and often EEG. These tests help identify or exclude alternative diagnoses and assist in the differentiation between a focal, as opposed to a diffuse, encephalitic process. Focal findings in a patient with encephalitis should always raise the possibility of HSV encephalitis. Examples of focal findings include: (1) areas of increased signal intensity in the frontotemporal, cingulate, or insular regions of the brain on T2-weighted, FLAIR, or diffusion-weighted MRI (Fig. 40-3); (2) focal areas of low absorption, mass effect, and contrast enhancement on CT; or (3) periodic focal temporal lobe spikes on a background of slow or low-amplitude (“flattened”) activity on EEG. Approximately 10% of patients with PCR-documented HSV encephalitis will have a normal MRI, although nearly 80% will have abnormalities in the temporal lobe, and an additional 10% in extratemporal regions. The lesions are typically hyperintense on T2-weighted images. The addition of FLAIR and diffusion-weighted images to the standard MRI sequences enhances sensitivity. Children with HSV encephalitis may have atypical patterns of MRI lesions and often show involvement of brain regions outside the frontotemporal areas. CT is less sensitive than MRI and is normal in up to 20–35% of patients. EEG abnormalities occur in >75% of PCR-documented cases of HSV encephalitis; they typically involve the temporal lobes but are often nonspecific. Some patients with HSV encephalitis have a distinctive EEG pattern consisting of periodic, stereotyped, sharp-and-slow complexes originating in one or both temporal lobes and repeating at regular intervals of 2–3 s. The periodic complexes are typically noted between days 2 and 15 of the illness and are present in two-thirds of pathologically proven cases of HSV encephalitis.

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FIGURE 40-3

Coronal FLAIR magnetic resonance image from a patient with herpes simplex encephalitis. Note the area of increased signal in the right temporal lobe (left side of image) confined predominantly to the gray matter. This patient had predominantly unilateral disease; bilateral lesions are more common but may be quite asymmetric in their intensity.

Significant MRI abnormalities are found in only ~two-thirds of patients with WNV encephalitis, a frequency less than that with HSV encephalitis. When present, abnormalities often involve deep brain structures, including the thalamus, basal ganglia, and brainstem, rather than the cortex and may only be apparent on FLAIR images. EEGs in patients with WNV encephalitis typically show generalized slowing that may be more anteriorly prominent rather than the temporally predominant pattern of sharp or periodic discharges more characteristic of HSV encephalitis. Patients with VZV encephalitis may show multifocal areas of hemorrhagic and ischemic infarction, reflecting the tendency of this virus to produce a CNS vasculopathy rather than a true encephalitis. Immunocompromised adult patients with CMV often have enlarged ventricles with areas of increased T2 signal on MRI outlining the ventricles and subependymal enhancement on T1-weighted post-contrast images. Table 40-5 highlights specific diagnostic test results in encephalitis that can be useful in clinical decision-making.

TABLE 40-5

USE OF DIAGNOSTIC TESTS IN ENCEPHALITIS

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Brain biopsy

Brain biopsy is now generally reserved for patients in whom CSF PCR studies fail to lead to a specific diagnosis, who have focal abnormalities on MRI, and who continue to show progressive clinical deterioration despite treatment with acyclovir and supportive therapy.

DIFFERENTIAL DIAGNOSIS

Infection by a variety of other organisms can mimic viral encephalitis. In studies of biopsy-proven HSV encephalitis, common infectious mimics of focal viral encephalitis included mycobacteria, fungi, rickettsia, Listeria, Mycoplasma, and other bacteria (including Bartonella sp.).

Infection caused by the ameba Naegleria fowleri can also cause acute meningoencephalitis (primary amebic meningoencephalitis), whereas that caused by Acanthamoeba and Balamuthia more typically produces subacute or chronic granulomatous amebic meningoencephalitis. Naegleria thrive in warm, iron-rich pools of water, including those found in drains, canals, and both natural and human-made outdoor pools. Infection has typically occurred in immunocompetent children with a history of swimming in potentially infected water. The CSF, in contrast to the typical profile seen in viral encephalitis, often resembles that of bacterial meningitis with a neutrophilic pleocytosis and hypoglycorrhachia. Motile trophozoites can be seen in a wet mount of warm, fresh CSF. There have been an increasing number of cases of Balamuthia mandrillaris amebic encephalitis mimicking acute viral encephalitis in children and immunocompetent adults. This organism has also been associated with encephalitis in recipients of transplanted organs from a donor with unrecognized infection. No effective treatment has been identified, and mortality approaches 100%.

Encephalitis can be caused by the raccoon pinworm Baylisascaris procyonis. Clues to the diagnosis include a history of raccoon exposure, especially of playing in or eating dirt potentially contaminated with raccoon feces. Most patients are children, and many have an associated eosinophilia.

Once nonviral causes of encephalitis have been excluded, the major diagnostic challenge is to distinguish HSV from other viruses that cause encephalitis. This distinction is particularly important because in virtually every other instance the therapy is supportive, whereas specific and effective antiviral therapy is available for HSV, and its efficacy is enhanced when it is instituted early in the course of infection. HSV encephalitis should be considered when clinical features suggesting involvement of the inferomedial frontotemporal regions of the brain are present, including prominent olfactory or gustatory hallucinations, anosmia, unusual or bizarre behavior or personality alterations, or memory disturbance. HSV encephalitis should always be suspected in patients with signs and symptoms consistent with acute encephalitis with focal findings on clinical examination, neuroimaging studies, or EEG. The diagnostic procedure of choice in these patients is CSF PCR analysis for HSV. A positive CSF PCR establishes the diagnosis, and a negative test dramatically reduces the likelihood of HSV encephalitis (discussed earlier).

Image The anatomic distribution of lesions may provide an additional clue to diagnosis. Patients with rapidly progressive encephalitis and prominent brainstem signs, symptoms, or neuroimaging abnormalities may be infected by flaviviruses (WNV, St. Louis encephalitis virus, Japanese encephalitis virus), HSV, rabies, or L. monocytogenes. Significant involvement of deep gray matter structures, including the basal ganglia and thalamus, should also suggest possible flavivirus infection. These patients may present clinically with prominent movement disorders (tremor, myoclonus) or parkinsonian features. Patients with WNV infection can also present with a poliomyelitis-like acute flaccid paralysis, as can patients infected with enterovirus 71 and, less commonly, other enteroviruses. Acute flaccid paralysis is characterized by the acute onset of a lower motor neuron type of weakness with flaccid tone, reduced or absent reflexes, and relatively preserved sensation. Despite an aggressive World Health Organization poliovirus eradication initiative, 1733 cases of wild-type poliovirus-induced poliomyelitis were reported worldwide in 2009, with 73% occurring in India and Nigeria. There have been recent small outbreaks of poliomyelitis associated with vaccine strains of virus that have reverted to virulence through mutation or recombination with circulating wild-type enteroviruses in Hispaniola, China, the Philippines, Indonesia, Nigeria, and Madagascar.

Epidemiologic factors may provide important clues to the diagnosis of viral meningitis or encephalitis. Particular attention should be paid to the season of the year; the geographic location and travel history; and possible exposure to animal bites or scratches, rodents, and ticks. Although transmission from the bite of an infected dog remains the most common cause of rabies worldwide, in the United States very few cases of dog rabies occur, and the most common risk factor is exposure to bats—although a clear history of a bite or scratch is often lacking. The classic clinical presentation of encephalitic (furious) rabies is of fever, fluctuating consciousness, and autonomic hyperactivity. Phobic spasms of the larynx, pharynx, neck muscles, and diaphragm can be triggered by attempts to swallow water (hydrophobia) or by inspiration (aerophobia). Patients may also present with paralytic (dumb) rabies characterized by acute ascending paralysis. Rabies due to the bite of a bat has a different clinical presentation than classic rabies due to a dog or wolf bite. Patients present with focal neurologic deficits, myoclonus, seizures, and hallucinations; phobic spasms are not a typical feature. Patients with rabies have a CSF lymphocytic pleocytosis and may show areas of increased T2 signal abnormality in the brainstem, hippocampus, and hypothalamus. Diagnosis can be made by finding rabies virus antigen in brain tissue or in the neural innervation of hair follicles at the nape of the neck. PCR amplification of viral nucleic acid from CSF and saliva or tears may also enable diagnosis. Serology is frequently negative in both serum and CSF in the first week after onset of infection, which limits its acute diagnostic utility. No specific therapy is available, and cases are almost invariably fatal, with isolated survivors having devastating neurologic sequelae.

State public health authorities provide a valuable resource concerning isolation of particular agents in individual regions. Regular updates concerning the number, type, and distribution of cases of arboviral encephalitis can be found on the CDC and U.S. Geological Survey (USGS) websites (http://www.cdc.gov and http://diseasemaps.usgs.gov).

