Central Nervous System Infections

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1 Central Nervous System Infections Karen L. Roos 11 Abstract The central nervous system infections that are neurological emergencies are meningitis, encephalitis, focal infectious mass lesions (brain abscess and subdural empyema), and spinal epidural abscess. This chapter will review the diagnosis and management of these neuroinfectious diseases. Keywords Meningitis Encephalitis Subdural empyema Spinal epidural abscess Meningitis Meningitis is the most worrisome illness in the patient who presents to the emergency department with fever and headache. The classic triad of meningitis is fever, headache and meningismus, which is resistance to passive flexion of the neck due to pain. A stiff neck is the pathognomonic sign of meningeal irritation from any process. Viral Meningitis The clinical presentation of viral meningitis is fever, headache, nausea, photophobia and meningismus. Individuals with viral meningitis appear K.L. Roos, MD ( ) The John and Nancy Nelson Professor of Neurology and Professor of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA kroos@iupui.edu acutely ill and complain of a severe headache but are typically awake and alert. They may be lethargic, but are not stuporous or comatose. They do not present with seizures or focal neurological deficits. The most common viruses to cause meningitis are the enteroviruses. The enteroviruses are the coxsackievirues, the echoviruses, and the viruses identified by number (enteroviruses 68 71). Herpes simplex virus type 2 (HSV-2), the human immunodeficiency virus (HIV-1), and the arthropod-borne viruses are also fairly common etiologic agents of meningitis. Bacterial Meningitis Patients with bacterial meningitis have either a subacute illness that has progressed over h or a fulminant illness that developed over several hours. The initial symptoms of bacterial meningitis include any of the following: fever, headache, lethargy, stupor, confusion, nausea, vomiting, K.L. Roos (ed.), Emergency Neurology, DOI / _11, Springer Science+Business Media, LLC

2 196 K.L. Roos and photophobia. It is the altered level of consciousness that is the single symptom that distinguishes the patient with bacterial meningitis from the patient with viral meningitis. Seizures occur in 40% of patients with bacterial meningitis and typically occur in the first week of illness. In children, symptoms of bacterial meningitis are often preceded by an upper respiratory tract infection or an otitis media [ 1 ]. Nuchal rigidity may be absent early in the course of the illness; therefore, the absence of a stiff neck should not exclude the diagnosis of bacterial meningitis [ 2 ]. In both children and adults, vomiting is a frequent, but often overlooked, symptom of bacterial meningitis. Predisposing and associated conditions for bacterial meningitis are as follows: (1) pneumonia, (2) otitis, mastoiditis, sinusitis, (3) diabetes, (4) alcoholism, (5) head trauma with basilar skull fracture, (6) asplenia, (7) congenital or acquired deficiency in the terminal common complement pathway (C3 and C5 to C9) or hypo- or agammaglobulinemia, and (8) endocarditis. It is important to note that the predisposing and associated conditions are often not known at the time of presentation. The most common causative organisms of bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitidis. The incidence of meningitis due to N. meningitidis has decreased with the vaccination of children and adolescents with the tetravalent (serogroups A, C, W-135, and Y) meningococcal glycoconjugate vaccine. The vaccine does not contain serogroup B, which is responsible for one third of cases of meningococcal disease [ 3 ]. Meningitis due to otitis, mastoiditis, or sinusitis may be due to Streptococci spp. (including S. pneumoniae ), gram-negative anaerobes, S. aureus, Haemophilus sp., or Enterobacteriaceae. Patients with congenital or acquired deficiency in the terminal common complement pathway (C3 and C5 to C9), immunoglobulin deficiency or asplenia are at risk for meningitis due to N. meningitidis or S. pneumoniae. Patients with defects of cell-mediated immunity are at risk for meningitis due to Listeria monocytogenes. Meningitis complicating endocarditis may be due to viridans streptococci, S. aureus, S. bovis, the HACEK group ( Haemophilus sp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae ), or enterococci. Meningitis in the postneurosurgical patient and/or the patient with a ventriculostomy may be due to staphylococci, gram-negative bacilli, or anaerobes. The presence of a diffuse erythematous maculopapular and/or petechial rash on the trunk and lower extremities, in the mucous membranes and conjunctiva, and occasionally on the palms and soles is typical of meningococcemia. It is the location of the rash on the trunk and lower extremities that should raise a concern for meningococcemia. A viral exanthem typically appears as a maculopapular rash on the head and neck. Aseptic Meningitis Aseptic meningitis is an old term that is of little use today. The criteria for aseptic meningitis were described by Wallgren in 1925 and are as follows: (1) acute onset; (2) fever, headache, and meningismus; (3) CSF abnormalities typical of meningitis with a predominance of mononuclear cells; (4) absence of bacteria by smear and by culture of cerebrospinal fluid; (5) no parameningeal focus of infection; and (6) self-limited benign course [ 4 6 ]. The term aseptic meningitis can really only be applied to viral meningitis, meningitis following posterior fossa surgery, and medication-induced meningitis, and as such, should be labeled by these terms rather than as an aseptic meningitis. In both medication-induced meningitis and meningitis following posterior fossa surgery, the CSF glucose concentration may be low. Lyme Disease Lyme disease, due to the spirochete Borrelia burgdorferi, is endemic in New England, parts of Minnesota and Wisconsin and the mid-atlantic states, and in areas of northern California. Patients with meningitis due to B. burgdorferi complain

