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InternalMed_Harrison. FIGURE 164-1 The management of patients with suspected central nervous system (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. Viral culture: CSF, throat, stool If skin lesions DFA for HSV, VZV HIV serology Serology for enteroviruses and arthropod-borne viruses Fungal: CSF cryptococcal Ag, fungal cultures Bacterial: VDRL and bacterial culture, PCR Mycobacterial: CSF AFB stain and TB PCR, TB culture, CXR, PPD


InternalMed_Harrison

InternalMed_Harrison. Fungal: CSF cryptococcal Ag, fungal cultures Bacterial: VDRL and bacterial culture, PCR Mycobacterial: CSF AFB stain and TB PCR, TB culture, CXR, PPD Tier 2 Evaluation (if above negative): EBV: Serum serology, CSF PCR Mycoplasma: Serum serology, CSF PCR Influenza A, B: Serology, respiratory culture, CSF PCR Adenovirus: Serology, throat swab. CSF PCR Fungal: CSF & serum coccidioidal antibody, Histoplasma antigen & antibody Rabies Raccoon exposure or Hx of pica Baylisascaris procyonis Pet bird (Psittacine) exposure Chlamydia psittaci (Psittacosis) Exposure to cattle or unpasteurized dairy products Brucella spp. (Brucellosis) Coxiella burnetii (Q fever) Wild rodent or hamster exposure Bat exposure Animal bite Cat exposure LCMV Swimming in lakes or ponds or nonchlorinated water Acanthamoeba or Naegleria fowleri (amebic meningoencephalitis) Bartonella spp. (cat scratch fever) B


InternalMed_Harrison

InternalMed_Harrison. 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, subarachnoid space, and brain parenchyma are all frequently involved in the inflammatory reaction (meningoencephalitis). 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 influenzae type 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.


InternalMed_Harrison

InternalMed_Harrison. N. meningitidis is the causative organism of recurring epidemics of meningitis every 8 to 12 years. S. pneumoniae (Chap. 173) 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.


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InternalMed_Harrison. The incidence of meningitis due to N. meningitidis (Chap. 180) has decreased with the routine immunization of 11to 18-year-olds with the quadrivalent (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.


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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, and head trauma associated with CSF rhinorrhea or otorrhea. Otitis, mastoiditis, and sinusitis are predisposing and associated conditions for meningitis due to Streptococci sp., gram-negative anaerobes,


InternalMed_Harrison

InternalMed_Harrison. Meningitis, Encephalitis, Brain Abscess, and Empyema 886 Staphylococcus aureus, Haemophilus sp., and Enterobacteriaceae. and complications of bacterial meningitis result from the immune Meningitis complicating endocarditis may be due to viridans strepto-response to the invading pathogen rather than from direct bacteria-cocci, S. aureus, Streptococcus bovis, the HACEK group (Haemophilus induced tissue injury. As a result, neurologic injury can progress even sp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, after the CSF has been sterilized by antibiotic therapy. Eikenella corrodens, Kingella kingae), or enterococci. The lysis of bacteria with the subsequent release of cell-wall compo-Group B Streptococcus, or Streptococcus agalactiae, was previously nents into the subarachnoid space is the initial step in the induction of responsible for meningitis predominantly in neonates, but it has been the inflammatory response and the formation of a purulent exudate in reported


InternalMed_Harrison

InternalMed_Harrison. space is the initial step in the induction of responsible for meningitis predominantly in neonates, but it has been the inflammatory response and the formation of a purulent exudate in reported with increasing frequency in individuals >50 years of age, the subarachnoid space (Fig. 164-2). Bacterial cell-wall components, particularly those with underlying diseases. such as the lipopolysaccharide (LPS) molecules of gram-negative bac-