The major noninfectious etiologies that should be included in the differential diagnosis of acute encephalitis are nonvasculitic autoimmune inflammatory meningoencephalitis, which is frequently associated with serum antithyroid microsomal and antithyroglobulin antibodies (Hashimoto’s encephalopathy); paraneoplastic and non-paraneoplastic encephalitis associated with antineuronal antibodies (Chap. 44); acute disseminated encephalomyelitis and related fulminant demyelinating disorders (Chap. 39); and lymphoma. Finally, Creutzfeldt-Jakob disease (Chap. 43) can rarely present in an explosive fashion mimicking viral encephalitis.


TREATMENT Viral Encephalitis

Specific antiviral therapy should be initiated when appropriate. Vital functions, including respiration and blood pressure, should be monitored continuously and supported as required. In the initial stages of encephalitis, many patients will require care in an intensive care unit. Basic management and supportive therapy should include careful monitoring of ICP, fluid restriction, avoidance of hypotonic intravenous solutions, and suppression of fever. Seizures should be treated with standard anti-convulsant regimens, and prophylactic therapy should be considered in view of the high frequency of seizures in severe cases of encephalitis. As with all seriously ill, immobilized patients with altered levels of consciousness, encephalitis patients are at risk for aspiration pneumonia, stasis ulcers and decubiti, contractures, deep venous thrombosis and its complications, and infections of indwelling lines and catheters.

Acyclovir is of benefit in the treatment of HSV and should be started empirically in patients with suspected viral encephalitis, especially if focal features are present, while awaiting viral diagnostic studies. Treatment should be discontinued in patients found not to have HSV encephalitis, with the possible exception of patients with severe encephalitis due to VZV or EBV. HSV, VZV, and EBV all encode an enzyme, deoxypyrimidine (thymidine) kinase, that phosphorylates acyclovir to produce acyclovir-5'-monophosphate. Host cell enzymes then phosphorylate this compound to form a triphosphate derivative. It is the triphosphate that acts as an antiviral agent by inhibiting viral DNA polymerase and by causing premature termination of nascent viral DNA chains. The specificity of action depends on the fact that uninfected cells do not phosphorylate significant amounts of acyclovir to acyclovir-5'-monophosphate. A second level of specificity is provided by the fact that the acyclovir triphosphate is a more potent inhibitor of viral DNA polymerase than of the analogous host cell enzymes.

Adults should receive a dose of 10 mg/kg of acyclovir intravenously every 8 h (30 mg/kg per day total dose) for 14–21 days. CSF PCR can be repeated at the completion of this course, with PCR-positive patients receiving additional treatment, followed by a repeat CSF PCR test. Neonatal HSV CNS infection is less responsive to acyclovir therapy than HSV encephalitis in adults; it is recommended that neonates with HSV encephalitis receive 20 mg/kg of acyclovir every 8 h (60 mg/kg per day total dose) for a minimum of 21 days.

Prior to intravenous administration, acyclovir should be diluted to a concentration <7 mg/mL. (A 70-kg person would receive a dose of 700 mg, which would be diluted in a volume of 100 mL.) Each dose should be infused slowly over 1 h, rather than by rapid or bolus infusion, to minimize the risk of renal dysfunction. Care should be taken to avoid extravasation or intramuscular or subcutaneous administration. The alkaline pH of acyclovir can cause local inflammation and phlebitis (9%). Dose adjustment is required in patients with impaired renal glomerular filtration. Penetration into CSF is excellent, with average drug levels ~50% of serum levels. Complications of therapy include elevations in blood urea nitrogen and creatinine levels (5%), thrombocytopenia (6%), gastrointestinal toxicity (nausea, vomiting, diarrhea) (7%), and neurotoxicity (lethargy or obtundation, disorientation, confusion, agitation, hallucinations, tremors, seizures) (1%). Acyclovir resistance may be mediated by changes in either the viral deoxypyrimidine kinase or DNA polymerase. To date, acyclovir-resistant isolates have not been a significant clinical problem in immunocompetent individuals. However, there have been reports of clinically virulent acyclovir-resistant HSV isolates from sites outside the CNS in immunocompromised individuals, including those with AIDS.

Oral antiviral drugs with efficacy against HSV, VZV, and EBV, including acyclovir, famciclovir, and valacyclovir, have not been evaluated in the treatment of encephalitis either as primary therapy or as supplemental therapy following completion of a course of parenteral acyclovir. A National Institute of Allergy and Infectious Disease (NIAID)/National Institute of Neurological Disorders and Stroke–sponsored phase III trial of supplemental oral valacyclovir therapy (2 g tid for 3 months) following the initial 14- to 21-day course of therapy with parenteral acyclovir is ongoing in patients with HSV encephalitis (www.clinicaltrials.gov, identifier NCT00031486); this may help clarify the role of extended oral antiviral therapy.

Ganciclovir and foscarnet, either alone or in combination, are often utilized in the treatment of CMV-related CNS infections, although their efficacy remains unproven. Cidofovir (see later) may provide an alternative in patients who fail to respond to ganciclovir and foscarnet, although data concerning its use in CMV CNS infections are extremely limited.

Ganciclovir is a synthetic nucleoside analogue of 2'-deoxyguanosine. The drug is preferentially phosphorylated by virus-induced cellular kinases. Ganciclovir triphosphate acts as a competitive inhibitor of the CMV DNA polymerase, and its incorporation into nascent viral DNA results in premature chain termination. Following intravenous administration, CSF concentrations of ganciclovir are 25–70% of coincident plasma levels. The usual dose for treatment of severe neurologic illnesses is 5 mg/kg every 12 h given intravenously at a constant rate over 1 h. Induction therapy is followed by maintenance therapy of 5 mg/kg every day for an indefinite period. Induction therapy should be continued until patients show a decline in CSF pleocytosis and a reduction in CSF CMV DNA copy number on quantitative PCR testing (where available). Doses should be adjusted in patients with renal insufficiency. Treatment is often limited by the development of granulocytopenia and thrombocytopenia (20–25%), which may require reduction in or discontinuation of therapy. Gastrointestinal side effects, including nausea, vomiting, diarrhea, and abdominal pain, occur in ~20% of patients. Some patients treated with ganciclovir for CMV retinitis have developed retinal detachment, but the causal relationship to ganciclovir treatment is unclear. Valganciclovir is an orally bioavailable prodrug that can generate high serum levels of ganciclovir, although studies of its efficacy in treating CMV CNS infections are limited.

Foscarnet is a pyrophosphate analogue that inhibits viral DNA polymerases by binding to the pyrophosphate-binding site. Following intravenous infusion, CSF concentrations range from 15 to 100% of coincident plasma levels. The usual dose for serious CMV-related neurologic illness is 60 mg/kg every 8 h administered by constant infusion over 1 h. Induction therapy for 14–21 days is followed by maintenance therapy (60–120 mg/kg per day). Induction therapy may need to be extended in patients who fail to show a decline in CSF pleocytosis and a reduction in CSF CMV DNA copy number on quantitative PCR tests (where available). Approximately one-third of patients develop renal impairment during treatment, which is reversible following discontinuation of therapy in most, but not all, cases. This is often associated with elevations in serum creatinine and proteinuria and is less frequent in patients who are adequately hydrated. Many patients experience fatigue and nausea. Reduction in serum calcium, magnesium, and potassium occur in ~15% of patients and may be associated with tetany, cardiac rhythm disturbances, or seizures.

Cidofovir is a nucleotide analogue that is effective in treating CMV retinitis and equivalent to or better than ganciclovir in some experimental models of murine CMV encephalitis, although data concerning its efficacy in human CMV CNS disease are limited. The usual dose is 5 mg/kg intravenously once weekly for 2 weeks, then biweekly for two or more additional doses, depending on clinical response. Patients must be prehydrated with normal saline (e.g., 1 L over 1–2 h) prior to each dose and treated with probenecid (e.g., 1 g 3 h before cidofovir and 1 g 2 and 8 h after cidofovir). Nephrotoxicity is common; the dose should be reduced if renal function deteriorates.

Intravenous ribavirin (15–25 mg/kg per day in divided doses given every 8 h) has been reported to be of benefit in isolated cases of severe encephalitis due to California encephalitis (LaCrosse) virus. Ribavirin might be of benefit for the rare patients, typically infants or young children, with severe adenovirus or rotavirus encephalitis and in patients with encephalitis due to LCMV or other arenaviruses. However, clinical trials are lacking. Hemolysis, with resulting anemia, has been the major side effect limiting therapy.

