ACUTE MENINGITIS a the First Step in the Management Karen L

KEY POINTS: ACUTE MENINGITIS A The first step in the management Karen L. Roos of acute bacterial meningitis is to obtain blood cultures and ABSTRACT initiate adjunctive Acute meningitis is most often caused by bacteria or viruses. As soon as the and antimicrobial diagnosis is suspected, and prior to head computed tomography and spinal fluid therapy. analysis, empiric therapy is initiated. An increasing number of polymerase chain A The choice reaction assays on cerebrospinal fluid are available, and this, in combination with of antibiotic serological assays, has greatly improved the ability to identify the meningeal for empiric pathogen. In this chapter, the epidemiology, clinical presentation, diagnosis, and antimicrobial treatment of acute meningitis are reviewed. therapy is based on the possibility that a OVERVIEW (coxsackieviruses A and B, echovi- penicillin- and Acute meningitis refers to a syndrome ruses, and the viruses identified by cephalosporin- of fever, headache, and meningismus numbers [ie, enteroviruses 68 to 71]), resistant strain of associated with a cerebrospinal fluid arthropod-borne viruses, herpes sim- Streptococcus (CSF) pleocytosis due to infection plex virus type 2 (HSV-2), Epstein- pneumoniae is and inflammation in the subarachnoid Barr virus, human immunodeficiency the causative space. Bacteria or viruses most often virus type 1 (HIV-1), and varicella-zoster organism of the cause acute meningitis. Acute menin- virus. Less commonly, lymphocytic meningitis. gitis is differentiated from chronic choriomeningitis virus, mumps virus, meningitis by the duration of the and adenovirus cause meningitis. signs and symptoms. Chronic menin- The first step in the management gitis refers to a syndrome of fever, of the patient with fever, headache, headache, and meningismus of greater and stiff neck is to obtain blood cul- than 4 weeks’ duration associated tures and initiate antimicrobial and with a CSF pleocytosis. Acute bacte- adjunctive therapy. The choice of rial meningitis is now a disease pre- antibiotic for empiric antimicrobial dominately of young adults and older therapy is based on the possibility adults rather than of infants and young that a penicillin- and cephalosporin- children due to the profound re- resistant strain of S. pneumoniae is duction by vaccination in the inci- the causative organism of the menin- 13 dence of invasive infections caused gitis and on the patient’s age and any by Haemophilus influenzae type b. associated conditions that may have The most common causative organ- predisposed the patient to meningitis. isms of bacterial meningitis in adults Empiric therapy of bacterial meningi- aged 15 to 50 years are Streptococcus tis in neonates younger than 1 month pneumoniae and Neisseria meningi- should include a combination of am- tidis. The most common organisms picillin and cefotaxime. Empiric thera- causing meningitis in adults older py in infants older than 1 month and than 50 years are S. pneumoniae and in children and adults up to age enteric gram-negative bacilli; however, 50 should include a combination of meningitis caused by Listeria mono- either a third- or fourth-generation cytogenes and H. influenzae is in- cephalosporin plus vancomycin. Em- creasingly recognized. piric therapy of bacterial meningitis in The viruses that cause acute men- adults older than 50 years and in the ingitis are the nonpolio enteroviruses immunocompromised patient should