3 11 Central Nervous System Infections of headache and fatigue and some have myalgias and arthralgias. A unilateral or bilateral facial nerve palsy may be present or a painful radiculopathy. Inquire about and examine the patient for the classic erythema migrans lesion. Tuberculous Meningitis Suspect tuberculous meningitis in the patient with either several weeks of headache, fever, and night sweats or a fulminant presentation with fever, altered mental status, and focal neurological deficits. Differential Diagnosis The differential diagnosis of the triad of fever, headache, and stiff neck is bacterial or viral meningitis, fungal meningitis, tuberculous meningitis, syphilitic meningitis, drug-induced aseptic meningitis, carcinomatous or lymphomatous meningitis, and aseptic meningitis associated with inflammatory diseases (systemic lupus erythematosus, sarcoidosis, Sjögren s syndrome, etc.). If the presentation is that of headache and stiff neck, subarachnoid hemorrhage is in the differential diagnosis [ 7 ]. When impaired consciousness, focal neurological deficits, or new onset seizures are added to the classic triad, the differential diagnosis includes viral encephalitis, intracranial venous thrombosis, tick-borne bacterial infections, and infectious intracranial mass lesions. The differential diagnosis in HIV-infected patients who present with meningeal signs includes, in addition to meningitis caused by HIV, meningitis caused by Cryptococcus neoformans, Mycobacterium tuberculosis, and Treponema pallidum. Initial Management The patient with fever and headache should be managed as if they have bacterial meningitis until bacterial meningitis is ruled out. Recommendations 197 for initial management include adjunctive and antimicrobial therapy and the diagnostic studies that have the highest yield for distinguishing between bacterial and viral meningitis. Those diagnostic studies include Gram s stain and bacterial blood cultures, serum procalcitonin and C-reactive protein, and spinal fluid analysis. Serum procalcitonin (>2 ng/ml) and C-reactive protein (>40 mg/l) are significantly higher in patients with bacterial meningitis than in those with viral meningitis, and can help in diagnosis when the results of spinal fluid analysis are available. Empiric antimicrobial therapy for bacterial meningitis includes antibiotic therapy, as well as acyclovir for herpes simplex virus encephalitis as that is in the differential diagnosis and doxycycline for a tick-borne bacterial infection during the season when ticks are biting. The most common causative organisms of community acquired bacterial meningitis in children and adults are S. pneumoniae and N. meningitidis. Empiric therapy of bacterial meningitis is based on predisposing and associated conditions (Table 11.1 ), and based on the possibility that a penicillin and cephalosporin-resistant strain of S. pneumoniae is the causative organism. In infants older than 1 month of age, children, and adults up to the age of 55, empiric therapy includes a third- or fourth-generation cephalosporin, either ceftriaxone (pediatric dose: 100 mg/kg/day in a 12-h dosing interval; adult dose: 2 g every 12 h) or cefepime (pediatric dose: 150 mg/kg/day in an 8-h dosing interval; adult dose: 2 g every 8 h) plus vancomycin (pediatric dose: mg/kg/day in a 6- or 12-h dosing interval; adult dose: mg/kg/day in an 8-h dosing interval). Metronidazole (1,500 2,000 mg/day in an 8-h dosing interval) is added to the empiric regimen to cover anaerobic bacteria in patients with the predisposing conditions of otitis, mastoiditis, sinusitis, neurosurgical procedures, and head trauma. Ampicillin should be added to the empiric regimen for coverage of L. monocytogenes in individuals over the age of 55 years, and in individuals with impaired cellmediated immunity due to a chronic illness,

4 198 K.L. Roos Table 11.1 Empiric antibiotic therapy based on predisposing and associated conditions Predisposing condition Bacterial pathogen Antibiotic Neonate Group B streptococcus, Escherichia coli, Listeria monocytogenes Ampicillin plus cefotaxime or an aminoglycoside Children and adults community acquired Streptococcus pneumoniae and Neisseria meningitidis Third- or fourth-generation cephalosporin plus vancomycin Otitis, mastoiditis, sinusitis Streptococci spp., gram-negative anaerobes ( Bacteroides sp., Fusobacterium sp.), S. aureus, Haemophilus sp., Enterobacteriaceae Third- or fourth-generation cephalosporin plus vancomycin plus metronidazole Adults over the age of 55 and those with chronic illness S. pneumoniae, gram-negative bacilli, N. meningitidis, L. monocytogenes, Haemophilus infl uenzae Endocarditis Viridans streptococci, S. aureus, Streptococcus bovis, HACEK group, enterococci Immunosuppressed S. pneumoniae, L. monocytogenes, H. infl uenzae Third- or fourth-generation cephalosporin plus vancomycin plus ampicillin Third- or fourth-generation cephalosporin plus vancomycin Third- or fourth-generation cephalosporin plus vancomycin plus ampicillin Postneurosurgical Staphylococci, gram-negative bacilli Vancomycin plus meropenem Intraventricular device Staphylococci, gram-negative bacilli, anaerobes or vancomycin plus ceftazidime Vancomycin plus meropenem plus metronidazole or vancomycin plus ceftazidime plus metronidazole organ transplantation, pregnancy, AIDS, malignancy, or immunosuppressive therapy, if they have not been on trimethoprim sulfamethoxazole prophylactic therapy. Gentamicin is added to ampicillin in critically ill patients with L. monocytogenes meningitis. The dose of ampicillin is 2 g every 4 h, and the dose of gentamicin is 7.5 mg/kg/day in an 8-h dosing interval. Prior to or with the first dose of antibiotic, dexamethasone (infants and children 2 months of age and older: 0.15 mg/kg of body weight intravenously every 6 h for 2 4 days; adults: 10 mg intravenously every 6 h for 4 days) should be administered in patients with possible pneumococcal meningitis. Dexamethasone is administered either min before the first dose of an antimicrobial agent or with the first dose of an antimicrobial agent. In patients in whom herpes simplex virus encephalitis is suspected, acyclovir 10 mg/kg every 8 h is added to the empiric regimen. Doxycycline 100 mg every 12 h can be added to the empiric regimen during tick season if tickborne bacterial infections are suspected. Doxycycline is relatively contraindicated in pregnant and lactating women and in children younger than 8 years of age. Neuroimaging A head CT scan prior to lumbar puncture is recommended in patients with any of the following criteria: an abnormal level of consciousness, a new onset seizure, a focal neurological deficit, an immunocompromised state, papilledema, or poorly visualized fundi. A CT scan prior to LP should also be obtained in patients from an endemic area for cysticercosis and at risk for an intraventricular cyst. The primary argument against imaging prior to lumbar puncture is that imaging delays the lumbar puncture by 2 3 h and subsequently delays the initiation of antimicrobial therapy. Obtain blood cultures, initiate adjunctive and antimicrobial therapy, obtain a cranial CT if any of the above criteria are met, and then perform spinal fluid analysis.