No specific antiviral therapy of proven efficacy is currently available for treatment of WNV encephalitis. Patients have been treated with α-interferon, ribavirin, WNV-specific antisense oligonucleotides (ClinicalTrials. gov, identifier NCT0091845), an Israeli IVIg preparation that contains high-titer anti-WNV antibody (Omr-IgG-am) (ClinicalTrials.gov, identifier NCT00069316 and 0068055), and humanized monoclonal antibodies directed against the viral envelope glycoprotein (ClinicalTrials.gov, identifier NCT00927953 and 00515385). WNV chimeric vaccines, in which WNV envelope and premembrane proteins are inserted into the background of another flavivirus, are already undergoing human clinical testing for safety and immunogenicity (ClinicalTrials.gov, identifier NCT00746798 and 00442169). Both chimeric and killed inactivated WNV vaccines have been found to be safe and effective in preventing equine WNV infection, and several effective flavivirus vaccines are already in human use, creating optimism that a safe and effective human WNV vaccine can also be developed.


SEQUELAE

There is considerable variation in the incidence and severity of sequelae in patients surviving viral encephalitis. In the case of EEE virus infection, nearly 80% of survivors have severe neurologic sequelae. At the other extreme are infections due to EBV, California encephalitis virus, and Venezuelan equine encephalitis virus, where severe sequelae are unusual. For example, approximately 5–15% of children infected with LaCrosse virus have a residual seizure disorder, and 1% have persistent hemiparesis. Detailed information about sequelae in patients with HSV encephalitis treated with acyclovir is available from the NIAID-Collaborative Antiviral Study Group (CASG) trials. Of 32 acyclovir-treated patients, 26 survived (81%). Of the 26 survivors, 12 (46%) had no or only minor sequelae, 3 (12%) were moderately impaired (gainfully employed but not functioning at their previous level), and 11 (42%) were severely impaired (requiring continuous supportive care). The incidence and severity of sequelae were directly related to the age of the patient and the level of consciousness at the time of initiation of therapy. Patients with severe neurologic impairment (Glasgow coma score 6) at initiation of therapy either died or survived with severe sequelae. Young patients (<30 years) with good neurologic function at initiation of therapy did substantially better (100% survival, 62% with no or mild sequelae) compared with their older counterparts (>30 years; 64% survival, 57% no or mild sequelae). Some recent studies using quantitative HSV CSF PCR tests indicate that clinical outcome following treatment also correlates with the amount of HSV DNA present in CSF at the time of presentation. Many patients with WNV infection have sequelae, including cognitive impairment; weakness; and hyper- or hypokinetic movement disorders, including tremor, myoclonus, and parkinsonism. In a large longitudinal study of prognosis in 156 patients with WNV infection, the mean time to achieve recovery (defined as 95% of maximal predicted score on specific validated tests) was 112–148 days for fatigue, 121–175 days for physical function, 131–139 days for mood, and 302–455 days for mental function (the longer interval in each case representing patients with neuroinvasive disease).

SUBACUTE MENINGITIS

CLINICAL MANIFESTATIONS

Patients with subacute meningitis typically have an unrelenting headache, stiff neck, low-grade fever, and lethargy for days to several weeks before they present for evaluation. Cranial nerve abnormalities and night sweats may be present. This syndrome overlaps that of chronic meningitis, discussed in detail in Chap. 41.

ETIOLOGY

Common causative organisms include M. tuberculosisC. neoformansH. capsulatumC. immitis, and T. pallidum. Initial infection with M. tuberculosis is acquired by inhalation of aerosolized droplet nuclei. Tuberculous meningitis in adults does not develop acutely from hematogenous spread of tubercle bacilli to the meninges. Rather, millet seed–sized (miliary) tubercles form in the parenchyma of the brain during hematogenous dissemination of tubercle bacilli in the course of primary infection. These tubercles enlarge and are usually caseating. The propensity for a caseous lesion to produce meningitis is determined by its proximity to the subarachnoid space (SAS) and the rate at which fibrous encapsulation develops. Subependymal caseous foci cause meningitis via discharge of bacilli and tuberculous antigens into the SAS. Mycobacterial antigens produce an intense inflammatory reaction that leads to the production of a thick exudate that fills the basilar cisterns and surrounds the cranial nerves and major blood vessels at the base of the brain.

Image Fungal infections are typically acquired by the inhalation of airborne fungal spores. The initial pulmonary infection may be asymptomatic or present with fever, cough, sputum production, and chest pain. The pulmonary infection is often self-limited. A localized pulmonary fungal infection can then remain dormant in the lungs until there is an abnormality in cell-mediated immunity that allows the fungus to reactivate and disseminate to the CNS. The most common pathogen causing fungal meningitis is C. neoformans. This fungus is found worldwide in soil and bird excreta. H. capsulatum is endemic to the Ohio and Mississippi River valleys of the central United States and to parts of Central and South America. C. immitis is endemic to the desert areas of the southwest United States, northern Mexico, and Argentina.

Syphilis is a sexually transmitted disease that is manifest by the appearance of a painless chancre at the site of inoculation. T. pallidum invades the CNS early in the course of syphilis. Cranial nerves VII and VIII are most frequently involved.

LABORATORY DIAGNOSIS

The classic CSF abnormalities in tuberculous meningitis are as follows: (1) elevated opening pressure, (2) lymphocytic pleocytosis (10–500 cells/μL), (3) elevated protein concentration in the range of 1–5 g/L, and (4) decreased glucose concentration in the range of 1.1–2.2 mmol/L (20–40 mg/dL). The combination of unrelenting headache, stiff neck, fatigue, night sweats, and fever with a CSF lymphocytic pleocytosis and a mildly decreased glucose concentration is highly suspicious for tuberculous meningitis. The last tube of fluid collected at LP is the best tube to send for a smear for acid-fast bacilli (AFB). If there is a pellicle in the CSF or a cobweb-like clot on the surface of the fluid, AFB can best be demonstrated in a smear of the clot or pellicle. Positive smears are typically reported in only 10–40% of cases of tuberculous meningitis in adults. Cultures of CSF take 4–8 weeks to identify the organism and are positive in ~50% of adults. Culture remains the gold standard to make the diagnosis of tuberculous meningitis. PCR for the detection of M. tuberculosis DNA should be sent on CSF if available, but the sensitivity and specificity on CSF have not been defined. The Centers for Disease Control and Prevention recommend the use of nucleic acid amplification tests for the diagnosis of pulmonary tuberculosis.

The characteristic CSF abnormalities in fungal meningitis are a mononuclear or lymphocytic pleocytosis, an increased protein concentration, and a decreased glucose concentration. There may be eosinophils in the CSF in C. immitismeningitis. Large volumes of CSF are often required to demonstrate the organism on india ink smear or grow the organism in culture. If spinal fluid examined by LP on two separate occasions fails to yield an organism, CSF should be obtained by high-cervical or cisternal puncture.

The cryptococcal polysaccharide antigen test is a highly sensitive and specific test for cryptococcal meningitis. A reactive CSF cryptococcal antigen test establishes the diagnosis. The detection of the histoplasma polysaccharide antigen in CSF establishes the diagnosis of a fungal meningitis but is not specific for meningitis due to H. capsulatum. It may be falsely positive in coccidioidal meningitis. The CSF complement fixation antibody test is reported to have a specificity of 100% and a sensitivity of 75% for coccidioidal meningitis.

The diagnosis of syphilitic meningitis is made when a reactive serum treponemal test (fluorescent treponemal antibody absorption test [FTA-ABS] or microhemagglutination assay–T. pallidum [MHA-TP]) is associated with a CSF lymphocytic or mononuclear pleocytosis and an elevated protein concentration, or when the CSF Venereal Disease Research Laboratory (VDRL) is positive. A reactive CSF FTA-ABS is not definitive evidence of neurosyphilis. The CSF FTA-ABS can be falsely positive from blood contamination. A negative CSF VDRL does not rule out neurosyphilis. A negative CSF FTA-ABS or MHA-TP rules out neurosyphilis.


TREATMENT Subacute Meningitis

Empirical therapy of tuberculous meningitis is often initiated on the basis of a high index of suspicion without adequate laboratory support. Initial therapy is a combination of isoniazid (300 mg/d), rifampin (10 mg/kg per day), pyrazinamide (30 mg/kg per day in divided doses), ethambutol (15–25 mg/kg per day in divided doses), and pyridoxine (50 mg/d). When the antimicrobial sensitivity of the M. tuberculosis isolate is known, ethambutol can be discontinued. If the clinical response is good, pyrazinamide can be discontinued after 8 weeks and isoniazid and rifampin continued alone for the next 6–12 months. A 6-month course of therapy is acceptable, but therapy should be prolonged for 9–12 months in patients who have an inadequate resolution of symptoms of meningitis or who have positive mycobacterial cultures of CSF during the course of therapy. Dexamethasone therapy is recommended for HIV-negative patients with tuberculous meningitis. The dose is 12–16 mg per day for 3 weeks, then tapered over 3 weeks.