KEY POINTS: include a combination of a third- or sis, diagnosis, and management can be A The most fourth-generation cephalosporin plus undertaken. common causative vancomycin plus ampicillin (Case 1-1). EPIDEMIOLOGY organisms of Prior to or with the first dose of anti- bacterial biotic, dexamethasone should be ad- The causative organism of acute bac- meningitis in ministered. The dose of dexamethasone terial meningitis can be predicted adults aged 15 for infants and children 2 months of based on the age of the patient, to 50 years are age and older is 0.15 mg/kg of body predisposing factors, and underlying S. pneumoniae weight intravenously every 6 hours for conditions. The most common causa- and Neisseria 2 to 4 days. The dose of dexametha- tive organisms of community-acquired meningitides. sone for adults is 10 mg intravenously bacterial meningitis in adults ages 15 A Several factors every 6 hours for 4 days. Once anti- to 50 years are S. pneumoniae and predispose to microbial therapy and adjunctive ther- N. meningitidis. The most important pneumococcal apy have been initiated, thoughtful antecedent illnesses for pneumococcal meningitis consideration to the epidemiology, clin- meningitis are pneumonia, acute oti- including a ical presentation, differential diagno- tis media, and acute sinusitis. Several complement deficiency, hypogammaglobulinemia, Case 1-1 splenectomy, A 20-year-old man presents to the emergency department in early June head trauma, complaining of 6 hours of fever, headache, and pain on flexion of his CSF leak, neck. He underwent renal transplantation 1 year ago. On examination alcoholism, he is febrile and has meningismus. There is a slight erythematous diabetes, and maculopapular rash on his chest. The neurological examination is normal sickle cell with the exception of meningismus. Blood cultures are obtained. The disease. patient is treated with dexamethasone 10 mg intravenously followed by cefepime 2 grams intravenously, vancomycin 1 gram intravenously, and ampicillin 3 grams intravenously. Over the course of an hour, he becomes increasingly lethargic and has a focal motor seizure with secondary generalization. Acyclovir 10 mg/kg and doxycycline 100 mg are added to the empiric regimen. Head computed tomographic (CT) scan is normal. Spinal fluid analysis demonstrates an opening pressure of 3 320 mm H2O, 1000 white blood cells per mm with a predominance of polymorphonuclear leukocytes, a glucose concentration of 10 mg/dL, and a protein concentration of 100 mg/dL. Gram’s stain of CSF demonstrates gram-positive lancet-shaped diplococci in pairs. Ampicillin, acyclovir, and 14 doxycycline are discontinued. Comment. Empiric therapy of bacterial meningitis is based on the possibility that a penicillin- and cephalosporin-resistant strain of S. pneumoniae is the causative organism of the meningitis and should include a combination of either a third- or fourth-generation cephalosporin plus vancomycin. The patient is an organ transplant recipient and thus is at risk for L. monocytogenes meningitis. Ampicillin is added to the empiric regimen until the results of the Gram’s stain are known. When the patient has a focal seizure, empiric therapy for HSV encephalitis is added. As it is June, the possibility of a tick-borne bacterial infection, either Rocky Mountain spotted fever or an ehrlichia infection, should be considered in the differential diagnosis and empiric therapy with doxycycline initiated until another diagnosis is made. Once the antimicrobial sensitivities of the organism are available, the antibiotic regimen is modified.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS: factors predispose to pneumococcal The causative organism of bacterial A Host defense meningitis, including complement meningitis in an immunocompromised against patient can be predicted based on deficiency, hypogammaglobulinemia, meningitis splenectomy, head trauma with basilar the patient’s type of immune abnor- due to skull fracture and CSF rhinorrhea, mality and the duration of immuno- polysaccharide- alcoholism, diabetes, sickle cell dis- suppression. Patients with defects in encapsulated ease, thalassemia major, and multi- cell-mediated immunity are most sus- bacteria such ple myeloma (Musher, 1992). Less ceptible to central nervous system as S. common causative organisms of bac- infections by microorganisms that are pneumoniae terial meningitis in adults in this intracellular parasites, the eradication and N. age range are L. monocytogenes, staph- of which depends on an intact T- meningitidis ylococci, enteric gram-negative bacilli lymphocyte–macrophage system. L. depends on including Escherichia coli, Klebsi- monocytogenes is the most common the presence of serum ella species, Enterobacter, and Pseu- cause of bacterial meningitis in patients bactericidal with defective cell-mediated immunity. domonas aeruginosa, and rarely H. antibodies and influenzae. This includes patients with hematolog- an intact S. pneumoniae is the most common ical malignancies, pregnancy, organ complement cause of meningitis following trau- transplantation, cancer and cancer system. matic head injury in association with chemotherapy, HIV infection, and A The most the formation of a dural sinus fistula. chronic corticosteroid therapy (Arm- common strong and Wong, 1982). Patients with N. meningitidis initially colonizes organisms the nasopharynx. The risk of invasive defective humoral immunity are unable causing disease following nasopharyngeal col- to mount an antibody response to a meningitis in a onization depends on both the viru- bacterial infection, and they are there- patient who lence of the organism and host fore unable to control infection caused has undergone immune-defense mechanisms. Host by polysaccharide-encapsulated bacte- a neurosurgical defense against invasive meningococ- ria such as S. pneumoniae and N. procedure, with cal disease depends on the presence meningitidis. Young age, old age, and the exception of serum bactericidal antibodies and congenital or acquired immunodefi- of a shunting an intact complement system. In ciency states are associated with anti- procedure, are addition, deficiency or dysfunction in body deficiency or dysfunction. Con- gram-negative bacilli and the properdin (ie, alternate) pathway genital or acquired splenic dysfunction staphylococci. may also result in invasive or severe or a complement deficiency or dys- infections due to N. meningitidis. function increases the risk of infection A Enteroviruses Properdin promotes activation of the caused by polysaccharide-encapsulated are the most alternate pathway of complement pathogens (Overturf, 2003). common cause 15 (Overturf, 2003). Recurrent bacterial meningitis oc- of viral meningitis. The most common organisms caus- curs in patients with previous head ing meningitis in a patient who has trauma and a skull fracture or dural CSF undergone a neurosurgical procedure, leak, those who have had a splenecto- with the exception of a shunting my, those with congenital defects such procedure, are gram-negative bacilli as meningomyelocele, those with defi- and staphylococci. Coagulase negative ciencies of any of the complement staphylococci and Staphylococcus au- components or hypogammaglobuline- reus are the most common pathogens mia (Case 1-2), and those with a causing CSF shunt infections and parameningeal focus of infection. meningitis that occur as a complica- Acute meningitis may be due to a tion of the use of a subcutaneous virus. Enteroviruses are the most com- Ommaya reservoir for the administra- mon cause of viral meningitis. The en- tion of intrathecal chemotherapy. teroviruses include the coxsackieviruses,