5 11 Central Nervous System Infections Spinal Fluid Analysis The CSF abnormalities characteristic of bacterial meningitis are: An opening pressure >180 mm H O. 2 A polymorphonuclear pleocytosis. The CSF should be examined promptly after it is obtained because white blood cells in the CSF begin to lyse after about 90 min. A low glucose concentration. A glucose concentration of <40 mg/dl occurs in approximately 58% of patients with bacterial meningitis. A normal CSF-to-serum glucose ratio is 0.6. A CSF-to-serum glucose ratio of less than 0.31 is seen in approximately 70% of patients with bacterial meningitis. An elevated protein concentration. Gram s stain is positive in identifying the organism in 60 90% of cases of bacterial meningitis [8]. However, the probability of detecting bacteria on a Gram s stain specimen depends on the number of organisms present. Most smears will be positive when the CSF bacterial concentration is >10 5 CFU/mL. Only 25% of smears are positive when the bacterial concentration is 10 3 CFU/mL or less [ 1 ]. Latex agglutination tests, which detect the antigens of common meningeal pathogens, are no longer routinely available or recommended for the rapid determination of the bacterial etiology of meningitis. Cerebrospinal fluid PCR assays have been developed to detect bacterial nucleic acid in CSF. There is a 16S ribosomal DNA-conserved sequence broad-based bacterial PCR that is routinely available, and a PCR for the detection of N. meningitidis and S. pneumoniae that is available in many hospitals. The CSF PCR assays for Escherichia coli, Streptococcus agalactiae, Staphylococcus aureus, Haemophilus influenzae, L. monocytogenes, and Mycoplasma pneumoniae are less readily available [9]. The sensitivity and specificity of bacterial PCRs have not been defined. PCR will not replace culture as culture is critical for antimicrobial sensitivity testing. Table 11.2 Cerebrospinal fluid studies for meningitis Cell count with differential Glucose and protein concentration Stain and culture Gram s stain and bacterial culture India ink and fungal culture Viral culture Acid fast smear and M. tuberculosis culture Antigens Cryptococcal polysaccharide antigen Histoplasma polysaccharide antigen Polymerase chain reaction Broad-range bacterial PCR (16S ribosomal DNA) Specific meningeal pathogen PCR Reverse transcriptase PCR for enteroviruses PCR for herpes simplex virus type 1 and 2 PCR for West Nile virus PCR for Epstein Barr virus PCR for varicella zoster virus PCR for M. tuberculosis PCR for HIV RNA Antibodies Herpes simplex virus (serum:csf antibody ratio of <20:1) Varicella zoster virus IgM, and IgG antibody index Arthropod-borne viruses (West Nile virus IgM) Borrelia burgdorferi antibody index C. immitis complement fixation antibody VDRL, FTA-ABS 199 The CSF abnormalities typical of viral meningitis are: A normal opening pressure A lymphocytic pleocytosis A normal or mildly decreased glucose concentration A normal or mildly elevated protein concentration Table 11.2 provides a list of cerebrospinal fluid diagnostic studies for the patient with suspected meningitis. The basic studies that should be performed on CSF in every patient with fever, headache, and meningismus are the following: (1) cell count with differential, (2) glucose and protein concentration, (3) Gram s stain and bacterial culture, (4) viral culture for enteroviruses, (5) the broad-based bacterial PCR (16S ribosomal DNA) if available, and (6) the reverse transcriptase PCR for enteroviruses. The remaining diagnostic tests listed in Table 11.2 should be obtained