InternalMed_Harrison

InternalMed_Harrison. L. monocytogenes (Chap. 176) is an increasingly important cause teria and teichoic acid and peptidoglycans of S. pneumoniae, induce of meningitis in neonates (<1 month of age), pregnant women, indi-meningeal inflammation by stimulating the production of inflammaviduals >60 years, and immunocompromised individuals of all ages. tory cytokines and chemokines by microglia, astrocytes, monocytes, Infection is acquired by ingesting foods contaminated by Listeria. microvascular endothelial cells, and CSF leukocytes. In experimental Foodborne human listerial infection has been reported from contami-models of meningitis, cytokines including tumor necrosis factor nated coleslaw, milk, soft cheeses, and several types of “ready-to-eat” alpha (TNF-α) and interleukin 1β (IL-1β) are present in CSF within foods, including delicatessen meat and uncooked hotdogs. 1–2 h of intracisternal inoculation of LPS. This cytokine response is


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InternalMed_Harrison. The frequency of H. influenzae type b (Hib) meningitis in children quickly followed by an increase in CSF protein concentration and has declined dramatically since the introduction of the Hib conjugate leukocytosis. Chemokines (cytokines that induce chemotactic vaccine, although rare cases of Hib meningitis in vaccinated children migration in leukocytes) and a variety of other proinflammatory cytohave been reported. More frequently, H. influenzae causes meningitis kines are also produced and secreted by leukocytes and tissue cells that in unvaccinated children and older adults, and non-b H. influenzae is are stimulated by IL-1β and TNF-α. In addition, bacteremia and the an emerging pathogen. inflammatory cytokines induce the production of excitatory amino


InternalMed_Harrison

InternalMed_Harrison. S. aureus and coagulase-negative staphylococci (Chap. 172) are acids, reactive oxygen and nitrogen species (free oxygen radicals, nitric important causes of meningitis that occurs following invasive neu-oxide, and peroxynitrite), and other mediators that can induce death of rosurgical procedures, particularly shunting procedures for hydro-brain cells, especially in the dentate gyrus of the hippocampus. cephalus, or as a complication of the use of subcutaneous Ommaya Much of the pathophysiology of bacterial meningitis is a direct consereservoirs for administration of intrathecal chemotherapy. quence of elevated levels of CSF cytokines and chemokines. TNF-α and


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. A critical event in the pathogenesis of bacterial meningitis is the inflammatory reaction induced by the invading bacteria. FIGURE 164-2 The pathophysiology of the neurologic complications of bacterial meningitis. Many of the neurologic manifestations CSF, cerebrospinal fluid; SAS, subarachnoid space.


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InternalMed_Harrison. Invasion of SAS by meningeal pathogens Multiplication of organisms and lysis of organisms by bactericidal antibiotics Release of bacterial cell-wall components (endotoxin, teichoic acid) Production of inflammatory cytokines Altered blood-brain barrier permeability Adherence of leukocytes to cerebral capillary endothelial cells Permeability of blood vessels with leakage of plasma proteins into CSF Leukocytes migrate into CSF, degranulate, and release toxic metabolites Alterations in cerebral blood flow Production of excitatory amino acids and reactive oxygen and nitrogen species Cell injury and death blood flow Cerebral ischemia Vasogenic edema Exudate in SAS obstructs outflow and resorption of CSF and surrounds and infiltrates cerebral vasculature Obstructive and communicating hydrocephalus and interstitial edema Cytotoxic edema, stroke, seizures blood flow


InternalMed_Harrison

InternalMed_Harrison. 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. 164-2). The sub-arachnoid 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.


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InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 330). 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.


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InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. Specific clinical features may provide clues to the diagnosis of individual organisms and are discussed in more detail in specific chapters devoted to individual pathogens. 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.