Case 1-2 A 46-year-old man presents for evaluation of recurrent bacterial meningitis. He is presently not symptomatic, but on three occasions over the past year he has had fever, headache, stiff neck, and lethargy. He has no history of head trauma except for being hit in the head with a baseball during a Little League game as a child. He has no history of surgery and no chronic medical conditions, nor is he an alcoholic. Spinal fluid analysis each time has demonstrated an increased opening pressure, a polymorphonuclear pleocytosis, a decreased glucose concentration in the range of 0 mg/dL to 20 mg/dL, and an increased protein concentration. Prior to each episode of meningitis he has been treated with oral antibiotics for a sinusitis. The CSF Gram’s stain and bacterial culture have always been negative. A broad-range polymerase chain reaction (PCR) has not been available in the hospitals where he has been hospitalized. On examination, he is awake and alert. No evidence of rhinorrhea is present. There is a mild left sixth nerve palsy, but findings from the neurological examination are otherwise normal. An isotope cisternogram, obtained to determine if there is a dural sinus fistula, is normal. Laboratory testing demonstrates a C2 deficiency and hypogammaglobulinemia. Comment. Complement levels and immunoglobulin levels should be part of the evaluation of every patient with bacterial meningitis. These patients should also be vaccinated with both the pneumococcal and meningococcal vaccines, and their antibody levels should be monitored.

echoviruses, polioviruses, and human rodents. Varicella-zoster virus meningitis enteroviruses 68 to 71. Infection with may occur in association with chicken these viruses is acquired primarily by pox or shingles and in the months fecal-oral contamination and less com- following shingles. Varicella-zoster virus monly by respiratory droplets. HSV-2 meningitis may also occur without a may cause a viral meningitis at the time history or present evidence of shingles. of or shortly after primary genital Meningitis may complicate acute infection and may cause recurrent epi- Epstein-Barr virus infection. sodes of meningitis with or without 16 genital herpetic lesions. HIV-1 seeds the meninges and CSF early during the CLINICAL PRESENTATION course of infection and may cause an The classic triad of symptoms and aseptic meningitis syndrome at the time signs of bacterial meningitis are fever, of seroconversion. It may also cause headache, and stiff neck. Patients may episodes of acute and chronic meningi- also complain of nausea, vomiting, tis during the course of HIV infection photophobia, and lethargy. The level (DiStefanoetal,1996).Arthropod-borne of consciousness progressively deteri- viruses (arboviruses) are acquired by a orates from lethargy to stupor and mosquito or tick bite and may cause a then coma. It is the altered level of viral meningitis. A less common cause of consciousness in association with the viral meningitis today is the lymphocytic classic triad that is most suggestive of choriomeningitis virus, which can cause the presence of bacterial meningitis. meningitis in individuals exposed to Patients may also present with seizure house mice, hamsters, or laboratory activity or focal neurological deficits.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT: Patients with viral meningitis have hands and feet and in the oropharynx A Patients with viral fever, headache, photophobia, nuchal (hand-foot-mouth). Identification of meningitis may rigidity, and chills. Constitutional signs genital vesicular lesions or complaints have lethargy and symptoms of viral infection may of urinary retention or radicular symp- or drowsiness, also be present, including nausea toms in association with headache, but a more and vomiting, anorexia, rash, diarrhea, fever, and mild photophobia are typ- profound cough and upper respiratory symp- ical of HSV meningitis. alteration in toms, and myalgias (Rotbart, 2000). At least 50% of patients with acute consciousness Patients with viral meningitis may have bacterial meningitis develop neurolog- such as stupor lethargy or drowsiness, but a more ical complications, including cerebral or coma does profound alteration in consciousness edema, hydrocephalus, septic venous not occur and, such as stupor or coma does not sinus thrombosis, arteritis, seizures, if present, is occur and, if present, is suggestive of cranial nerve palsies (most commonly suggestive of bacterial bacterial meningitis. Focal neurological hearing impairment due to purulent meningitis. deficits and seizure activity also do not labyrinthitis), septic shock, disseminat- Focal occur in viral meningitis with the ed intravascular coagulation, renal neurological exception of febrile seizures, which failure, syndrome of inappropriate anti- deficits and may complicate viral meningitis in diuretic hormone secretion, or rarely, seizure activity children. central diabetes insipidus and cerebral also do not The classic signs of meningeal salt wasting syndrome, and adult res- occur in viral irritation are nuchal rigidity and Brud- piratory distress syndrome. meningitis with zinski’s and Kernig’s signs. Today, the exception of febrile both Brudzinski’s sign and Kernig’s DIFFERENTIAL DIAGNOSIS sign are elicited with the patient in a seizures, which The differential diagnosis of a clinical supine position. Brudzinski’s sign is may complicate presentation of fever, headache, and positive when passive flexion of the viral meningitis stiff neck is bacterial or viral meningi- in children. neck results in flexion of the hips and tis, fungal meningitis, tuberculous knees. To elicit Kernig’s sign, the thigh meningitis, drug-induced hypersensi- is flexed on the abdomen, and with tivity meningitis, carcinomatous or the knee flexed, the leg is then lymphomatous meningitis, meningitis passively extended. When meningeal associated with inflammatory disor- inflammation is present, the patient ders (eg, sarcoidosis, systemic lupus resists leg extension. erythematosus, Behc¸et’s disease, Sjo¨g- The presence of a diffuse erythem- ren syndrome), and subarachnoid atous maculopapular rash with symp- hemorrhage (Case 1-3). When an al- toms of meningitis suggests that either 17 tered level of consciousness, new-onset the causative organism is an enterovi- seizure activity, or focal neurological rus or the rash may be an early deficits are added to the classic triad, the manifestation of meningococcemia. differential diagnosis includes viral en- The lesions of meningococcemia rap- cephalitis, tick-borne bacterial infec- idly become purpuric or petechial. tions (ie, Rocky Mountain spotted Petechiae are found on the trunk and fever and ehrlichia infections), fungal lower extremities, in the mucous meningitis, brain abscess, epidural ab- membranes and conjunctiva, and oc- scess, subdural empyema, and venous casionally on the palms and soles. sinus thrombosis. Petechiae can occur, but rarely, in H. influenzae, pneumococcal, and staph- ylococcal meningitis. DIAGNOSIS Coxsackievirus and enterovirus 71 When the signs and symptoms suggest can cause vesicular lesions on the bacterial meningitis, blood cultures