6 200 K.L. Roos Table 11.3 Appearance of the organism on Gram s stain Organism Neisseria meningitidis Streptococcus pneumoniae Gram s stain Biscuit- or kidney-shaped gram-negative diplococci Gram-positive lancetshaped diplococci which tend to associate in pairs rather than in short chains Gram-negative bacilli Gram-negative bacilli Gram-positive roda Gram-positive cocci Gram-positive cocci Escherichia coli Pseudomonas aeruginosa Listeria monocytogenes Staphylococcus aureus Staphylococcus epidermidis a Listeria monocytogenes may appear coccoid on Gram s stains of clinical specimens, particularly CSF, and are often mistaken for pneumococci. Listeria monocytogenes resembles diphtheroids and may thus be dismissed as a contaminant. depen ding on the time of the year (i.e., if mosquitoes are biting), place of residence and travel history (i.e., fungal antigens and antibodies, B. burgdorferi antibodies), and risk factors (i.e., HIV, herpes simplex virus-2, VDRL). Meningitis due to M. tuberculosis is a consideration in the patient with a fulminant presentation and in the patient with a subacute course of illness. A Gram s stain on CSF can be completed within minutes. When positive, the physician is paged with the results. Table 11.3 lists the appearance of the organism on Gram s stain. Never send tube #1 for Gram s stain as the CSF in tube #1 is at risk for being contaminated by Staphylococcus epidermidis that is normally found on the skin. This will result in a false-positive result of grampositive cocci in CSF. There may initially be a predominance of polymorphonuclear leukocytes in enteroviral meningitis early in the disease course with a transition to a lymphocytic pleocytosis within 24 h. Enteroviruses can either be isolated in CSF culture or detected in CSF by the reverse transcriptase polymerase chain reaction (RT-PCR) technique or both. Serology should be sent to detect a fourfold increase in IgG between acute and convalescent sera obtained 4 weeks later. Herpes simplex virus type 2 DNA can be detected in CSF by PCR. CSF culture is positive for HSV-2 in the majority of cases of meningitis associated with primary genital herpes, but is rarely positive in cases of meningitis associated with recurrent episodes of genital herpes. HIV-1 RNA levels can be measured in CSF and the virus can be cultured from CSF. In meningitis due to an arthropod-borne virus, there may be a polymorphonuclear leukocytosis early in infection with a shift to a lymphocytic or mononuclear pleocytosis during the first week of illness. Patients with West Nile virus meningitis may have a persistent CSF neutrophilic pleocytosis. There is a CSF PCR test available for West Nile virus, but the sensitivity and specificity has not been defined. The best diagnostic test for West Nile virus meningitis is the detection of West Nile virus IgM in CSF, but this may not be positive until 7 days after the onset of symptoms. The identification of an arthropod-borne virus as the causative agent of meningitis is often dependent on serology. According to The Centers for Disease Control and Prevention, a confirmed case of arboviral meningitis is defined as a febrile illness with mild neurological symptoms during a period when arboviral transmission is likely to occur plus at least one of the following criteria: (1) fourfold or greater increase in serum antibody titer between acute and convalescent sera; (2) viral isolation from tissue, blood, or CSF; or (3) specific immunoglobulin M (IgM) antibody to an arbovirus in the CSF. The diagnosis of Lyme disease meningitis typically begins with a serum ELISA (enzyme linked immunosorbent assay) to measure antibody to B. burgdorferi. A positive result is confirmed with a Western blot. Examination of the CSF demonstrates a lymphocytic pleocytosis with a normal glucose concentration and a mild to moderately elevated protein concentration. Intrathecal anti- Borrelia burgdorferi antibodies can be detected. The demonstration of anti- Borrelia burgdorferi antibodies in CSF should not be regarded as definitive evidence of neurologic Lyme disease based on the assumption that the presence of antibodies in CSF is evidence of intrathecal antibody production. The determination of the intrathecal production of antibodies to an organism requires more than the detection of antibodies in CSF, as antibodies can be passively transferred from

7 11 Central Nervous System Infections 201 Table 11.4 Recommendations for specific antibiotic therapy in bacterial meningitis Microorganism Streptococcus pneumoniae Penicillin susceptible MIC <0.1 mg/l Penicillin tolerant (MIC mg/l) Penicillin resistant (MIC >1 mg/l) or cefotaxime or ceftriaxone MIC ³1 mg/l Neisseria meningitidis Listeria monocytogenes Streptococcus agalactiae (group B streptococci) Escherichia coli and other Enterobacteriaceae Pseudomonas aeruginosa Staphylococcus aureus Methicillin susceptible Methicillin resistant Staphylococcus epidermidis Haemophilus infl uenzae Gram-positive anaerobic bacteria Actinomyces, Propionibacterium species Gram-negative anaerobic bacteria Fusobacterium, Bacteroides species Antibiotic Penicillin G or ceftriaxone (or cefotaxime or cefepime) Ceftriaxone (or cefotaxime or cefepime or meropenem) Cefepime (or cefotaxime or ceftriaxone) plus vancomycin Penicillin G or ampicillin Ceftriaxone or cefotaxime for penicillin-resistant strains Ampicillin Ampicillin plus gentamicin (see text) Ampicillin or penicillin G or cefotaxime Ceftriaxone or cefotaxime or cefepime Meropenem or cefepime or ceftazidime Nafcillin or oxacillin Vancomycin Vancomycin or linezolid Ceftriaxone or cefotaxime or cefepime Metronidazole serum to CSF, and Lyme antibodies may persist in the CSF for years. An antibody index is recommended to detect the intrathecal production of antibodies. The antibody index is the ratio of (anti-borrelia IgG in CSF/anti-Borrelia IgG in serum) to (total IgG in CSF/total IgG in serum) [10 ]. The antibody index is, in general, considered positive when the result is > The CSF abnormalities characteristic of asymptomatic and symptomatic syphilitic meningitis are a mononuclear pleocytosis, a slightly elevated protein concentration, and a positive VDRL. A positive CSF FTA-ABS is not diagnostic of neurosyphilis, but a negative FTA-ABS is evidence against the diagnosis. In tuberculous meningitis, the CSF glucose concentration is typically only mildly decreased (35 40 mg/dl). Therapy of Bacterial Meningitis Once the meningeal pathogen has been identified, antibiotic therapy is modified. Table 11.4 lists the recommended antibiotics based on bacterial pathogen and therapy should be further modified when the results of antimicrobial sensitivity testing is available. Table 11.5 is a list of the recommended dose. The Infectious Diseases Society of America (IDSA) practice guidelines for the management of bacterial meningitis [ 11 ] and the European Federation of Neurological Societies (EFNS) guideline on the management of communityacquired bacterial meningitis [ 12 ] recommend the use of dexamethasone (0.15 mg/kg every 6 h for 2 4 days) in adults with suspected or proven pneumococcal meningitis. The first dose should be administered min before, or at least concomitant with, the first dose of antimicrobial agent. The EFNS Task Force recommends, in addition to the above, that dexamethasone be administered to children with suspected pneumococcal or H. infl uenzae type b meningitis. The IDSA practice guidelines recommend adjunctive therapy with dexamethasone in infants and children with H. infl uenzae type b meningitis, but recognizes there is controversy concerning the use of adjunctive dexamethasone therapy in infants and children with pneumococcal meningitis. The recommendation is that the potential benefits be weighed against the potential risks.