Meningitis due to C. neoformans in non-HIV, non-transplant patients is treated with induction therapy with amphotericin B (AmB) (0.7 mg/kg IV per day) plus flucytosine (100 mg/kg per day in four divided doses) for at least 4 weeks if CSF culture results are negative after 2 weeks of treatment. Therapy should be extended for a total of 6 weeks in the patient with neurologic complications. Induction therapy is followed by consolidation therapy with fluconazole 400 mg per day for 8 weeks. Organ transplant recipients are treated with liposomal AmB (3–4 mg/kg per day) or AmB lipid complex (ABLC) 5 mg/kg per day plus flucytosine (100 mg/kg per day in four divided doses) for at least 2 weeks or until CSF culture is sterile. Follow CSF yeast cultures for sterilization rather than the cryptococcal antigen titer. This treatment is followed by an 8- to 10-week course of fluconazole (400–800 mg/d [6–12 mg/kg] PO). If the CSF culture is sterile after 10 weeks of acute therapy, the dose of fluconazole is decreased to 200 mg/d for 6 months to a year. Patients with HIV infection are treated with AmB or a lipid formulation plus flucytosine for at least 2 weeks, followed by fluconazole for a minimum of 8 weeks. HIV-infected patients may require indefinite maintenance therapy with fluconazole 200 mg/d. Meningitis due to H. capsulatum is treated with AmB (0.7–1.0 mg/kg per day) for 4–12 weeks. A total dose of 30 mg/kg is recommended. Therapy with AmB is not discontinued until fungal cultures are sterile. After completing a course of AmB, maintenance therapy with itraconazole 200 mg twice daily is initiated and continued for at least 6 months to a year. C. immitis meningitis is treated with either high-dose fluconazole (1000 mg daily) as monotherapy or intravenous AmB (0.5–0.7 mg/kg per day) for >4 weeks. Intrathecal AmB (0.25–0.75 mg/d three times weekly) may be required to eradicate the infection. Lifelong therapy with fluconazole (200–400 mg daily) is recommended to prevent relapse. AmBisome (5 mg/kg per day) or AmB lipid complex (5 mg/kg per day) can be substituted for AmB in patients who have or who develop significant renal dysfunction. The most common complication of fungal meningitis is hydrocephalus. Patients who develop hydrocephalus should receive a CSF diversion device. A ventriculostomy can be used until CSF fungal cultures are sterile, at which time the ventriculostomy is replaced by a ventriculoperitoneal shunt.

Syphilitic meningitis is treated with aqueous penicillin G in a dose of 3–4 million units intravenously every 4 h for 10–14 days. An alternative regimen is 2.4 million units of procaine penicillin G intramuscularly daily with 500 mg of oral probenecid four times daily for 10–14 days. Either regimen is followed with 2.4 million units of benzathine penicillin G intramuscularly once a week for 3 weeks. The standard criterion for treatment success is reexamination of the CSF. The CSF should be reexamined at 6-month intervals for 2 years. The cell count is expected to normalize within 12 months, and the VDRL titer to decrease by two dilutions or revert to nonreactive within 2 years of completion of therapy. Failure of the CSF pleocytosis to resolve or an increase in the CSF VDRL titer by two or more dilutions requires retreatment.


CHRONIC ENCEPHALITIS

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Clinical features and pathology

Progressive multifocal leukoencephalopathy (PML) is characterized pathologically by multifocal areas of demyelination of varying size distributed throughout the brain but sparing the spinal cord and optic nerves. In addition to demyelination, there are characteristic cytologic alterations in both astrocytes and oligodendrocytes. Astrocytes are enlarged and contain hyperchromatic, deformed, and bizarre nuclei and frequent mitotic figures. Oligodendrocytes have enlarged, densely staining nuclei that contain viral inclusions formed by crystalline arrays of JC virus (JCV) particles. Patients often present with visual deficits (45%), typically a homonymous hemianopia; mental impairment (38%) (dementia, confusion, personality change); weakness, including hemior monoparesis; and ataxia. Seizures occur in ~20% of patients, predominantly in those with lesions abutting the cortex.

Almost all patients have an underlying immunosuppressive disorder. In recent series, the most common associated conditions were AIDS (80%), hematologic malignancies (13%), transplant recipients (5%), and chronic inflammatory diseases (2%). It has been estimated that up to 5% of AIDS patients will develop PML. There have been more than 30 reported cases of PML occurring in patients being treated for multiple sclerosis and inflammatory bowel disease with natalizumab, a humanized monoclonal antibody that inhibits lymphocyte trafficking into CNS and bowel mucosa by binding to α4 integrins. Risk in these patients has been estimated at 1 PML case per 1000 treated patients after a mean of 18 months of therapy. Additional cases have been reported in patients receiving other humanized monoclonal antibodies with immunomodulatory activity including efalizumab and rituximab. The basic clinical and diagnostic features appear to be similar to those seen in PML related to HIV and other forms of immunosuppression.

Diagnostic studies

The diagnosis of PML is frequently suggested by MRI. MRI reveals multifocal asymmetric, coalescing white matter lesions located periventricularly, in the centrum semiovale, in the parietal-occipital region, and in the cerebellum. These lesions have increased signal on T2 and FLAIR images and decreased signal on T1-weighted images. PML lesions are classically nonenhancing (90%) but may rarely show ring enhancement, especially in more immunocompetent patients. PML lesions are not typically associated with edema or mass effect. CT scans, which are less sensitive than MRI for the diagnosis of PML, often show hypodense nonenhancing white matter lesions.

The CSF is typically normal, although mild elevation in protein and/or IgG may be found. Pleocytosis occurs in <25% of cases, is predominantly mononuclear, and rarely exceeds 25 cells/μL. PCR amplification of JCV DNA from CSF has become an important diagnostic tool. The presence of a positive CSF PCR for JCV DNA in association with typical MRI lesions in the appropriate clinical setting is diagnostic of PML, reflecting the assay’s relatively high specificity (92–100%); however, sensitivity is variable and a negative CSF PCR does not exclude the diagnosis. In HIV-negative patients and HIV-positive patients not receiving highly active antiviral therapy (HAART), sensitivity is likely 70–90%. In HAART-treated patients, sensitivity may be closer to 60%, reflecting the lower JCV CSF viral load in this relatively more immunocompetent group. Studies with quantitative JCV CSF PCR indicate that patients with low JCV loads (<100 copies/μL) have a generally better prognosis than those with higher viral loads. Patients with negative CSF PCR studies may require brain biopsy for definitive diagnosis. In biopsy or necropsy specimens of brain, JCV antigen and nucleic acid can be detected by immunocytochemistry, in situ hybridization, or PCR amplification. Detection of JCV antigen or genomic material should only be considered diagnostic of PML if accompanied by characteristic pathologic changes, since both antigen and genomic material have been found in the brains of normal patients.

Serologic studies are of no utility in diagnosis due to high basal seroprevalence level (>80%).


TREATMENT Progressive Multifocal Leukoencephalopathy

No effective therapy for PML is available. There are case reports of potential beneficial effects of the 5-HT2a receptor antagonist mirtazapine, which may inhibit binding of JCV to its receptor on oligodendrocytes. Retrospective noncontrolled studies have also suggested a possible beneficial effect of treatment with interferonalpha. Neither of these agents has been tested in randomized controlled clinical trials. A clinical trial to evaluate the efficacy of the antimalarial drug mefloquine, which inhibits JCV replication in cell culture, is underway (www.clinicaltrials.gov, identifier NCT00746941). Intravenous and/or intrathecal cytarabine were not shown to be of benefit in a randomized controlled trial in HIV-associated PML, although some experts suggest that cytarabine may have therapeutic efficacy in situations where breakdown of the blood-brain barrier allows sufficient CSF penetration. A randomized controlled trial of cidofovir in HIV-associated PML also failed to show significant benefit. Since PML almost invariably occurs in immunocompromised individuals, any therapeutic interventions designed to enhance or restore immuno-competence should be considered. Perhaps the most dramatic demonstration of this is disease stabilization and, in rare cases, improvement associated with the improvement in the immune status of HIV-positive patients with AIDS following institution of HAART. In HIV-positive PML patients treated with HAART, 1-year survival is ~50%, although up to 80% of survivors may have significant neurologic sequelae. HIV-positive PML patients with higher CD4 counts (>300/μL3) and low or nondetectable HIV viral loads have a better prognosis than those with lower CD4 counts and higher viral loads. Although institution of HAART enhances survival in HIV + PML patients, the associated immune reconstitution in patients with an underlying opportunistic infection such as PML may also result in a severe CNS inflammatory syndrome (immune reconstitution inflammatory syndrome [IRIS]) associated with clinical worsening, CSF pleocytosis, and the appearance of new enhancing MRI lesions. Patients receiving natalizumab or other immunomodulatory antibodies, who are suspected of having PML, should have therapy halted and circulating antibodies removed by plasma exchange.