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InternalMed_Harrison. When bacterial meningitis is suspected, blood cultures should be immediately obtained and empirical antimicrobial and adjunctive dexamethasone therapy initiated without delay (Table 164-1). The diagnosis of bacterial meningitis is made by examination of the CSF (Table 164-2). 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. The classic CSF abnormalities in bacterial meningitis (Table 164-2) 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 men ingitis. Use of the CSF/serum glucose ratio corrects for hyperglycemia Preterm infants to infants Ampicillin + cefotaxime <1 month Immunocompetent Cefotaxime, ceftriaxone, or cefepime + children >3 months and vancomycin adults <55 Adults >55 and adults of Ampicillin + cefotaxime, ceftriaxone or any age with alcoholism cefepime + vancomycin or other debilitating illnesses


InternalMed_Harrison

InternalMed_Harrison. Adults >55 and adults of Ampicillin + cefotaxime, ceftriaxone or any age with alcoholism cefepime + vancomycin or other debilitating illnesses Hospital-acquired Ampicillin + ceftazidime or meropenem + meningitis, posttraumatic vancomycin or postneurosurgery meningitis, neutropenic patients, or patients with impaired cell-mediated immunity


InternalMed_Harrison

InternalMed_Harrison. Ampicillin 300 (mg/kg)/d, q6h 12 g/d, q4h Cefepime 150 (mg/kg)/d, q8h 6 g/d, q8h Cefotaxime 225-300 (mg/kg)/d, q6h 12 g/d, q4h Ceftriaxone 100 (mg/kg)/d, q12h 4 g/d, q12h Ceftazidime 150 (mg/kg)/d, q8h 6 g/d, q8h Gentamicin 7.5 (mg/kg)/d, q8hb 7.5 (mg/kg)/d, q8h Meropenem 120 (mg/kg)/d, q8h 6 g/d, q8h Metronidazole 30 (mg/kg)/d, q6h 1500–2000 mg/d, q6h Nafcillin 100–200 (mg/kg)/d, q6h 9–12 g/d, q4h Penicillin G 400,000 (U/kg)/d, q4h 20–24 million U/d, q4h Vancomycin 45-60 (mg/kg)/d, q6h 45-60 (mg/kg)d, q6–12hb aAll antibiotics are administered intravenously; doses indicated assume normal renal and hepatic function. bDoses should be adjusted based on serum peak and trough levels: gentamicin therapeutic level: peak: 5–8 μg/mL; trough: <2 μg/mL; vancomycin therapeutic level: peak: 25–40 μg/mL; trough: 5–15 μg/mL. Meningitis, Encephalitis, Brain Abscess, and Empyema White blood cells 10/μL to 10,000/μL; neutrophils predominate Glucose <2.2 mmol/L (<40 mg/dL) CSF/serum glucose <0.4


InternalMed_Harrison

InternalMed_Harrison. Meningitis, Encephalitis, Brain Abscess, and Empyema White blood cells 10/μL to 10,000/μL; neutrophils predominate Glucose <2.2 mmol/L (<40 mg/dL) CSF/serum glucose <0.4 Protein >0.45 g/L (>45 mg/dL) Latex agglutination May be positive in patients with meningitis due to Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b, Escherichia coli, group B streptococci Limulus lysate Positive in cases of gram-negative meningitis


InternalMed_Harrison

InternalMed_Harrison. Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b, Escherichia coli, group B streptococci Limulus lysate Positive in cases of gram-negative meningitis Abbreviation: PCR, polymerase chain reaction 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.


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InternalMed_Harrison. 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. pneumoniae, N. meningitidis, H. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. meningitidis antigens, 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Viral meningoencephalitis, and particularly herpes simplex virus (HSV) encephalitis, can mimic the clinical presentation of bacterial meningitis (see “Viral Encephalitis,” below). 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 the 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, fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted MRI images, high signal intensity lesions are seen in the orbitofrontal,


InternalMed_Harrison

InternalMed_Harrison. By contrast, in HSV encephalitis, on T2-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted 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 (see below).