8 202 K.L. Roos Table 11.5 Antibiotic agent Recommended dose of antibiotic therapy Total daily dosage (dosing interval in hours) Ampicillin Neonate: 150 mg/kg/day (q8 h) Infants and children: 300 mg/kg/day (q6 h) Adult: 12 g/day (q4 6 h) Cefepime Infants and children: 150 mg/kg/day (q8 h) Adult: 6 g/day (q8 h) Cefotaxime Neonate: mg/kg/day (q8 12 h) Infants and children: mg/kg/ day (q6 8 h) Adult: 8 12 g/day (q4 6 h) Ceftriaxone Infants and children: mg/kg/day (q12 h) Adult: 4 g/day (q12 h) Gentamicin Neonate: 5 mg/kg/day (q12 h) Infants and children: 7.5 mg/kg/day (q8 h) Adult: 5 mg/kg/day (q8 h) Meropenem Infants and children: 120 mg/kg/day (q8 h) Adult: 6 g/day (q8 h) Metronidazole Infants and children: 30 mg/kg/day (q6 h) Adult dose: 1,500 2,000 mg/day (q6 h) Nafcillin Neonates: 75 mg/kg/day (q8 12 h) Infants and children: 200 mg/kg/day (q6 h) Adult: 9 12 g/day (q4 h) Penicillin G Neonates: mu/kg/day (q8 12 h) Infants and children: 0.3 mu/kg/day (q4 6 h) Adult: 24 million units/day (q4 6 h) Rifampin Infants and children: mg/kg/day (q12 24 h) Adults: 600 1,200 mg/day (q12 h) Vancomycin Neonates: mg/kg/day (q8 12 h) Infants and children: 60 mg/kg/day (q6 h) Adults: mg/kg/day (q6 12 h) a Chemoprophylaxis Neisseria meningitidis Rifampin 600 mg twice daily for 2 days or ceftriaxone 250 mg intramuscular a Intraventricular vancomycin administration: children: 10 mg/day, adults: 20 mg/day. The IDSA practice guidelines also acknowledge that some authorities would initiate dexamethasone in all adults with suspected bacterial meningitis because the etiology of meningitis is not always ascertained at initial evaluation [ 11 ]. Therapy of Viral Meningitis Viral meningitis is treated with nonsteroidal antiinflammatory agents and amitriptyline. The initial lumbar puncture is often therapeutic in relieving the headache for several hours, but the headache returns, and in the case of enteroviral meningitis, may be quite troublesome for weeks to come. Therapy of Lyme Disease Meningitis Lyme disease meningitis in adults and children ³ 8 years of age is treated with doxycycline mg/day in two divided doses for days. Therapy of Syphilitic Meningitis Syphilitic meningitis is treated with intravenous aqueous crystalline penicillin G 3 4 mu every 4 h for days. Encephalitis Encephalitis should be suspected in every patient with fever and headache and one or more of the following: an altered level of consciousness, behavioral abnormalities or confusion, new onset seizure activity, and focal neurological deficits. Fever is expected, but fever is never a constant clinical feature. Encephalitis may be due to reactivation of a latent herpesvirus infection that was acquired in childhood (herpes simplex virus-1 and varicella zoster virus), primary infection with a herpesvirus, an arthropod-borne virus, a tick-borne bacterial infection, or rabies. Epidemiologic clues that are helpful in establishing the etiologic agent of the encephalitis include the season of the year, occupational exposures and recreational activities, travel history, the immune status of the patient, recent or chronic illness and their treatment (i.e., the risk of PML with hematologic malignancies and

9 11 Central Nervous System Infections with immunomodulating agents), vaccination history, and prevalence of disease in the local community [ 13 ]. Herpes Simplex Virus-1 Herpes simplex virus-1 encephalitis presents with a subacute progression of fever, hemicranial headache, behavioral abnormalities, focal seizure activity, and focal neurologic deficits, most often dysphasia or hemiparesis. In addition to fever and headache, confusion and word finding difficulties are the most common signs. Mosquito-Borne Viruses Mosquito-borne viral infections may cause a mild febrile illness with headache, an aseptic meningitis, or an encephalitis. The onset of symptoms of encephalitis may be preceded by an influenza-like prodrome of fever, malaise, myalgias, and nausea and vomiting. These symptoms may be followed by confusion and seizures. Patients with West Nile virus encephalitis may have tremor, or a maculopapular or roseolar rash. Patients with West Nile virus encephalitis or St. Louis virus encephalitis may have an acute asymmetric flaccid weakness due to anterior horn cell disease (a poliomyelitislike syndrome) or parkinsonian features. Varicella Zoster Virus Varicella zoster virus encephalitis occurs when previously acquired latent virus reactivates. Varicella zoster virus encephalitis due to the reactivation of latent varicella zoster virus can follow the cutaneous eruption of zoster, or occur in association with a diffuse varicella-like rash or occur without a varicella rash or a recent history of shingles. Approximately 40% of patients with varicella zoster virus encephalitis have no history of zoster or a varicella rash. The characteristic clinical presentation of varicella zoster virus encephalitis is headache, 203 malaise, confusion, and focal neurologic symptoms and signs. Varicella zoster virus encephalitis is due to ischemic and hemorrhagic infarctions of the cortical and subcortical gray matter and white matter. Multinucleated giant cells, inclusion bodies, herpesvirus particles, varicella zoster virus DNA, and antigen can be found in affected cerebral arteries. Vasculopathy may be recurrent and present with TIAs months after acute zoster [ 14 ]. Zoster reactivation may also cause demyelinating lesions or a ventriculitis and periventriculitis with hydrocephalus, altered mental status, and trouble with gait. Tick-Borne Bacterial Infections The most common tick-borne infection to cause encephalitis is Rickettsia rickettsii (Rocky Mountain spotted fever). Rocky Mountain spotted fever presents with fever, headache, altered mental status (stupor, confusion, delirium, and coma), seizures, and focal neurologic deficits. A petechial rash is characteristic of Rocky Mountain spotted fever. The rash of Rocky Mountain spotted fever consists initially of 1 5-mm pink macules that are often noted first on the wrists and ankles then spread centrally to the chest, face, and abdomen. The rash of Rocky Mountain spotted fever usually does not involve the mucous membranes. Petechial lesions in the axilla and around the ankles accompanied by lesions on the palms and soles of the feet are characteristic of Rocky Mountain spotted fever. The macules will initially blanch with pressure but after a few days they become fixed and turn dark red or purple. Diagnosis can be made by biopsy of the lesions. Ehrlichia typically cause a mild illness, but two human ehrlichoses may cause fever, headache, and an altered mental status. The headache is often intense [ 15 ]. Ehrlichia are bacteria that infect mononuclear cells and polymorphonuclear leukocytes. Human monocytic ehrlichiosis is caused by Ehrlichia chaffeensis, and human granulocytic anaplasmosis is caused by Anaplasma phagocytophilum.