SUBACUTE SCLEROSING PANENCEPHALITIS (SSPE)

SSPE is a rare chronic, progressive demyelinating disease of the CNS associated with a chronic nonpermissive infection of brain tissue with measles virus. The frequency has been estimated at 1 in 100,000–500,000 measles cases. An average of five cases per year are reported in the United States. The incidence has declined dramatically since the introduction of a measles vaccine. Most patients give a history of primary measles infection at an early age (2 years), which is followed after a latent interval of 6–8 years by the development of a progressive neurologic disorder. Some 85% of patients are between 5 and 15 years old at diagnosis. Initial manifestations include poor school performance and mood and personality changes. Typical signs of a CNS viral infection, including fever and headache, do not occur. As the disease progresses, patients develop progressive intellectual deterioration, focal and/or generalized seizures, myoclonus, ataxia, and visual disturbances. In the late stage of the illness, patients are unresponsive, quadriparetic, and spastic, with hyperactive tendon reflexes and extensor plantar responses.

Diagnostic studies

MRI is often normal early, although areas of increased T2 signal develop in the white matter of the brain and brainstem as disease progresses. The EEG may initially show only nonspecific slowing, but with disease progression, patients develop a characteristic periodic pattern with bursts of high-voltage, sharp, slow waves every 3–8 s, followed by periods of attenuated (“flat”) background. The CSF is acellular with a normal or mildly elevated protein concentration and a markedly elevated gamma globulin level (>20% of total CSF protein). CSF antimeasles antibody levels are invariably elevated, and oligoclonal antimeasles antibodies are often present. Measles virus can be cultured from brain tissue using special cocultivation techniques. Viral antigen can be identified immunocytochemically, and viral genome can be detected by in situ hybridization or PCR amplification.


TREATMENT Subacute Sclerosing Panencephalitis

No definitive therapy for SSPE is available. Treatment with isoprinosine (Inosiplex, 100 mg/kg per day), alone or in combination with intrathecal or intraventricular alpha interferon, has been reported to prolong survival and produce clinical improvement in some patients but has never been subjected to a controlled clinical trial.


PROGRESSIVE RUBELLA PANENCEPHALITIS

This is an extremely rare disorder that primarily affects males with congenital rubella syndrome, although isolated cases have been reported following childhood rubella. After a latent period of 8–19 years, patients develop progressive neurologic deterioration. The manifestations are similar to those seen in SSPE. CSF shows a mild lymphocytic pleocytosis, slightly elevated protein concentration, markedly increased gamma globulin, and rubella virus–specific oligoclonal bands. No therapy is available. Universal prevention of both congenital and childhood rubella through the use of the available live attenuated rubella vaccine would be expected to eliminate the disease.

BRAIN ABSCESS

DEFINITION

A brain abscess is a focal, suppurative infection within the brain parenchyma, typically surrounded by a vascularized capsule. The term cerebritis is often employed to describe a nonencapsulated brain abscess.

EPIDEMIOLOGY

Image A bacterial brain abscess is a relatively uncommon intracranial infection, with an incidence of ~0.3–1.3:100,000 persons per year. Predisposing conditions include otitis media and mastoiditis, paranasal sinusitis, pyogenic infections in the chest or other body sites, penetrating head trauma or neurosurgical procedures, and dental infections. In immunocompetent individuals the most important pathogens are Streptococcus spp. (anaerobic, aerobic, and viridans [40%]), Enterobacteriaceae (Proteus spp., E. coli sp., Klebsiella spp. [25%]), anaerobes (e.g., Bacteroides spp., Fusobacterium spp. [30%]), and staphylococci (10%). In immunocompromised hosts with underlying HIV infection, organ transplantation, cancer, or immunosuppressive therapy, most brain abscesses are caused by Nocardia spp., Toxoplasma gondiiAspergillus spp., Candida spp., and C. neoformans. In Latin America and in immigrants from Latin America, the most common cause of brain abscess is Taenia solium(neurocysticercosis). In India and the Far East, mycobacterial infection (tuberculoma) remains a major cause of focal CNS mass lesions.

ETIOLOGY

A brain abscess may develop (1) by direct spread from a contiguous cranial site of infection, such as paranasal sinusitis, otitis media, mastoiditis, or dental infection; (2) following head trauma or a neurosurgical procedure; or (3) as a result of hematogenous spread from a remote site of infection. In up to 25% of cases, no obvious primary source of infection is apparent (cryptogenic brain abscess).

Approximately one-third of brain abscesses are associated with otitis media and mastoiditis, often with an associated cholesteatoma. Otogenic abscesses occur predominantly in the temporal lobe (55–75%) and cerebellum (20–30%). In some series, up to 90% of cerebellar abscesses are otogenic. Common organisms include streptococci, Bacteroides spp., Pseudomonas spp., Haemophilus spp., and Enterobacteriaceae. Abscesses that develop as a result of direct spread of infection from the frontal, ethmoidal, or sphenoidal sinuses and those that occur due to dental infections are usually located in the frontal lobes. Approximately 10% of brain abscesses are associated with paranasal sinusitis, and this association is particularly strong in young males in their second and third decades of life. The most common pathogens in brain abscesses associated with paranasal sinusitis are streptococci (especially S. milleri), Haemophilus spp., Bacteroides spp., Pseudomonas spp., and S. aureus. Dental infections are associated with ~2% of brain abscesses, although it is often suggested that many “cryptogenic” abscesses are in fact due to dental infections. The most common pathogens in this setting are streptococci, staphylococci, Bacteroides spp., and Fusobacterium spp.

Hematogenous abscesses account for ~25% of brain abscesses. Hematogenous abscesses are often multiple, and multiple abscesses often (50%) have a hematogenous origin. These abscesses show a predilection for the territory of the middle cerebral artery (i.e., posterior frontal or parietal lobes). Hematogenous abscesses are often located at the junction of the gray and white matter and are often poorly encapsulated. The microbiology of hematogenous abscesses is dependent on the primary source of infection. For example, brain abscesses that develop as a complication of infective endocarditis are often due to viridans streptococci or S. aureus. Abscesses associated with pyogenic lung infections such as lung abscess or bronchiectasis are often due to streptococci, staphylococci, Bacteroides spp., Fusobacteriumspp., or Enterobacteriaceae. Abscesses that follow penetrating head trauma or neurosurgical procedures are frequently due to methicillin-resistant S. aureus (MRSA), S. epidermidis, Enterobacteriaceae, Pseudomonas spp., and Clostridium spp. Enterobacteriaceae and P. aeruginosa are important causes of abscesses associated with urinary sepsis. Congenital cardiac malformations that produce a right-to-left shunt, such as tetralogy of Fallot, patent ductus arteriosus, and atrial and ventricular septal defects, allow bloodborne bacteria to bypass the pulmonary capillary bed and reach the brain. Similar phenomena can occur with pulmonary arteriovenous malformations. The decreased arterial oxygenation and saturation from the right-to-left shunt and polycythemia may cause focal areas of cerebral ischemia, thus providing a nidus for microorganisms that bypassed the pulmonary circulation to multiply and form an abscess. Streptococci are the most common pathogens in this setting.

PATHOGENESIS AND HISTOPATHOLOGY

Results of experimental models of brain abscess formation suggest that for bacterial invasion of brain parenchyma to occur, there must be preexisting or concomitant areas of ischemia, necrosis, or hypoxemia in brain tissue. The intact brain parenchyma is relatively resistant to infection. Once bacteria have established infection, brain abscess frequently evolves through a series of stages, influenced by the nature of the infecting organism and by the immunocompetence of the host. The early cerebritis stage (days 1–3) is characterized by a perivascular infiltration of inflammatory cells, which surround a central core of coagulative necrosis. Marked edema surrounds the lesion at this stage. In the late cerebritis stage (days 4–9), pus formation leads to enlargement of the necrotic center, which is surrounded at its border by an inflammatory infiltrate of macrophages and fibroblasts. A thin capsule of fibroblasts and reticular fibers gradually develops, and the surrounding area of cerebral edema becomes more distinct than in the previous stage. The third stage, early capsule formation (days 10–13), is characterized by the formation of a capsule that is better developed on the cortical than on the ventricular side of the lesion. This stage correlates with the appearance of a ring-enhancing capsule on neuroimaging studies. The final stage, late capsule formation (day 14 and beyond), is defined by a well-formed necrotic center surrounded by a dense collagenous capsule. The surrounding area of cerebral edema has regressed, but marked gliosis with large numbers of reactive astrocytes has developed outside the capsule. This gliotic process may contribute to the development of seizures as a sequelae of brain abscess.

CLINICAL PRESENTATION

A brain abscess typically presents as an expanding intracranial mass lesion rather than as an infectious process. Although the evolution of signs and symptoms is extremely variable, ranging from hours to weeks or even months, most patients present to the hospital 11–12 days following onset of symptoms. The classic clinical triad of headache, fever, and a focal neurologic deficit is present in <50% of cases. The most common symptom in patients with a brain abscess is headache, occurring in >75% of patients. The headache is often characterized as a constant, dull, aching sensation, either hemicranial or generalized, and it becomes progressively more severe and refractory to therapy. Fever is present in only 50% of patients at the time of diagnosis, and its absence should not exclude the diagnosis. The new onset of focal or generalized seizure activity is a presenting sign in 15–35% of patients. Focal neurologic deficits including hemiparesis, aphasia, or visual field defects are part of the initial presentation in >60% of patients.