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InternalMed_Harrison. Rickettsial disease can resemble bacterial meningitis (Chap. 211). 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


InternalMed_Harrison

InternalMed_Harrison. 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, confusion, 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,


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. Focal suppurative CNS infections (see below), 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.


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InternalMed_Harrison. A number of noninfectious CNS disorders can mimic bacterial meningitis. Subarachnoid hemorrhage (SAH; Chap. 330) 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. 165) may be considered in the differential diagnosis of acute meningitis. The principal causes include Mycobacterium tuberculosis (Chap. 202), Cryptococcus neoformans (Chap. 239), Histoplasma capsulatum (Chap. 236), Coccidioides immitis (Chap. 237), and Treponema pallidum (Chap. 206).


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InternalMed_Harrison. (Table 164-1) 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 (Chap. 171) and N. meningitidis (Chap. 180) are the most common etiologic organisms of community-acquired bacterial meningitis. Due to the emergence of penicillinand cephalosporin-resistant S. pneumoniae, empirical therapy of community-acquired suspected bacterial meningitis in children and adults should include a combination of dexamethasone, a thirdor 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 provides good coverage for


InternalMed_Harrison

InternalMed_Harrison. encephalitis is the leading disease in the differential diagnosis, and doxycycline during tick season to treat tick-borne bacterial infections. Ceftriaxone or cefotaxime provides 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


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InternalMed_Harrison. 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 neurosurgical 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, because ceftriaxone and cefotaxime do not provide adequate activity against CNS


InternalMed_Harrison

InternalMed_Harrison. or meropenem should be substituted for ceftriaxone or cefotaxime in neurosurgical patients and in neutropenic patients, because 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.


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InternalMed_Harrison. SPECIFIC ANTIMICROBIAL THERAPY Meningococcal Meningitis (Table 164-3) 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 and are increasing in incidence worldwide. CSF isolates of N. meningitidis should 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


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InternalMed_Harrison. Gram-negative bacilli (except Ceftriaxone or cefotaxime Pseudomonas spp.) Staphylococci spp. Fusobacterium spp. Metronidazole aDoses are as indicated in Table 164-1. 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.


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InternalMed_Harrison. 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 164-3). 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 and to be resistant when the MIC is >0.12 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


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InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 penicillinand 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.


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InternalMed_Harrison. Listeria Meningitis Meningitis due to L. monocytogenes is treated with ampicillin for at least 3 weeks (Table 164-3). Gentamicin is added in critically ill patients (2 mg/kg loading dose, then 7.5 mg/kg per day Meningitis, Encephalitis, Brain Abscess, and Empyema 890 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.


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InternalMed_Harrison. Staphylococcal Meningitis Meningitis due to susceptible strains of S. aureus or coagulase-negative staphylococci is treated with nafcillin (Table 164-3). Vancomycin is the drug of choice for methicillinresistant 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 164-3). A 3-week course of intravenous antibiotic therapy is recommended for meningitis due to gram-negative bacilli.


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InternalMed_Harrison. 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 meningitis due to H. influenzae, S. pneumoniae, and N. meningitidis have demonstrated its efficacy in decreasing meningeal inflammation and neurologic sequelae such as the incidence of sensorineural hearing loss.


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InternalMed_Harrison. 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%, p = .03) including death (7 vs. 15%, p = .04). 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, to assure reliable


InternalMed_Harrison

InternalMed_Harrison. 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, to assure reliable penetration of vancomycin into the CSF, children and adults are treated with vancomycin in a dose of 45–60 mg/kg per day. Alternatively, vancomycin can be administered by the intra-ventricular route.


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InternalMed_Harrison. 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 highand 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 micro-biologically 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. 330.


InternalMed_Harrison

InternalMed_Harrison. Mortality rate is 3–7% for meningitis caused by H. influenzae, N. 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 concentration (<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,


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InternalMed_Harrison. ~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.