10 204 K.L. Roos Table 11.6 Epstein Barr Virus Encephalitis can complicate acute Epstein Barr virus infection, occur as a parainfectious immunemediated demyelinating disorder, or present as an encephalomyeloradiculitis. Rabies Routine tests for encephalopathy Metabolic Infectious Toxic Electrolytes CBC with differential Serum and urine tox screens Glucose Blood cultures Creatinine Chest X-ray Liver function Urinalysis tests Ammonia Urine culture Rabies due to the bite of a bat presents with focal neurological deficits (hemiparesis or hemisensory deficits), choreiform movements, myoclonus, seizures, and hallucinations. Phobic spasms are not a cardinal feature of bat rabies. Differential Diagnosis An encephalopathy is in the differential diagnosis of every patient with an altered level of consciousness or acute confusional state. An encephalopathy may be infectious, autoimmune, metabolic, toxic, ischemic, or anoxic. Although the specific diagnostic tests for encephalitis are serology, magnetic resonance imaging, specifically fluid attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI), and spinal fluid analysis, routine tests for encephalopathy should be sent as outlined in Table Initial Management Initial management should be Gram s stain of blood, blood cultures, and PCR for bacterial nucleic acid where available. This is followed by empiric therapy for bacterial and viral encephalitis, and a Table 11.7 tick-borne infection and includes dexamethasone, a third- or fourth-generation cephalosporin, vancomycin, ampicillin (for patients meeting the criteria described above), acyclovir, and doxycycline. Diagnosis Serological tests for encephalitis IgM and IgG antibodies for St. Louis encephalitis virus West Nile encephalitis virus a Eastern equine encephalitis virus Western equine encephalitis virus Japanese encephalitis virus Dengue virus Epstein Barr virus (VCA IgM and IgG and EBNA) Varicella zoster virus Herpes simplex virus-1 Rabies virus HIV Tick-borne bacterial infection IgG and IgM by indirect immunofluorescence for Rocky Mountain spotted fever b Ehrlichia chaffeensis, Anaplasma phagocytophilum a West Nile virus IgM and IgG antibody titers that are positive by ELISA should be confirmed by the more specific plaque-reduction neutralization assay and cell culture. b In addition to the indirect fluorescent antibody test for rickettsial infections, there are increasing enzyme-linked immunosorbent assays and flow immunoassays available, as well as PCR. Serology Table 11.7 is a list of serological tests for encephalitis. The determination of which tests to send should be individualized for each patient based on the season of the year, the area where the patient lives or has traveled to, the patient s occupation and recreational activities, and the patient s risk factors. During mosquito season, serological testing should be done to detect IgM and IgG antibodies to St. Louis encephalitis virus, West Nile encephalitis virus, and any other mosquito-borne viruses that are endemic in the area in which the patient has lived or traveled to. West Nile virus IgM and IgG antibody titers that are positive by enzymelinked immunosorbent assay should be confirmed by the more specific plaque-reduction neutralization assay and cell culture. Serology should also

11 11 Central Nervous System Infections 205 Fig ( a ) Axial and ( b ) coronal T2-weighted MRI demonstrating a lesion of increased signal intensity in the left anteromedial temporal lobe in HSV-1 encephalitis. Courtesy of Darren O Neill M.D be sent for rabies virus IgM and IgG if there is any possibility of exposure to a bat. During the season when ticks are biting, serological testing to detect IgG and IgM by indirect fluorescent antibodies (IFA) and PCR assays for Rocky Mountain spotted fever should be obtained. Serial samples over a number of days are recommended to detect a rise in the antibody titer. The serological tests for rickettsial infections have a low sensitivity early in the disease [ 16 ]. Not all patients will have a serological response. Skin lesions should be biopsied. The diagnosis of infection with either E. chaffeensis or A. phagocytophilum is made by serology and by the examination of blood smears for morulae, which are Ehrlichia inclusion bodies, in mononuclear cells ( E. chaffeensis ) or polymorphonuclear leukocytes ( A. phagocytophilum ). Use serology to diagnose acute Epstein Barr virus infection. Acute Epstein Barr virus infection is confirmed by the detection of antiviral capsid antigen (VCA) IgM antibodies and the absence of antibodies to virus-associated nuclear antigen (anti-ebna IgG). Virus capsid antigen IgG antibodies develop after IgM antibodies. In subsequent serum samples (collected 36 days after the onset of illness), there should be a decrease in the VCA IgG antibody titer and an increase in anti-ebna IgG. The detection of IgG antibodies against viral capsid antigen but no EBNA antibodies is also evidence of recent infection. Neuroimaging Herpes Simplex Virus-1 MR fluid attenuated inversion recovery (FLAIR), T2-weighted images, and diffusion-weighted sequences demonstrate an abnormal lesion of increased signal intensity in the temporal lobe in 90% of adult patients with herpes simplex virus encephalitis at 48 h from symptom onset (Fig. 11.1a, b ). Mosquito-Borne Virus In encephalitis due to the flaviviruses (Japanese encephalitis virus, West Nile virus, and St. Louis encephalitis virus), hyperintense lesions on T2-weighted and FLAIR images may be seen in the thalami, substantia nigra, and basal ganglia. Varicella Zoster Virus On neuroimaging in varicella zoster virus encephalitis there may be evidence of ischemic and hemorrhagic infarctions of the cortical and subcortical gray matter and white matter, demyelinating lesions, or periventricular enhancement.