KEY POINT: A A cranial CT scan Case 1-3 is not required A 52-year-old woman 1 year after diagnosis with breast cancer complains prior to lumbar of headache, fever, and stiff neck. She lives on a farm in the Midwest, and puncture in her husband complains there are far too many animals in the house. every patient. She has been taking nonsteroidal anti-inflammatory agents to treat her Cranial CT headaches and tamoxifen for breast cancer. Therapy is initiated with scanning dexamethasone, cefepime, vancomycin, ampicillin, and acyclovir. Spinal should be fluid analysis demonstrates a normal opening pressure, a lymphocytic obtained prior pleocytosis of 340 cells/mm3, a normal glucose concentration, and an to lumbar increased protein concentration of 100 mg/dL. Gram’s stain and bacterial puncture in the culture are negative. Dexamethasone and the antibiotics are discontinued. patient with Acyclovir is continued pending the results of CSF varicella-zoster virus suspected IgM and PCR. India ink and fungal culture are negative. CSF smear for bacterial acid-fast bacilli is negative. Mycobacterium tuberculosis culture is pending. meningitis and CSF broad-range PCR for bacterial nucleic acid is negative. CSF RT-PCR any of the for enteroviruses is negative as is viral culture. No varicella-zoster virus following: focal antibodies are detected in CSF. PCR for varicella-zoster virus nucleic neurological acid is negative. CSF cytology is negative. Serology for lymphocytic deficit, choriomeningitis virus is positive, and the patient admits to recently new-onset acquiring a hamster. seizure, altered Comment. The clinical presentation and the CSF formula suggest that level of this is a viral meningitis, although in a patient with a history of breast consciousness, cancer, carcinomatous meningitis is also a possibility. In carcinomatous papilledema, or meningitis, the opening pressure is typically elevated, the protein an immuno- concentration is moderately to markedly increased, and the glucose compromised concentration is either normal or decreased. L. monocytogenes and state. varicella-zoster virus meningitis may have a CSF formula as above, and both may occur in a patient with defective cell-mediated immunity. T-cell subsets should be evaluated in all patients with a recent history of cancer for the possibility of a defect in T-cell mediated immunity. Nonsteroidal anti-inflammatory agents, intravenous immunoglobulin, trimethoprim, sulfonamides, and OKT3 monoclonal antibodies can all cause a drug-induced hypersensitivity meningitis. Spinal fluid analysis usually shows a pleocytosis of several hundred to several thousand cells/mm3, a normal glucose concentration, and an increased protein concentration. If there is no other explanation for the meningitis, the patient should discontinue the drug, and the symptoms should resolve. 18 CSF white blood cell count may be abnormal for months in the patient with meningitis due to lymphocytic choriomeningitis virus.

should be obtained and empiric anti- are as follows: (1) focal neurological microbial and adjunctive therapy be- deficit; (2) new-onset seizure; (3) pa- gun prior to lumbar puncture and pilledema; (4) abnormal level of con- before the patient is sent to the CT sciousness; and (5) immunocompro- scanner. A cranial CT scan is not mised state (Tunkel et al, 2004). The required prior to lumbar puncture in practice of obtaining CSF prior to the every patient. The recommended cri- initiation of antimicrobial therapy is teria for patients with suspected bac- strongly discouraged. The yield of CSF terial meningitis who should undergo Gram’s stain and culture may be dimi- CT scanning prior to lumbar puncture nished by antimicrobial therapy given

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT: for several hours prior to lumbar abnormal. As serum hyperglycemia A In bacterial puncture, but antimicrobial therapy will may increase the CSF glucose concen- meningitis, the not affect the CSF white blood cell tration, the CSF glucose concentration presence or count and glucose concentration such is best determined by the CSF–serum absence of that bacterial meningitis is not sus- glucose ratio in the presence of abnormalities pected. In addition, antimicrobial ther- hyperglycemia. The CSF glucose con- on cranial CT apy will not affect the result of the PCR, centration is low when the CSF–blood cannot reliably which detects nucleic acid of bacteria glucose ratio is less than 0.6. A CSF– predict who will in CSF. blood glucose ratio of 0.40 or less is and who will In bacterial meningitis, cranial CT highly predictive of bacterial meningi- not herniate cannot reliably predict who will and tis. The question often arises as to from lumbar who will not herniate from lumbar how to interpret the CSF glucose puncture. puncture. In patients with either an concentration when an ampule of altered level of consciousness or D50 (50 mL of 50% glucose) has been papilledema and suspected increased given en route to or on arrival in the intracranial pressure, a bolus dose of emergency department. It takes at mannitol 1 gm/kg of body weight can least 30 minutes and more likely as be given intravenously and lumbar long as 4 hours for the glucose puncture performed 20 minutes later. concentration to reach equilibrium Alternatively, the patient can be intu- between blood and CSF. Therefore, bated and hyperventilated in addition an ampule of D50 will not influence to being treated with mannitol. If the the CSF glucose concentration until at clinician is concerned about a risk of least 30 minutes after it has been herniation with lumbar puncture, lum- given. In clinical practice, in patients bar puncture can be delayed while the with acute bacterial meningitis, the patient is being treated with empiric CSF glucose concentration is often antimicrobial therapy until either the very low and may even be 0. Gram’s patient stabilizes enough that lumbar stain is positive in identifying the puncture is safe or the organism is organism in 60% to 90% of cases of identified by blood culture. bacterial meningitis. The probability of The CSF abnormalities characteris- detecting bacteria on a Gram’s stain tic of bacterial meningitis include an specimen depends on the number opening pressure greater than 180 of organisms present. The higher the mm/H2O, a polymorphonuclear leu- CSF bacterial concentration, the more kocytosis, a decreased glucose con- likely the smear is to be positive. CSF centration, and an increased protein culture is positive in 80% of untreated 19 concentration. Normal uninfected CSF patients. does not contain polymorphonuclear Latex particle agglutination tests leukocytes; however, following centrif- that detect antigens of N. meningi- ugation, an occasional polymorphonu- tidis, S. pneumoniae, H. influenzae, clear leukocyte may be seen. The and Streptococcus agalactiae can presence of more than five white provide diagnostic confirmation, but blood cells per mm3 in CSF is abnor- they are not routinely available. In- mal in individuals aged 8 weeks and creasingly, laboratories are offering a older. The normal CSF glucose con- broad range PCR that can detect small centration is between 45 mg/dL and 80 numbers of viable and nonviable mg/dL with a serum glucose of 70 mg organisms in CSF. When the broad- dL to 120 mg/dL or approximately 65% range PCR is positive, a PCR that uses of the serum glucose. CSF glucose specific bacterial primers to detect concentrations below 40 mg/dL are the nucleic acid of S. pneumoniae,

KEY POINT: A Definitive Case 1-4 diagnosis of A 16-year-old girl presents with complaints of sore throat, painful nodes in an arboviral her neck, headache, and fever. Therapy is initiated with dexamethasone, meningitis cefepime, vancomycin, and acyclovir. Examination of the CSF demonstrates requires either a lymphocytic pleocytosis, a normal glucose concentration, and a normal the detection protein concentration. Gram’s stain is negative. Dexamethasone, cefepime of viral IgM and vancomycin are discontinued. CSF RT-PCR for enteroviruses is negative. in CSF, the CSF-PCR for HSV DNA is negative. HIV serology is negative. Antiviral detection of capsid antigen (VCA) IgG titers are 1:320, and Epstein-Barr virus VCA IgM viral nucleic antibody is positive. Anti–Epstein-Barr (virus) nuclear antigen (EBNA) IgG acid in CSF or is negative. EBV DNA is detected in CSF by PCR assay. The diagnosis is a fourfold or meningitis due to acute EBV infection. greater increase Comment. Acute EBV infection is confirmed by the detection of VCA IgG in serum titers of 1:320 or higher, positive IgM antibody titers to the VCA (EBV VCA antibody titer IgM antibody), and the absence of antibodies to virus-associated nuclear between antigen (anti-EBNA IgG). In subsequent serum specimens a fourfold acute and decrease should occur in the IgG antibody titer to VCA and a 16-fold convalescent increase in anti-EBNA IgG (Connelly and DeWitt, 1994). sera, or the isolation of the virus from the brain or N. meningitidis, E. coli, L. monocyto- globulin M (IgM) and immunoglobulin spinal cord. genes, H. influenzae, and S. agalac- G (IgG) antibody titers should be sent tiae should be done. on serum and CSF, and CSF should be In viral meningitis there is typically a sent for the detection of viral nucleic lymphocytic pleocytosis, a normal or acid to West Nile virus. Definitive mildly decreased glucose concentra- diagnosis of an arboviral meningitis tion, and a normal or mildly increased requires either the detection of viral protein concentration. Rarely, poly- IgM in CSF, the detection of viral morphonuclear leukocytes may pre- nucleic acid in CSF or a fourfold or dominate in the first 48 hours of the greater increase in serum antibody illness, especially in patients with titer between acute and convalescent meningitis due to echovirus 9, West sera, or the isolation of the virus from Nile virus, eastern equine encephalitis brain or spinal cord. A diagnosis of virus, or mumps. meningitis due to HSV-2 can be made In patients with suspected viral by detecting HSV DNA in CSF. Menin- 20 meningitis, viral cultures, viral anti- gitis due to HIV-1 can be diagnosed by bodies, and the PCR assay should be detecting HIV-1 RNA in CSF but in performed on CSF. Enteroviruses can addition requires the exclusion of be grown in culture of CSF, and other infections. HIV-1 RNA can be enteroviral RNA can be detected with detected in CSF routinely in patients the reverse transcriptase (RT)-PCR with HIV infection. The diagnosis of assay. Enteroviruses can be isolated meningitis due to Epstein-Barr virus is from throat and stool cultures. Isola- made by a combination of the CSF- tion of an enterovirus from a throat or PCR assay and serology (Case 1-4). stool culture in the setting of fever, Epstein-Barr virus DNA is found in headache, stiff neck, and CSF lympho- peripheral blood mononuclear cells cytic pleocytosis is presumptive evi- and can contaminate the CSF if the dence of enteroviral meningitis, but it lumbar puncture is traumatic. is not diagnostic. In cases of suspected CSF studies that can rapidly differ- arboviral meningitis, virus immuno- entiate bacterial from viral meningitis