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InternalMed_Harrison. Immunocompetent adult patients with viral meningitis usually present with headache, fever, and signs of meningeal irritation coupled with an inflammatory CSF profile (see below). 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Using a variety of diagnostic techniques, including CSF PCR, culture, and serology, a specific viral cause can be found in 60–90% of cases of viral meningitis. The most important agents are enteroviruses (including echoviruses and coxsackieviruses in addition to numbered enteroviruses), varicella-zoster virus (VZV), HSV (HSV-2 > HSV-1), HIV, and arboviruses (Table 164-4). CSF cultures are positive in 30–70% of patients, with 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 (see below).


InternalMed_Harrison

InternalMed_Harrison. Viral meningitis is not a nationally reportable disease; however, it has been estimated that the incidence is ~60,000–75,000 cases per year. In temperate climates, there is a substantial increase in cases during the nonwinter months, reflecting the seasonal predominance of enterovirus and arthropod-borne virus (arbovirus) infections in the summer and fall, with a peak monthly incidence of about 1 reported case per 100,000 population. Enteroviruses (coxsackieviruses, echo-Herpes simplex virus 1 viruses, and human enteroviruses aImmunocompromised host. bThe most common cause of sporadic encephalitis. cThe most common cause of epidemic encephalitis.


InternalMed_Harrison

InternalMed_Harrison. 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 pleocytosis, 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. 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. Lymphocytes are typically the predominant cell. 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 PMN pleocytosis occurs in 45% of patients with West Nile virus (WNV) meningitis and can persist for a week or longer before shifting to a


InternalMed_Harrison

InternalMed_Harrison. virus, eastern equine encephalitis (EEE) virus, or mumps. A PMN pleocytosis 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. PMN pleocytosis with low glucose may also be a feature of cytomegalovirus (CMV) infections in immunocompromised hosts. 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 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 echo-viruses and other enteroviruses, HSV-2, and VZV. As a rule, a lymphocytic pleocytosis with a low glucose concentration should suggest fungal or


InternalMed_Harrison

InternalMed_Harrison. concentration occur in cases of meningitis due to echo-viruses and other enteroviruses, HSV-2, and 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).


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InternalMed_Harrison. 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 891 widely used for diagnostic purposes.


InternalMed_Harrison

InternalMed_Harrison. 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, CSF PCR has become the diagnostic procedure of choice and is substantially more sensitive than viral cultures. HSV CSF 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 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. PCR of throat washings may assist in diagnosis of


InternalMed_Harrison

InternalMed_Harrison. CSF IgM. PCR is also useful in the diagnosis of CNS infection caused by Mycoplasma pneumoniae, which can mimic viral meningitis and encephalitis. PCR of throat washings may assist in diagnosis of enteroviral and mycoplasmal CNS infections. PCR of stool specimens may also assist in diagnosis of enteroviral infections (see below).


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. Serologic Studies For many arboviruses including WNV, serologic studies remain important diagnostic tools. 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. For viruses with high seroprevalence such as VZV and HSV, demonstration of synthesis of virus-specific antibodies in CSF, as shown by an increased IgG index or the presence of CSF IgM antibodies, may be useful 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 serum IgM has been shown to persist in some patients for >1


InternalMed_Harrison

InternalMed_Harrison. and CSF IgM antibodies generally persist for only a few months after acute infection, there are exceptions to this rule. For example, WNV serum 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. In the case of EBV, demonstration of antibody responses consistent with recent/acute infection (e.g., IgM viral capsid antibody, antibody against early antigen, absence of antibody against EBV-associated nuclear antigen) may assist in diagnosis.


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InternalMed_Harrison. 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 noninfectious 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 preferable to CT) are not absolutely necessary in patients with uncomplicated viral meningitis but should be performed in patients with altered consciousness, seizures, focal neurologic signs or symptoms, atypical CSF profiles, or underlying immunocompromising treatments or conditions.


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InternalMed_Harrison. Meningitis, Encephalitis, Brain Abscess, and Empyema 892 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 Mycoplasma, Listeria 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 autoimmune and 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


InternalMed_Harrison

InternalMed_Harrison. 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 developed. One such prospectively validated system, the bacterial meningitis score, suggests that the probability of bacterial meningitis is 0.3% or less (negative predictive value 99.7%, 95% confidence interval 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.


InternalMed_Harrison

InternalMed_Harrison. Enteroviruses (EV) (Chap. 228) 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. 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


InternalMed_Harrison

InternalMed_Harrison. 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. PCR of


InternalMed_Harrison

InternalMed_Harrison. 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. PCR of throat washings or stool specimens may be positive for several weeks, and positive results can help support the diagnosis of an acute enteroviral infection. The sensitivity of routine enteroviral PCRs for detecting EV71 is low, and specific testing may be required. Treatment is supportive, and patients usually recover without sequelae. Chronic and severe infections can occur in neonates and in individuals with hypoor agammaglobulinemia.


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InternalMed_Harrison. Arbovirus infections (Chap. 233) 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 WNV, 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, ~45% of patients


InternalMed_Harrison

InternalMed_Harrison. Arbovirus meningoencephalitis is typically associated with a CSF lymphocytic pleocytosis, normal glucose concentration, and normal or mildly elevated protein concentration. However, ~45% of patients with WNV meningoencephalitis have CSF neutrophilia, which can persist for a week or more. The rarity of hypoglycorrhachia in WNV infection, the absence of positive Gram’s stains, and the negative cultures help distinguish these patients from those with bacterial meningitis. Definitive diagnosis of arboviral meningoencephalitis is based on demonstration of viral-specific IgM in CSF or seroconversion. The prevalence of CSF IgM increases progressively during the first week after infection, peaking at >80% in patients with neuroinvasive disease; as a result, repeat studies may be needed when disease suspicion is high and an early study is negative. CSF PCR tests are available for some viruses in selected diagnostic laboratories and at the Centers for Disease Control and Prevention (CDC), but


InternalMed_Harrison

InternalMed_Harrison. suspicion is high and an early study is negative. 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. WNV CSF PCR may be useful in immunocompromised patients who may have absent or reduced antibody responses.


InternalMed_Harrison

InternalMed_Harrison. HSV meningitis (Chap. 216) 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. In adults, the majority of cases of uncomplicated meningitis are due to HSV-2, whereas HSV-1 is responsible for 90% of cases of HSV encephalitis. 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 because 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


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InternalMed_Harrison. CSF PCR because 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. 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 due to HSV.


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InternalMed_Harrison. VZV meningitis should be suspected in the presence of concurrent chickenpox or shingles. However, it is important to recognize that VZV is being increasingly identified as an important cause of both meningitis and encephalitis in patients without 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. VZV serologic studies complement PCR testing, and 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.


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InternalMed_Harrison. 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 false-positive results may reflect viral reactivation associated with other infectious or inflammatory processes or the presence of latent viral DNA in lymphocytes recruited due to other inflammatory conditions. HIV meningitis should be suspected in any patient presenting with a viral meningitis with known or suspected risk factors for HIV infection.


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InternalMed_Harrison. 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 seroconversion. For further discussion of HIV infection, see Chap. 226.


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InternalMed_Harrison. Mumps (Chap. 231e) should be considered when meningitis occurs in the late winter or early spring, especially in males (male-to-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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. LCMV infection (Chap. 233) 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 above, 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.


InternalMed_Harrison

InternalMed_Harrison. 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 (see above). 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 patients who have an atypical CSF profile should be hospitalized. Oral or intravenous acyclovir may be of benefit in


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InternalMed_Harrison. suggesting the possibility of encephalitis or parenchymal brain involvement; and 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 893 HIV meningitis should receive highly active antiretroviral therapy (Chap. 226). There is no specific therapy of proven benefit for patients with arboviral encephalitis, including that caused by WNV.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Vaccination is an effective method of preventing the development of meningitis and other neurologic complications associated with poliovirus, mumps, measles, rubella, and varicella 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 after ~10 years to maintain immunity. A related vaccine (Zostavax) is recommended for prevention of herpes zoster (shingles) in adults over the age of 60. An inactivated varicella vaccine is available for transplant recipients and others for whom live viral vaccines are contraindicated


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InternalMed_Harrison. 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. 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).


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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,” below).


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InternalMed_Harrison. In the United States, there are an estimated ~20,000 cases of encephalitis per year, although the actual number of cases is likely to be significantly larger. Despite comprehensive diagnostic efforts, the


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InternalMed_Harrison. Meningitis, Encephalitis, Brain Abscess, and Empyema 894 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 164-4). 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, La Crosse 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


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InternalMed_Harrison. virus serogroup, La Crosse 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. WNV caused 2873 confirmed cases of neuroinvasive disease (encephalitis, meningitis, or myelitis) in 2012 with 286 deaths. States reporting >200 cases included Texas (1868 cases), California (479), Louisiana (335), Illinois (290), Mississippi (249), South Dakota (203), and Michigan (202). In 2013, there were 1140 neuroinvasive cases with 100 deaths. States reporting >100 cases included California (357 cases), Colorado (315), Nebraska (213), Texas (157), South Dakota (148), North Dakota (123), and Illinois (106). It is important to recognize that WNV epidemics are unpredictable and that cases have occurred in every state in the continental


InternalMed_Harrison

InternalMed_Harrison. (157), South Dakota (148), North Dakota (123), and Illinois (106). It is important to recognize that WNV epidemics are unpredictable and that cases have occurred in every state in the continental United States. New causes of viral CNS infections are constantly appearing, as evidenced by the 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. Parechoviruses including human parechovirus 3 (HPeV3), members of the Picornavirus family, have recently been reported as causes of fever, sepsis, and meningitis in infants (age <3 months) in the United States and abroad.


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InternalMed_Harrison. 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. Ideally at least 20 mL should be collected with 5–10 mL stored frozen for later studies as needed. 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. CSF PCR has become the primary diagnostic test for CNS infections caused by CMV, EBV, HHV-6, and enteroviruses (see “Viral Meningitis,” above). 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 vary with the virus being tested. The sensitivity (~96%) and specificity (~99%) of HSV CSF PCR are equivalent to or exceed those 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. The sensitivity and specificity of CSF PCR tests for viruses other than HSV have not been definitively characterized. Enteroviral (EV) CSF PCR appears to have a sensitivity and specificity of >95%. EV PCR sensitivity for EV71 may be considerably lower (~30% in some reports). Parechoviruses are also not detected by standard EV RT-PCRs. 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, because 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 because 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 because 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. MRI, CT, and 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. 164-3); (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


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InternalMed_Harrison. 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


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InternalMed_Harrison. FIGURE 164-3 Coronal fluid-attenuated inversion recovery (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. patients with HSV encephalitis have a distinctive EEG pattern consist-895 ing 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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InternalMed_Harrison. Significant MRI abnormalities are found in only approximately 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 postcontrast images. Table 164-5 highlights


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InternalMed_Harrison. with CMV often have enlarged ventricles with areas of increased T2 signal on MRI outlining the ventricles and subependymal enhancement on T1-weighted postcontrast images. Table 164-5 highlights specific diagnostic test results in encephalitis that can be useful in clinical decision making.


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InternalMed_Harrison. 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. Infection by a variety of other organisms can mimic viral encephalitis. In studies of biopsy-proven HSV encephalitis, common infectious uSE of DIAgnoSTIC TESTS In EnCEPHALITIS The best test for WNV encephalitis is the CSF IgM antibody test. The prevalence of positive CSF IgM tests increases by about 10% per day after illness onset and reaches 70–80% by the end of the first week. Serum WNV IgM can provide evidence for recent WNV infection, but in the absence of other findings does not establish the diagnosis of neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis).


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InternalMed_Harrison. Approximately 80% of patients with proven HSV encephalitis have MRI abnormalities involving the temporal lobes. This percentage likely increases to >90% when FLAIR and diffusion-weighted MRI sequences are also used. The absence of temporal lobe lesions on MRI reduces the likelihood of HSV encephalitis and should prompt consideration of other diagnostic possibilities. The CSF HSV PCR test may be negative in the first 72 h of symptoms of HSV encephalitis. A repeat study should be considered in patients with an initial early negative PCR in whom diagnostic suspicion of HSV encephalitis remains high and no alternative diagnosis has yet been established.


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InternalMed_Harrison. Detection of intrathecal synthesis (increased CSF/serum HSV antibody ratio corrected for breakdown of the blood-brain barrier) of HSV-specific antibody may be useful in diagnosis of HSV encephalitis in patients in whom only late (>1 week after onset) CSF specimens are available and PCR studies are negative. Serum serology alone is of no value in diagnosis of HSV encephalitis due to the high seroprevalence rate in the general population. Negative CSF viral cultures are of no value in excluding the diagnosis of HSV or EBV encephalitis. VZV CSF IgM antibodies may be present in patients with a negative VZV CSF PCR. Both tests should be performed in patients with suspected VZV CNS disease.


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InternalMed_Harrison. VZV CSF IgM antibodies may be present in patients with a negative VZV CSF PCR. Both tests should be performed in patients with suspected VZV CNS disease. The specificity of EBV CSF PCR for diagnosis of CNS infection is unknown. Positive tests may occur in patients with a CSF pleocytosis due to other causes. Detection of EBV CSF IgM or intrathecal synthesis of antibody to VCA supports the diagnosis of EBV encephalitis. Serologic studies consistent with acute EBV infection (e.g., IgM VCA, presence of antibodies against EA but not against EBNA) can help support the diagnosis.


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InternalMed_Harrison. Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DWI, diffusion-weighted imaging; EA, early antigen; EBNA, EBV-associated nuclear antigen; EBV, Epstein-Barr virus; FLAIR, fluid-attenuated inversion recovery; HSV, herpes simplex virus; IgM, immunoglobulin M; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; VCA, viral capsid antibody; VZV, varicella-zoster virus; WNV, West Nile virus.


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InternalMed_Harrison. Meningitis, Encephalitis, Brain Abscess, and Empyema 896 mimics of focal viral encephalitis included mycobacteria, fungi, rickettsiae, Listeria, Mycoplasma, and other bacteria (including Bartonella sp.). Autoimmune causes of encephalitis, including those associated with antibodies against N-methyl-d-aspartate (NMDA) receptor, voltage-gated potassium channels (VGKC), α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA), and γ-aminobutyric acid (GABA) receptors, and GAD-65, have been increasingly recognized as causes of encephalitis that can mimic that caused by viral infection. In most cases, diagnosis is made by detection of the specific autoantibodies in serum and/or CSF. NMDA receptor antibodies have recently been reported in some patients with HSE encephalitis, and their presence should not exclude appropriate testing and treatment for HSV encephalitis. Autoimmune encephalitis may also be associated with specific cancers (paraneoplastic) and onconeuronal antibodies (e.g.,


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InternalMed_Harrison. should not exclude appropriate testing and treatment for HSV encephalitis. Autoimmune encephalitis may also be associated with specific cancers (paraneoplastic) and onconeuronal antibodies (e.g., anti-Hu, Yo, Ma2, amphiphysin, CRMP5, CV2) (Chap. 122). Subacute or chronic forms of encephalitis may occur in association with auto-antibodies against thyroglobulin and thyroperoxidase (Hashimoto’s encephalopathy) and with prion diseases. 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


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InternalMed_Harrison. 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