The clinical presentation of a brain abscess depends on its location, the nature of the primary infection if present, and the level of the ICP. Hemiparesis is the most common localizing sign of a frontal lobe abscess. A temporal lobe abscess may present with a disturbance of language (dysphasia) or an upper homonymous quadrantanopia. Nystagmus and ataxia are signs of a cerebellar abscess. Signs of raised ICP—papilledema, nausea and vomiting, and drowsiness or confusion—can be the dominant presentation of some abscesses, particularly those in the cerebellum. Meningismus is not present unless the abscess has ruptured into the ventricle or the infection has spread to the subarachnoid space.

DIAGNOSIS

Diagnosis is made by neuroimaging studies. MRI (Fig. 40-4) is better than CT for demonstrating abscesses in the early (cerebritis) stages and is superior to CT for identifying abscesses in the posterior fossa. Cerebritis appears on MRI as an area of low-signal intensity on T1-weighted images with irregular postgadolinium enhancement and as an area of increased signal intensity on T2-weighted images. Cerebritis is often not visualized by CT scan but, when present, appears as an area of hypodensity. On a contrast-enhanced CT scan, a mature brain abscess appears as a focal area of hypodensity surrounded by ring enhancement with surrounding edema (hypodensity). On contrast-enhanced T1-weighted MRI, a mature brain abscess has a capsule that enhances surrounding a hypodense center and surrounded by a hypodense area of edema. On T2-weighted MRI, there is a hyperintense central area of pus surrounded by a well-defined hypointense capsule and a hyperintense surrounding area of edema. It is important to recognize that the CT and MR appearance, particularly of the capsule, may be altered by treatment with glucocorticoids. The distinction between a brain abscess and other focal CNS lesions such as primary or metastatic tumors may be facilitated by the use of diffusion-weighted imaging sequences on which brain abscesses typically show increased signal due to restricted diffusion.

Image

FIGURE 40-4

Pneumococcal brain abscess. Note that the abscess wall has hyperintense signal on the axial T1-weighted MRI (Ablack arrow), hypointense signal on the axial proton density images (Bblack arrow), and enhances prominently after gadolinium administration on the coronal T1-weighted image (C). The abscess is surrounded by a large amount of vasogenic edema and has a small “daughter” abscess (Cwhite arrow). (Courtesy of Joseph Lurito, MD; with permission.)

Microbiologic diagnosis of the etiologic agent is most accurately determined by Gram’s stain and culture of abscess material obtained by CT-guided stereotactic needle aspiration. Aerobic and anaerobic bacterial cultures and mycobacterial and fungal cultures should be obtained. Up to 10% of patients will also have positive blood cultures. LP should not be performed in patients with known or suspected focal intracranial infections such as abscess or empyema; CSF analysis contributes nothing to diagnosis or therapy, and LP increases the risk of herniation.

Additional laboratory studies may provide clues to the diagnosis of brain abscess in patients with a CNS mass lesion. About 50% of patients have a peripheral leukocytosis, 60% an elevated ESR, and 80% an elevated C-reactive protein. Blood cultures are positive in ~10% of cases overall but may be positive in >85% of patients with abscesses due to Listeria.

DIFFERENTIAL DIAGNOSIS

Conditions that can cause headache, fever, focal neurologic signs, and seizure activity include brain abscess, subdural empyema, bacterial meningitis, viral meningoencephalitis, superior sagittal sinus thrombosis, and acute disseminated encephalomyelitis. When fever is absent, primary and metastatic brain tumors become the major differential diagnosis. Less commonly, cerebral infarction or hematoma can have an MRI or CT appearance resembling brain abscess.


TREATMENT Brain Abscess

Optimal therapy of brain abscesses involves a combination of high-dose parenteral antibiotics and neurosurgical drainage. Empirical therapy of community-acquired brain abscess in an immunocompetent patient typically includes a third- or fourth-generation cephalosporin (e.g., cefotaxime, ceftriaxone, or cefepime) and metronidazole (see Table 40-1 for antibiotic dosages). In patients with penetrating head trauma or recent neurosurgical procedures, treatment should include ceftazidime as the third-generation cephalosporin to enhance coverage of Pseudomonas spp. and vancomycin for coverage of staphylococci. Meropenem plus vancomycin also provides good coverage in this setting.

Aspiration and drainage of the abscess under stereotactic guidance are beneficial for both diagnosis and therapy. Empirical antibiotic coverage should be modified based on the results of Gram’s stain and culture of the abscess contents. Complete excision of a bacterial abscess via craniotomy or craniectomy is generally reserved for multiloculated abscesses or those in which stereotactic aspiration is unsuccessful.

Medical therapy alone is not optimal for treatment of brain abscess and should be reserved for patients whose abscesses are neurosurgically inaccessible, for patients with small (<2–3 cm) or nonencapsulated abscesses (cerebritis), and patients whose condition is too tenuous to allow performance of a neurosurgical procedure. All patients should receive a minimum of 6–8 weeks of parenteral antibiotic therapy. The role, if any, of supplemental oral antibiotic therapy following completion of a standard course of parenteral therapy has never been adequately studied.

In addition to surgical drainage and antibiotic therapy, patients should receive prophylactic anticonvulsant therapy because of the high risk (~35%) of focal or generalized seizures. Anticonvulsant therapy is continued for at least 3 months after resolution of the abscess, and decisions regarding withdrawal are then based on the EEG. If the EEG is abnormal, anticonvulsant therapy should be continued. If the EEG is normal, anticonvulsant therapy can be slowly withdrawn, with close follow-up and repeat EEG after the medication has been discontinued.

Glucocorticoids should not be given routinely to patients with brain abscesses. Intravenous dexamethasone therapy (10 mg every 6 h) is usually reserved for patients with substantial periabscess edema and associated mass effect and increased ICP. Dexamethasone should be tapered as rapidly as possible to avoid delaying the natural process of encapsulation of the abscess.

Serial MRI or CT scans should be obtained on a monthly or twice-monthly basis to document resolution of the abscess. More frequent studies (e.g., weekly) are probably warranted in the subset of patients who are receiving antibiotic therapy alone. A small amount of enhancement may remain for months after the abscess has been successfully treated.


PROGNOSIS

The mortality rate of brain abscess has declined in parallel with the development of enhanced neuroimaging techniques, improved neurosurgical procedures for stereotactic aspiration, and improved antibiotics. In modern series, the mortality rate is typically <15%. Significant sequelae, including seizures, persisting weakness, aphasia, or mental impairment, occur in >20% of survivors.

NONBACTERIAL CAUSES OF INFECTIOUS FOCAL CNS LESIONS

ETIOLOGY

Neurocysticercosis is the most common parasitic disease of the CNS worldwide. Humans acquire cysticercosis by the ingestion of food contaminated with the eggs of the parasite T. solium. Toxoplasmosis is a parasitic disease caused by T. gondii and acquired from the ingestion of undercooked meat and from handling cat feces.

CLINICAL PRESENTATION

The most common manifestation of neurocysticercosis is new-onset partial seizures with or without secondary generalization. Cysticerci may develop in the brain parenchyma and cause seizures or focal neurologic deficits. When present in the subarachnoid or ventricular spaces, cysticerci can produce increased ICP by interference with CSF flow. Spinal cysticerci can mimic the presentation of intraspinal tumors. When the cysticerci first lodge in the brain, they frequently cause little in the way of an inflammatory response. As the cysticercal cyst degenerates, it elicits an inflammatory response that may present clinically as a seizure. Eventually the cyst dies, a process that may take several years and is typically associated with resolution of the inflammatory response and, often, abatement of seizures.

Primary Toxoplasma infection is often asymptomatic. However, during this phase parasites may spread to the CNS, where they become latent. Reactivation of CNS infection is almost exclusively associated with immuno-compromised hosts, particularly those with HIV infection. During this phase patients present with headache, fever, seizures, and focal neurologic deficits.

DIAGNOSIS

The lesions of neurocysticercosis are readily visualized by MRI or CT scans. Lesions with viable parasites appear as cystic lesions. The scolex can often be visualized on MRI. Lesions may appear as contrast-enhancing lesions surrounded by edema. A very early sign of cyst death is hypointensity of the vesicular fluid on T2-weighted images when compared with CSF. Parenchymal brain calcifications are the most common finding and evidence that the parasite is no longer viable. MRI findings of toxoplasmosis consist of multiple lesions in the deep white matter, the thalamus, and basal ganglia and at the gray-white junction in the cerebral hemispheres. With contrast administration, the majority of the lesions enhance in a ringed, nodular, or homogeneous pattern and are surrounded by edema. In the presence of the characteristic neuroimaging abnormalities of T. gondii infection, serum IgG antibody to T. gondiishould be obtained and, when positive, the patient should be treated.


TREATMENT Infectious Focal CNS Lesions

Anticonvulsant therapy is initiated when the patient with neurocysticercosis presents with a seizure. There is controversy about whether or not anthelmintic therapy should be given to all patients, and recommendations are based on the stage of the lesion. Cysticerci appearing as cystic lesions in the brain parenchyma with or without pericystic edema or in the subarachnoid space at the convexity of the cerebral hemispheres should be treated with anticysticidal therapy. Cysticidal drugs accelerate the destruction of the parasites, resulting in a faster resolution of the infection. Albendazole and praziquantel are used in the treatment of neurocysticercosis. Approximately 85% of parenchymal cysts are destroyed by a single course of albendazole, and ~75% are destroyed by a single course of praziquantel. The dose of albendazole is 15 mg/kg per day in two doses for 8 days. The dose of praziquantel is 50 mg/kg per day for 15 days, although a number of other dosage regimens are also frequently cited. Prednisone or dexamethasone is given with anticysticidal therapy to reduce the host inflammatory response to degenerating parasites. Many, but not all, experts recommend anticysticidal therapy for lesions that are surrounded by a contrast-enhancing ring. There is universal agreement that calcified lesions do not need to be treated with anticysticidal therapy. Antiepileptic therapy can be stopped once the follow-up CT scan shows resolution of the lesion. Long-term anti-epileptic therapy is recommended when seizures occur after resolution of edema and resorption or calcification of the degenerating cyst.

CNS toxoplasmosis is treated with a combination of sulfadiazine, 1.5–2.0 g orally qid, plus pyrimethamine, 100 mg orally to load, then 75–100 mg orally qd, plus folinic acid, 10–15 mg orally qd. Folinic acid is added to the regimen to prevent megaloblastic anemia. Therapy is continued until there is no evidence of active disease on neuroimaging studies, which typically takes at least 6 weeks, and then the dose of sulfadiazine is reduced to 2–4 g/d and pyrimethamine to 50 mg/d. Clindamycin plus pyrimethamine is an alternative therapy for patients who cannot tolerate sulfadiazine, but the combination of pyrimethamine and sulfadiazine is more effective.


SUBDURAL EMPYEMA

A subdural empyema (SDE) is a collection of pus between the dura and arachnoid membranes (Fig. 40-5).

Image

FIGURE 40-5

Subdural empyema.

EPIDEMIOLOGY

SDE is a rare disorder that accounts for 15–25% of focal suppurative CNS infections. Sinusitis is the most common predisposing condition and typically involves the frontal sinuses, either alone or in combination with the ethmoid and maxillary sinuses. Sinusitis-associated empyema has a striking predilection for young males, possibly reflecting sex-related differences in sinus anatomy and development. It has been suggested that SDE may complicate 1–2% of cases of frontal sinusitis severe enough to require hospitalization. As a consequence of this epidemiology, SDE shows an ~3:1 male/female predominance, with 70% of cases occurring in the second and third decades of life. SDE may also develop as a complication of head trauma or neurosurgery. Secondary infection of a subdural effusion may also result in empyema, although secondary infection of hematomas, in the absence of a prior neurosurgical procedure, is rare.

ETIOLOGY

Aerobic and anaerobic streptococci, staphylococci, Enterobacteriaceae, and anaerobic bacteria are the most common causative organisms of sinusitis-associated SDE. Staphylococci and gram-negative bacilli are often the etiologic organisms when SDE follows neurosurgical procedures or head trauma. Up to one-third of cases are culture-negative, possibly reflecting difficulty in obtaining adequate anaerobic cultures.

PATHOPHYSIOLOGY

Sinusitis-associated SDE develops as a result of either retrograde spread of infection from septic thrombophlebitis of the mucosal veins draining the sinuses or contiguous spread of infection to the brain from osteomyelitis in the posterior wall of the frontal or other sinuses. SDE may also develop from direct introduction of bacteria into the subdural space as a complication of a neurosurgical procedure. The evolution of SDE can be extremely rapid because the subdural space is a large compartment that offers few mechanical barriers to the spread of infection. In patients with sinusitis-associated SDE, suppuration typically begins in the upper and anterior portions of one cerebral hemisphere and then extends posteriorly. SDE is often associated with other intracranial infections, including epidural empyema (40%), cortical thrombophlebitis (35%), and intracranial abscess or cerebritis (>25%). Cortical venous infarction produces necrosis of underlying cerebral cortex and subcortical white matter, with focal neurologic deficits and seizures (discussed later).

CLINICAL PRESENTATION

A patient with SDE typically presents with fever and a progressively worsening headache. The diagnosis of SDE should always be suspected in a patient with known sinusitis who presents with new CNS signs or symptoms. Patients with underlying sinusitis frequently have symptoms related to this infection. As the infection progresses, focal neurologic deficits, seizures, nuchal rigidity, and signs of increased ICP commonly occur. Headache is the most common complaint at the time of presentation; initially it is localized to the side of the subdural infection, but then it becomes more severe and generalized. Contralateral hemiparesis or hemiplegia is the most common focal neurologic deficit and can occur from the direct effects of the SDE on the cortex or as a consequence of venous infarction. Seizures begin as partial motor seizures that then become secondarily generalized. Seizures may be due to the direct irritative effect of the SDE on the underlying cortex or result from cortical venous infarction (discussed earlier). In untreated SDE, the increasing mass effect and increase in ICP cause progressive deterioration in consciousness, leading ultimately to coma.

DIAGNOSIS

MRI (Fig. 40-6) is superior to CT in identifying SDE and any associated intracranial infections. The administration of gadolinium greatly improves diagnosis by enhancing the rim of the empyema and allowing the empyema to be clearly delineated from the underlying brain parenchyma. Cranial MRI is also extremely valuable in identifying sinusitis, other focal CNS infections, cortical venous infarction, cerebral edema, and cerebritis. CT may show a crescent-shaped hypodense lesion over one or both hemispheres or in the interhemispheric fissure. Frequently the degree of mass effect, exemplified by midline shift, ventricular compression, and sulcal effacement, is far out of proportion to the mass of the SDE.

Image

FIGURE 40-6

Subdural empyema. There is marked enhancement of the dura and leptomeninges (ABstraight arrows) along the left medial hemisphere. The pus is hypointense on T1-weighted images (AB) but markedly hyperintense on the proton density–weighted (Ccurved arrow) image. (Courtesy of Joseph Lurito, MD; with permission.)

CSF examination should be avoided in patients with known or suspected SDE as it adds no useful information and is associated with the risk of cerebral herniation.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of the combination of headache, fever, focal neurologic signs, and seizure activity that progresses rapidly to an altered level of consciousness includes subdural hematoma, bacterial meningitis, viral encephalitis, brain abscess, superior sagittal sinus thrombosis, and acute disseminated encephalomyelitis. The presence of nuchal rigidity is unusual with brain abscess or epidural empyema and should suggest the possibility of SDE when associated with significant focal neurologic signs and fever. Patients with bacterial meningitis also have nuchal rigidity but do not typically have focal deficits of the severity seen with SDE.


TREATMENT Subdural Empyema

SDE is a medical emergency. Emergent neurosurgical evacuation of the empyema, either through craniotomy, craniectomy, or burr-hole drainage, is the definitive step in the management of this infection. Empirical antimicrobial therapy for community-acquired SDE should include a combination of a third-generation cephalosporin (e.g., cefotaxime or ceftriaxone), vancomycin, and metronidazole (see Table 40-1 for dosages). Patients with hospital-acquired SDE may have infections due to Pseudomonas spp. or MRSA and should receive coverage with a carbapenem (e.g., meropenem) and vancomycin. Metronidazole is not necessary for anti-anaerobic therapy when meropenem is being used. Parenteral antibiotic therapy should be continued for a minimum of 3–4 weeks after SDE drainage. Patients with associated cranial osteomyelitis may require longer therapy. Specific diagnosis of the etiologic organisms is made based on Gram’s stain and culture of fluid obtained via either burr holes or craniotomy; the initial empirical antibiotic coverage can be modified accordingly.


PROGNOSIS

Prognosis is influenced by the level of consciousness of the patient at the time of hospital presentation, the size of the empyema, and the speed with which therapy is instituted. Long-term neurologic sequelae, which include seizures and hemiparesis, occur in up to 50% of cases.

CRANIAL EPIDURAL ABSCESS

Cranial epidural abscess is a suppurative infection occurring in the potential space between the inner skull table and dura (Fig. 40-7).

Image

FIGURE 40-7

Cranial epidural abscess is a collection of pus between the dura and the inner table of the skull.