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. in the initial hours of the illness are TABLE1-1 Recommended Cerebrospinal important. The best test, of course, is Fluid Routine the Gram’s stain. The CSF lactate Studies for Acute concentration is, in general, nonspe- Meningitis cific but does appear to be valuable for the diagnosis of bacterial meningitis in " Opening pressure postoperative neurosurgical patients. " Cell count and chemistries In the postoperative neurosurgical patient, empiric antimicrobial therapy Cell count with differential for bacterial meningitis should be Glucose and protein initiated if the CSF lactate concentra- concentration tion is 4.0 mmol/L or greater (Tunkel " Stain and culture et al, 2004). Gram’s stain and bacterial Measurement of C-reactive protein culture may be helpful in patients with CSF India ink and fungal culture Viral culture TABLE1-2 Diagnostic Studies in Addition to Acid fast smear and Cerebrospinal Mycobacterium tuberculosis Fluid for Acute culture Meningitis " Antigens " C-reactive protein Cryptococcal polysaccharide antigen " Plasma procalcitonin Histoplasma polysaccharide " Cultures antigen Blood cultures " Antibodies Throat and stool cultures for Complement fixation enteroviruses antibody titers for " Serology Coccidioides immitis Paired acute and convalescent Viral-specific IgM antibodies sera for IgG antibodies " Polymerase chain reaction Enteroviruses Broad range PCR for bacterial Arthropod-borne viruses nucleic acid 21 Virus-specific IgM antibodies Bacterial-specific PCR Human immunodeficiency Reverse transcriptase PCR virus serology for enteroviruses Antiviral capsid antigen (VCA) PCR for West Nile virus RNA titer (Epstein-Barr virus acute PCR for herpes simplex virus infection) type 2 DNA Epstein-Barr virus VCA IgM PCR for Epstein-Barr virus DNA antibodies PCR for human Anti–Epstein-Barr virus nuclear immunodeficiency virus antigen IgG antibodies (past type 1 RNA infection or latent infection) IgM = immunoglobulin M; PCR = poly- IgG = immunoglobulin G; IgM = immu- merase chain reaction. noglobulin M.

TABLE1-3 Recommendations for Specific Antibiotic Therapy in Bacterial Meningitis

Microorganism Antibiotic

Streptococcus pneumoniae Penicillin susceptible Penicillin G or ceftriaxone (or cefotaxime or cefepime) Penicillin tolerant (MIC 0.1 mg/mL Ceftriaxone (or cefotaxime to 1.0 mg/mL) or cefepime) or meropenem

Penicillin resistant (MIC greater Cefepime* (or ceftriaxone than 1 mg/mL) or cefotaxime) plus vancomycin

Neisseria meningitidis Penicillin G* or ampicillin* Ceftriaxone or cefotaxime for penicillin-resistant strains Listeria monocytogenes Ampicillin* Ampicillin plus gentamicin for critically ill patient Streptococcus agalactiae Ampicillin* or penicillin G (group B streptococci) or cefotaxime

Gram-negative Enterobacteriaceae Ceftriaxone* or cefotaxime* (ie, Klebsiella, Escherichia coli, Proteus) or cefepime*

Pseudomonas aeruginosa Meropenem* or cefepime Staphylococcus aureus Methicillin susceptible Nafcillin* or oxacillin* Methicillin resistant Vancomycin* Staphylococcus epidermidis Vancomycin* or Linezolid Haemophilus influenzae Ceftriaxone* or cefotaxime* or cefepime* 22 *Recommended antibiotic. MIC = minimum inhibitory concentration.

findings consistent with meningitis can be useful in differentiating bacte- based on the data that a normal C- rial from viral meningitis. Table 1-1 reactive protein has a high negative lists the recommended CSF routine predictive value in the diagnosis of studies for acute meningitis. Table 1-2 bacterial meningitis (Tunkel et al, lists diagnostic studies in addition to 2004). Plasma procalcitonin is helpful CSF for acute meningitis. in the differential diagnosis of meningitis due to either bacteria or viruses TREATMENT (Viallon et al, 1999). Procalcitonin is a Once the bacterial pathogen is isolat- polypeptide that increases in patients ed and the sensitivity of the organism with severe bacterial infections and to the antibiotic is confirmed by in

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE1-4 Recommended Doses for the Antibiotics Commonly Used in the Treatment of Bacterial Meningitis

Antibiotic Agent Total Daily Dosage (Dosing Interval in Hours)

Ampicillin Neonate: 150 mg/kg/d (every 8 hours) Infants and children: 300 mg/kg/d (every 6 hours) Adult: 12 g/d (every 4 to 6 hours)

Cefepime Infants and children: 150 mg/kg/d (every 8 hours) Adult: 6 g/d (every 8 hours)

Cefotaxime Neonate: 100 mg/kg/d to 150 mg/kg/d (every 8 to 12 hours) Infants and children: 225 mg/kg/d to 300 mg/kg/d (every 6 to 8 hours) Adult: 8 g/d to 12 g/d (every 4 to 6 hours)

Ceftriaxone Infants and children: 80 mg/kg/d to 100 mg/kg/d (every 12 hours) Adult: 4 g/d (every 12 hours)

Gentamicin Neonate: 5 mg/kg/d (every 12 hours) Infants and children: 7.5 mg/kg/d (every 8 hours) Adult: 5 mg/kg/d (every 8 hours)

Meropenem Infants and children: 120 mg/kg/d (every 8 hours) Adult: 6 g/d (every 8 hours)

Nafcillin Neonates: 75 mg/kg/d (every 8 to 12 hours) Infants and children: 200 mg/kg/d (every 6 hours) Adult: 9 g/d to 12 g/d (every 4 hours)

Penicillin G Neonates: 0.15 mU/kg/d to 0.2 mU/kg/d (every 8 to 12 hours) Infants and children: 0.3 mU/kg/d (every 4 to 6 hours) 23 Adult: 24 mU/d (every 4 to 6 hours)

Rifampin Infants and children: 10 mg/kg/d to 20 mg/kg/d (every 12 to 24 hours) Adults: 600 mg/d to 1200 mg/d (every 12 hours)

y Vancomycin* Neonates: 20 mg/kg/d to 30 mg/kg/d (every 8 to 12 hours) Infants and children: 60 mg/kg/d (every 6 hours) Adults: 2 g/d to 3 g/d (every 6 to 12 hours)

*For intravenous vancomycin therapy, maintain serum trough concentrations of 15 mg/mL to 20 mg/mL. Recommended peak levels 1 hour after intravenous administration, vancomycin 25 mg/mL. yIntraventricular vancomycin administration: children 1 mg/d to 2 mg/d, adults 10 mg/d to 20 mg/d.

KEY POINTS: vitro testing, antimicrobial therapy is tokines, including an increased per- A Dexamethasone modified accordingly. Table 1-3 lists meability of the blood-brain barrier exerts its beneficial effect the recommended antibiotic therapy that allows for the leakage of serum by inhibiting based on meningeal pathogen. Table proteins into the CSF, resulting in the synthesis 1-4 lists the recommended doses for the formation of a purulent exudate, of the the antibiotics commonly used in the obstructive and communicating hydro- inflammatory treatment of bacterial meningitis. cephalus, vasogenic, cytotoxic and in- cytokines and The results of a prospective, ran- terstitial cerebral edema, cerebrovascular by decreasing domized, multicenter, double-blind complications, seizures, and coma. CSF outflow trial of adjunctive dexamethasone Dexamethasone exerts its beneficial resistance and therapy for bacterial meningitis in effect by inhibiting the synthesis of stabilizing the 301 adults in five European countries the inflammatory cytokines and by blood-brain over a period of 9 years demonstrated decreasing CSF outflow resistance and barrier. that dexamethasone improves the stabilizing the blood-brain barrier. Dexamethasone outcome in adults with acute bacterial should be Dexamethasone should be adminis- administered meningitis and reduces mortality (de tered either before or with the first either before Gans et al, 2002). The benefits were dose of antibiotic. or with the most striking in the patients with Bacterial meningitis due to S. pneu- first dose of pneumococcal meningitis. Dexameth- moniae, H. influenzae, and group B antibiotic. asone was administered in a dose of streptococci is usually treated with 10 mg 15 to 20 minutes before or A Patients with intravenous antibiotics for 10 to 14 clinically with the first dose of antibiotic and days. Meningitis due to N. meningi- suspected given every 6 hours for 4 days. Pre- tidis is treated for 5 to 7 days. Patients meningococcal viously, the efficacy of dexamethasone with clinically suspected meningococ- meningitis must had been demonstrated in animal cal meningitis must be isolated for be isolated for models of bacterial meningitis and in the first 24 hours after initiation of the first 24 childhood bacterial meningitis if be- antibiotic therapy and treated with hours after gun with or before antibiotics. In bac- rifampin 600 mg every 12 hours for initiation of terial meningitis, it is not the pathogen 2 days after they finish a course of antibiotic itself that causes the neurological intravenous antimicrobial therapy to therapy. complications: it is the inflammatory eradicate nasopharyngeal coloniza- response that is initiated by the lysis tion. Meningitis due to L. monocyto- of bacteria with the release of bac- genes and Enterobacteriaceae is terial cell wall components in the treated for 3 to 4 weeks. Gentamicin subarachnoid space that leads to the is added to ampicillin in critically ill 24 neurological complications. Compo- patients with L. monocytogenes men- nents of bacterial cell walls, such as ingitis. Current recommendations are lipopolysaccharide molecules (endo- that all patients with pneumococcal toxin), a cell wall component of gram- meningitis have CSF reexamined 48 negative bacteria, and teichoic acid and hours after antimicrobial therapy has peptidoglycan cell wall components been initiated to determine that the of the pneumococcus induce menin- CSF culture is negative. The CSF white geal inflammation by stimulating the blood cell count and glucose concen- production of inflammatory cytokines tration will still be abnormal and are and chemokines by microglia, astro- not used to monitor therapy. cytes, monocytes, microvascular endo- Meropenem is the preferred anti- thelial cells, and white blood cells in biotic for P. aeruginosa meningitis. the CSF space. A number of patho- Intraventricular vancomycin is safe and physiological consequences result from can be used for patients who are not the formation of the inflammatory cy- responding to parenteral vancomycin.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Linezolid is a newer antimicrobial agent times daily, which is usually poorly with activity against penicillin-susceptible tolerated by the patient. For meningi- and penicillin-resistant S. pneumoniae, tis associated with recurrent genital methicillin-susceptible and methicillin- herpes, valacyclovir 1000 mg orally resistant S. aureus, and vancomycin- 2 times daily or famciclovir 500 mg 3 susceptible and vancomycin-resistant times daily or acyclovir 200 mg orally Enterococcus faecalis and Enterococ- 5 times daily is recommended for 5 cus faecium. The usual dose of line- days. Patients with HIV meningitis zolid is 600 mg every 12 hours. Adverse should receive potent antiretroviral effects include bone marrow suppres- therapy. Meningitis due to varicella- sion with thrombocytopenia, rash, liver zoster virus is treated the same as the function abnormalities, and renal in- treatment of acute herpes zoster with sufficiency. The emergence of linezolid either valacyclovir 1000 mg 3 times resistance in both E. faecium and daily or famciclovir 500 mg 3 times methicillin-resistant S. aureus has been daily for 7 to 10 days. Acyclovir can be reported. used, but the dose is 800 mg 5 times Patients with viral meningitis often daily for 7 to 10 days. have transient relief of their headache with lumbar puncture. The headache returns and often persists for months. PREVENTION Nonsteroidal anti-inflammatory agents The pneumococcal polysaccharide vac- and amitriptyline are the best combi- cine is recommended for individuals nation to manage these headaches. over age 65, those with asplenia, and Pleconaril is an antipicornavirus agent immunocompetent persons older than that blocks the viral encoding process age 2 who are at risk for pneumococcal by binding to the virus protein capsid, disease due to chronic illness. Most thus blocking the release of viral DNA. adults have protective antibody levels Pleconaril looks promising for reduc- for 5 years, but antibody concentra- ing the duration of headache in tions should be monitored in patients patients with enteroviral meningitis, with recurrent bacterial meningitis. but it is not yet readily available. For The Advisory Committee on Immu- meningitis associated with a primary nization Practices recommends vaccina- HSV-2 infection, valacyclovir 1000 mg tion with the meningococcal conjugate orally 2 times daily or famciclovir 500 vaccine (groups A, C, Y, and W-135) mg 3 times daily is given for a 10-day prior to entry into high school. The course of therapy. Some insurance hope is to soon vaccinate adolescents 25 companies only pay for acyclovir. The aged 11 to 12 in order to reduce the dose of acyclovir is 200 mg orally 5 incidence of meningococcal meningitis.