12 206 K.L. Roos JC Virus In progressive multifocal leukoencephalopathy, there are one or more nonenhancing subcortical white matter hyperintensities on T2 and FLAIR sequences. Spinal Fluid Analysis The characteristic findings on lumbar puncture in viral encephalitis are an increased opening pressure, a lymphocytic pleocytosis, a mild to moderate increase in the protein concentration, and a normal (or rarely mildly decreased) glucose concentration. Herpes Simplex Virus-1 The CSF HSV-1 polymerase chain reaction (PCR) may be falsely negative in the first 72 h of symptoms of HSV encephalitis and detection rates decrease 10 days after the onset of symptoms. Antibodies to HSV-1 can be detected in CSF beginning at about day 8 after the onset of symptoms and for approximately 3 months. A serum:csf antibody ratio of less than 20:1 is diagnostic of recent HSV-1 encephalitis. Mosquito-Borne Viruses Patients with West Nile virus encephalitis may have a CSF lymphocytic or neutrophilic pleocytosis. The best test for West Nile virus encephalitis or myelitis is the CSF IgM antibody test. This may take a week or longer to be positive. Serum West Nile virus IgM and IgG are evidence of exposure to the virus but cannot be used to make a diagnosis of West Nile virus encephalitis. The CSF PCR for West Nile virus nucleic acid has a poor sensitivity but a 100% specificity. Tick-Borne Bacterial Infections In Rocky Mountain spotted fever, human monocytic ehrlichiosis, and human granulocytic anaplasmosis, there is a CSF lymphocytic pleocytosis, but it is often low grade. Varicella Zoster Virus The best test for varicella zoster virus encephalitis is the detection of varicella zoster virus IgM antibodies in CSF. Table 11.8 Cerebrospinal fluid diagnostic studies for encephalitis Cell count with differential Glucose and protein concentration Stain and culture Gram s stain and bacterial culture India ink and fungal culture Viral culture Acid fast smear and M. tuberculosis culture Antigens Cryptococcal polysaccharide antigen Histoplasma polysaccharide antigen Polymerase chain reaction Broad-range bacterial PCR (16S ribosomal DNA) Specific meningeal pathogen PCR Reverse transcriptase PCR for enteroviruses PCR for herpes simplex virus type 1 and 2 PCR for West Nile virus PCR for Epstein Barr virus PCR for varicella zoster virus PCR for JC virus PCR for M. tuberculosis PCR for HIV RNA RT-PCR for rabies virus Antibodies Herpes simplex virus (serum:csf antibody ratio of <20:1) Varicella zoster virus Arthropod-borne viruses C. immitis complement fixation antibody Rabies virus Pitfalls Epstein Barr virus DNA can be found in peripheral blood latently infected mononuclear cells and may be positive in CSF in any CNS inflammatory disorder. The detection of HHV-6 nucleic acid in CSF is not definitive evidence that HHV-6 is the etiological organism of the encephalitis. Send CSF for HHV-6 IgM. Pearl A rhombencephalitis (brainstem encephalitis), presenting with cranial nerve deficits and ataxia, may be due to HSV-1, enterovirus 71, or L. monocytogenes. Table 11.8 is a list of the cerebrospinal fluid diagnostic studies for encephalitis.

13 11 Central Nervous System Infections Therapy Herpes simplex virus-1 encephalitis is treated with acyclovir 10 mg/kg every 8 h for 21 days. Varicella zoster virus encephalitis is treated with acyclovir mg/kg every 8 h for a minimum of 14 days. The tick-borne bacterial infections are treated with doxycycline 100 mg every 12 h for a minimum of 7 days and for at least 48 h after defervescence. A number of agents have been investigated for the treatment of mosquito-borne viral encephalitis, many of which have been specifically investigated for West Nile virus encephalitis. These agents include ribavirin, interferon, and intravenous immunoglobulin containing high titers of anti-west Nile virus antibodies. None of these agents has been shown to be efficacious to date, but trials are ongoing. Parainfectious or Postinfectious Encephalitis Parainfectious or postinfectious immunemediated encephalitis occurs within days to weeks of a viral infection, such as H1N1, or a vaccination [17 ]. This is an acute monophasic, inflammatory disorder of the central nervous system. It is primarily a disease of white matter, but gray matter may also be affected. There is typically an abrupt onset of multifocal neurological deficits and an altered level of consciousness days to weeks after a viral illness or vaccination. On T2-weighted and FLAIR magnetic resonance imaging, there are bilateral, asymmetric areas of increased signal abnormality in the subcortical white matter, cerebellum, periventricular white matter, and brainstem. On T1 imaging, the lesions enhance in a nodular, spotty, ring, or heterogenous pattern after the administration of gadolinium. Spinal fluid analysis demonstrates a lymphocytic or mononuclear pleocytosis, a normal glucose concentration, and an elevated protein concentration. Myelin basic protein and oligoclonal bands may be detected. Therapy is with intravenous 207 high-dose corticosteroids. Plasma exchange is recommended for patients who do not respond to treatment with corticosteroids. Infectious Mass Lesions A brain abscess or a subdural empyema may present with fever, headache, focal neurological deficits, and an altered level of consciousness. The causative organism of an infectious mass lesion can be predicted from the suspected source of infection (i.e., sinusitis, otitis media, dental infections, trauma, and neurosurgical procedures), but in general, empiric antimicrobial therapy is initiated with a combination of a third- or fourth-generation cephalosporin, vancomycin, and metronidazole (see Table 11.5 ). Neuroimaging demonstrates the lesion. A subdural empyema requires emergent neurosurgical evacuation as the evolution of an empyema tends to be remarkably rapid once infection is established in the subdural space. As the empyema enlarges, there is a significant risk of increased intracranial pressure from the expanding mass lesion and brain herniation. Identification of the causative organism or organisms of a brain abscess is made by stereotactic aspiration, Gram s stain and culture of the purulent contents of the lesion, and of a subdural empyema, by Gram s stain and culture of the pus at the time of surgical evacuation of the empyema. Once the organism has been identified and the results of antimicrobial sensitivity testing are known, antimicrobial therapy is modified accordingly (see Table 11.5 ). Spinal Epidural Abscess A spinal epidural abscess is a purulent infection in the space outside the dura but within the spinal canal. An epidural abscess may develop from hematogenous spread of infection from a remote site of infection, by direct extension from a contiguous infection, such as a skin or soft tissue infection, or by inoculation of microorganisms into the epidural space during an invasive spinal