ETIOLOGY AND PATHOPHYSIOLOGY

Cranial epidural abscess is less common than either brain abscess or SDE and accounts for <2% of focal suppurative CNS infections. A cranial epidural abscess develops as a complication of a craniotomy or compound skull fracture or as a result of spread of infection from the frontal sinuses, middle ear, mastoid, or orbit. An epidural abscess may develop contiguous to an area of osteomyelitis, when craniotomy is complicated by infection of the wound or bone flap, or as a result of direct infection of the epidural space. Infection in the frontal sinus, middle ear, mastoid, or orbit can reach the epidural space through retrograde spread of infection from septic thrombophlebitis in the emissary veins that drain these areas or by way of direct spread of infection through areas of osteomyelitis. Unlike the subdural space, the epidural space is really a potential rather than an actual compartment. The dura is normally tightly adherent to the inner skull table, and infection must dissect the dura away from the skull table as it spreads. As a result, epidural abscesses are often smaller than SDEs. Cranial epidural abscesses, unlike brain abscesses, only rarely result from hematogenous spread of infection from extracranial primary sites. The bacteriology of a cranial epidural abscess is similar to that of SDE (discussed earlier). The etiologic organisms of an epidural abscess that arises from frontal sinusitis, middle-ear infections, or mastoiditis are usually streptococci or anaerobic organisms. Staphylococci or gram-negative organisms are the usual cause of an epidural abscess that develops as a complication of craniotomy or compound skull fracture.

CLINICAL PRESENTATION

Patients present with fever (60%), headache (40%), nuchal rigidity (35%), seizures (10%), and focal deficits (5%). Development of symptoms may be insidious, as the empyema usually enlarges slowly in the confined anatomic space between the dura and the inner table of the skull. Periorbital edema and Potts puffy tumor, reflecting underlying associated frontal bone osteomyelitis, are present in ~40%. In patients with a recent neuro-surgical procedure, wound infection is invariably present, but other symptoms may be subtle and can include altered mental status (45%), fever (35%), and headache (20%). The diagnosis should be considered when fever and headache follow recent head trauma or occur in the setting of frontal sinusitis, mastoiditis, or otitis media.

DIAGNOSIS

Cranial MRI with gadolinium enhancement is the procedure of choice to demonstrate a cranial epidural abscess. The sensitivity of CT is limited by the presence of signal artifacts arising from the bone of the inner skull table. The CT appearance of an epidural empyema is that of a lens or crescent-shaped hypodense extraaxial lesion. On MRI, an epidural empyema appears as a lenti-form or crescent-shaped fluid collection that is hyper-intense compared to CSF on T2-weighted images. On T1-weighted images, the fluid collection may be either isointense or hypointense compared to brain. Following the administration of gadolinium, there is linear enhancement of the dura on T1-weighted images. In distinction to subdural empyema, signs of mass effect or other parenchymal abnormalities are uncommon.


TREATMENT Epidural Abscess

Immediate neurosurgical drainage is indicated. Empirical antimicrobial therapy, pending the results of Gram’s stain and culture of the purulent material obtained at surgery, should include a combination of a third-generation cephalosporin, vancomycin, and metronidazole (Table 40-1). Ceftazidime or meropenem should be substituted for ceftriaxone or cefotaxime in neurosurgical patients. Metronidazole is not necessary for anti-anaerobic coverage in patients receiving meropenem. When the organism has been identified, antimicrobial therapy can be modified accordingly. Antibiotics should be continued for 3–6 weeks after surgical drainage. Patients with associated osteomyelitis may require additional therapy.


PROGNOSIS

The mortality rate is <5% in modern series, and full recovery is the rule in most survivors.

SUPPURATIVE THROMBOPHLEBITIS

DEFINITION

Suppurative intracranial thrombophlebitis is septic venous thrombosis of cortical veins and sinuses. This may occur as a complication of bacterial meningitis; SDE; epidural abscess; or infection in the skin of the face, paranasal sinuses, middle ear, or mastoid.

ANATOMY AND PATHOPHYSIOLOGY

The cerebral veins and venous sinuses have no valves; therefore, blood within them can flow in either direction. The superior sagittal sinus is the largest of the venous sinuses (Fig. 40-8). It receives blood from the frontal, parietal, and occipital superior cerebral veins and the diploic veins, which communicate with the meningeal veins. Bacterial meningitis is a common predisposing condition for septic thrombosis of the superior sagittal sinus. The diploic veins, which drain into the superior sagittal sinus, provide a route for the spread of infection from the meninges, especially in cases where there is purulent exudate near areas of the superior sagittal sinus. Infection can also spread to the superior sagittal sinus from nearby SDE or epidural abscess. Dehydration from vomiting, hypercoagulable states, and immunologic abnormalities, including the presence of circulating antiphospholipid antibodies, also contribute to cerebral venous sinus thrombosis. Thrombosis may extend from one sinus to another, and at autopsy thrombi of different histologic ages can often be detected in several sinuses. Thrombosis of the superior sagittal sinus is often associated with thrombosis of superior cortical veins and small parenchymal hemorrhages.

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FIGURE 40-8

Anatomy of the cerebral venous sinuses.

The superior sagittal sinus drains into the transverse sinuses (Fig. 40-8). The transverse sinuses also receive venous drainage from small veins from both the middle ear and mastoid cells. The transverse sinus becomes the sigmoid sinus before draining into the internal jugular vein. Septic transverse/sigmoid sinus thrombosis can be a complication of acute and chronic otitis media or mastoiditis. Infection spreads from the mastoid air cells to the transverse sinus via the emissary veins or by direct invasion. The cavernous sinuses are inferior to the superior sagittal sinus at the base of the skull. The cavernous sinuses receive blood from the facial veins via the superior and inferior ophthalmic veins. Bacteria in the facial veins enter the cavernous sinus via these veins. Bacteria in the sphenoid and ethmoid sinuses can spread to the cavernous sinuses via the small emissary veins. The sphenoid and ethmoid sinuses are the most common sites of primary infection resulting in septic cavernous sinus thrombosis.

CLINICAL MANIFESTATIONS

Septic thrombosis of the superior sagittal sinus presents with headache, fever, nausea and vomiting, confusion, and focal or generalized seizures. There may be a rapid development of stupor and coma. Weakness of the lower extremities with bilateral Babinski’s signs or hemiparesis is often present. When superior sagittal sinus thrombosis occurs as a complication of bacterial meningitis, nuchal rigidity and Kernig’s and Brudzinski’s signs may be present.

The oculomotor nerve, the trochlear nerve, the abducens nerve, the ophthalmic and maxillary branches of the trigeminal nerve, and the internal carotid artery all pass through the cavernous sinus (see Fig. 34-4). The symptoms of septic cavernous sinus thrombosis are fever, headache, frontal and retroorbital pain, and diplopia. The classic signs are ptosis, proptosis, chemosis, and extraocular dysmotility due to deficits of cranial nerves III, IV, and VI; hyperesthesia of the ophthalmic and maxillary divisions of the fifth cranial nerve and a decreased corneal reflex may be detected. There may be evidence of dilated, tortuous retinal veins and papilledema.

Headache and earache are the most frequent symptoms of transverse sinus thrombosis. A transverse sinus thrombosis may also present with otitis media, sixth nerve palsy, and retroorbital or facial pain (Gradenigo’s syndrome). Sigmoid sinus and internal jugular vein thrombosis may present with neck pain.

DIAGNOSIS

The diagnosis of septic venous sinus thrombosis is suggested by an absent flow void within the affected venous sinus on MRI and confirmed by magnetic resonance venography, CT angiogram, or the venous phase of cerebral angiography. The diagnosis of thrombophlebitis of intracerebral and meningeal veins is suggested by the presence of intracerebral hemorrhage but requires cerebral angiography for definitive diagnosis.


TREATMENT Suppurative Thrombophlebitis

Septic venous sinus thrombosis is treated with antibiotics, hydration, and removal of infected tissue and thrombus in septic lateral or cavernous sinus thrombosis. The choice of antimicrobial therapy is based on the bacteria responsible for the predisposing or associated condition. Optimal duration of therapy is unknown, but antibiotics are usually continued for 6 weeks or until there is radiographic evidence of resolution of thrombosis. Anticoagulation with dose-adjusted intravenous heparin is recommended for aseptic venous sinus thrombosis and in the treatment of septic venous sinus thrombosis complicating bacterial meningitis in patients who have progressive neurologic deterioration despite antimicrobial therapy and intravenous fluids. The presence of a small intracerebral hemorrhage from septic thrombophlebitis is not an absolute contraindication to heparin therapy. Successful management of aseptic venous sinus thrombosis has been reported with surgical thrombectomy, catheter-directed urokinase therapy, and with a combination of intrathrombus recombinant tissue plasminogen activator (rtPA) and intravenous heparin, but there is not enough data to recommend these therapies in septic venous sinus thrombosis.