REFERENCES

" Armstrong D, Wong B. Central nervous system infections in immunocompromised hosts. Annu Rev Med 1982;33:293–308. Although this paper is over 20 years old, the causative organism of bacterial meningitis can still be predicted in an immunocompromised patient based on: (1) the underlying disease and its treatment, (2) the duration of immunosuppression, and (3) the type of immune abnormality.

" Connelly KP, DeWitt LD. Neurologic complications of infectious mononucleosis. Pediatr Neurol 1994;10:181–184. An understanding of the serological tests for acute and past infection or long-term latent infection due to Epstein-Barr virus is critical in determining whether or not the neurological illness is due to an acute Epstein-Barr virus infection.

" de Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549–1556. A prospective, randomized, double-blind trial of adjunctive dexamethasone therapy for bacterial meningitis that demonstrated the efficacy of this therapy.

" Di Stefano M, Gray S, Leitner T, Chiodi F. Analysis of ENV V3 sequences from HIV-1-infected brain indicates restrained virus expression throughout the disease. J Med Virol 1996;49:41–48. HIV-1 can cause episodes of acute and chronic meningitis during the course of human immunodeficiency virus infection.

" Musher DM. Infections caused by Streptococcus pneumoniae: clinical spectrum, pathogenesis, immunity, and treatment. Clin Infect Dis 1992;14:801–807. The predisposing factors for pneumococcal meningitis are reviewed in this manuscript.

" Overturf GD. Indications for the immunological evaluation of patients with meningitis. Clin Infect Dis 2003;36:189–194. Look for antibody and complement deficiencies in every patient with bacterial meningitis, even those who have no known predisposing immunodeficiency.

" Rotbart HA. Viral meningitis. Semin Neurol 2000;20:277–292. This is a classic paper on viral meningitis.

" Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267–1284. These are the practice guidelines for bacterial meningitis of the Infectious Diseases Society of America.

" Viallon A, Zeni F, Lambert C, et al. High sensitivity and specificity of serum procalcitonin levels in adults with bacterial meningitis. Clin Infect Dis 26 1999;28:1313–1316. Procalcitonin is a polypeptide that increases in patients with severe bacterial infections.