14 208 K.L. Roos Fig ( a ) Sagittal and ( b ) axial images of spinal epidural abscess in the dorsal epidural space. From Roos KL, ed. Principles of Neurologic Infectious Diseases. New York: McGraw-Hill, 2005, p Reproduced with permission of the McGraw-Hill Companies procedure. Risk factors for spinal epidural abscess include diabetes mellitus, intravenous drug abuse, trauma, an immunocompromised state, and invasive procedures (injections in the epidural space, spinal catheters, and spinal operations) [ 18 ]. An epidural abscess is more common in the posterior epidural space of the spinal canal, but those associated with osteomyelitis/discitis have been reported to be more common in the anterior epidural space [19 ]. The clinical presentation of a spinal epidural abscess was described by Heusner in 1948 [ 20 ]. The initial symptom is back pain at the spinal level of the epidural abscess. About 50% of patients have fever. Back pain is followed by radicular pain due to nerve root compression. This is followed by the development of a neurological deficit with paresis of appendicular musculature, loss of sensation below the level of the lesion, and loss of bowel and bladder control. Finally, there is paraplegia and loss of all sensory modalities below the level of the lesion. The most common causative organisms of a spinal epidural abscess are S. aureus, coagulase-negative staphylococci, and gramnegative bacilli [ 21 ]. Spinal cord injury is due to either direct mechanical compression from the abscess or a result of ischemia from septic thrombophlebitis or a combination of these. A spinal epidural abscess may develop in the dorsal (Fig. 11.2a, b) or ventral epidural space (Fig ) [21 ]. Magnetic resonance imaging with gadolinium is the procedure of choice to demonstrate a spinal epidural abscess. The erythrocyte sedimentation rate and C-reactive protein are almost always elevated and there is often evidence of a peripheral leukocytosis. Empiric antibiotic therapy is initiated with vancomycin and a third- or fourth-generation cephalosporin. Emergency laminectomy with evacuation of the purulent material allows for decompression of the spinal cord and identification of the organism. Antimicrobial therapy is modified when the organism has been identified and the results of antimicrobial sensitivity testing are known. The preoperative neurological examination is the most important predictor of outcome. Emergency decompressive surgery is not

15 11 Central Nervous System Infections 209 Fig Sagittal T1 postcontrast MRI demonstrating extensive abnormal enhancement within the bone marrow intervertebral disk space and ventral epidural space at the T10 11 level, compatible with discitis/osteomyelitis and associated ventral epidural abscess. Marked resultant mass effect and compression of the distal thoracic spinal cord. Abnormal enhancement also present within the T9 vertebral body. Courtesy of Darren O Neill M.D indicated in patients who have been paralyzed for greater than h as the paralysis is unlikely to be reversible [ 22 ]. References 1. Klein JO, Feigin RD, McCracken GH. Report of the task force on diagnosis and management of meningitis. Pediatrics. 1986;78S: Valmari P, Peltola H, Ruuskanen O, et al. Childhood bacterial meningitis: initial symptoms and signs related to age, and reasons for consulting a physician. Eur J Pediatr. 1987;146: Gardner P. Prevention of meningococcal disease. N Engl J Med. 2006;355: Connolly KJ, Hammer SM. The acute aseptic meningitis syndrome. Infect Dis Clin North Am. 1990;4: Adair CV, Gauld RL, Smadel JE. Aseptic meningitis, a disease of diverse etiology: clinical and etiologic studies on 854 cases. Ann Intern Med. 1953; 39: Wallgren A. Une nouvelle maladie infectieuse du systeme nerveux central: (Meningite aseptique aique). Acta Pediatr. 1925;4: Schut ES, de Gans J, van de Beek D. Communityacquired bacterial meningitis in adults. Pract Neurol. 2008;8: Marton KL, Gean AD. The spinal tap: a new look at an old test. Ann Intern Med. 1986;104: Chiba N, Murayama SY, Morozumi M, Nakayama E, et al. Rapid detection of eight causative pathogens for the diagnosis of bacterial meningitis by real-time PCR. J Infect Chemother. 2009;15: Blanc F, Jaulhac B, Fleury M, de Seze J. Relevance of the antibody index to diagnose lyme neuroborreliosis among seropositive patients. Neurology. 2007;69: Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39: Chaudhuri A, Martin PM, Kennedy PGE, Andrew Seaton R, et al. EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS task force on acute bacterial meningitis in older children and adults. Eur J Neurol. 2008; 15: Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47: Gilden DH, Cohrs RJ, Mahalingam R. VZV vasculopathy and postherpetic neuralgia: progress and perspective on antiviral therapy. Neurology. 2005;64: Sexton DJ, Dasch GA. Rickettsial and ehrlichial infections. In: Roos KL, editor. Principles of neurologic infectious diseases. New York: McGraw-Hill; p Kirkland KB, Wilkerson WE, Sexton DJ. Therapeutic delay and mortality in cases of Rocky Mountain spotted fever. Clin Infect Dis. 1995;20: Akins PT, Belko J, Uyeki TM, Axelrod Y, et al. H1N1 encephalitis with malignant edema and review of neurologic complications from influenza. Neurocrit Care. 2010;13: Reihsaus E, Waldbaur H, Seeling W. Spinal epidural abscess: a meta-analysis of 915 patients. Neurosurg Rev. 2000;232: