ACUTE MENINGITIS. Karen L. Roos ABSTRACT

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1 CUTE MENINGITIS Karen L. Roos BSTRCT cute meningitis is most often caused by bacteria or viruses. s soon as the diagnosis is suspected, and prior to head computed tomography and spinal fluid analysis, empiric therapy is initiated. n increasing number of polymerase chain reaction assays on cerebrospinal fluid are available, and this, in combination with serological assays, has greatly improved the ability to identify the meningeal pathogen. In this chapter, the epidemiology, clinical presentation, diagnosis, and treatment of acute meningitis are reviewed. OVERVIEW cute meningitis refers to a syndrome of fever, headache, and meningismus associated with a cerebrospinal fluid (CSF) pleocytosis due to infection and inflammation in the subarachnoid space. Bacteria or viruses most often cause acute meningitis. cute meningitis is differentiated from chronic meningitis by the duration of the signs and symptoms. Chronic meningitis refers to a syndrome of fever, headache, and meningismus of greater than 4 weeks duration associated with a CSF pleocytosis. cute bacterial meningitis is now a disease predominately of young adults and older adults rather than of infants and young children due to the profound reduction by vaccination in the incidence of invasive infections caused by Haemophilus influenzae type b. The most common causative organisms of bacterial meningitis in adults aged 15 to 50 years are Streptococcus pneumoniae and Neisseria meningitidis. The most common organisms causing meningitis in adults older than 50 years are S. pneumoniae and enteric gram-negative bacilli; however, meningitis caused by Listeria monocytogenes and H. influenzae is increasingly recognized. The viruses that cause acute meningitis are the nonpolio enteroviruses (coxsackieviruses and B, echoviruses, and the viruses identified by numbers [ie, enteroviruses 68 to 71]), arthropod-borne viruses, herpes simplex virus type 2 (HSV-2), Epstein- Barr virus, human immunodeficiency virus type 1 (HIV-1), and varicella-zoster virus. Less commonly, lymphocytic choriomeningitis virus, mumps virus, and adenovirus cause meningitis. The first step in the management of the patient with fever, headache, and stiff neck is to obtain blood cultures and initiate antimicrobial and adjunctive therapy. The choice of antibiotic for empiric antimicrobial therapy is based on the possibility that a penicillin- and cephalosporinresistant strain of S. pneumoniae is the causative organism of the meningitis and on the patient s age and any associated conditions that may have predisposed the patient to meningitis. Empiric therapy of bacterial meningitis in neonates younger than 1 month should include a combination of ampicillin and cefotaxime. Empiric therapy in infants older than 1 month and in children and adults up to age 50 should include a combination of either a third- or fourth-generation cephalosporin plus vancomycin. Empiric therapy of bacterial meningitis in adults older than 50 years and in the immunocompromised patient should KEY POINTS: The first step in the management of acute bacterial meningitis is to obtain blood cultures and initiate adjunctive and antimicrobial therapy. The choice of antibiotic for empiric antimicrobial therapy is based on the possibility that a penicillin- and cephalosporinresistant strain of Streptococcus pneumoniae is the causative organism of the meningitis. 13

2 "CUTE MENINGITIS 14 KEY POINTS: The most common causative organisms of bacterial meningitis in adults aged 15 to 50 years are S. pneumoniae and Neisseria meningitides. Several factors predispose to pneumococcal meningitis including a complement deficiency, hypogammaglobulinemia, splenectomy, head trauma, CSF leak, alcoholism, diabetes, and sickle cell disease. include a combination of a third- or fourth-generation cephalosporin plus vancomycin plus ampicillin (Case 1-1). Prior to or with the first dose of antibiotic, dexamethasone should be administered. The dose of dexamethasone for infants and children 2 months of age and older is 0.15 mg/kg of body weight intravenously every 6 hours for 2 to 4 days. The dose of dexamethasone for adults is 10 mg intravenously every 6 hours for 4 days. Once antimicrobial therapy and adjunctive therapy have been initiated, thoughtful consideration to the epidemiology, clinical presentation, differential diagnosis, diagnosis, and management can be undertaken. EPIDEMIOLOGY The causative organism of acute bacterial meningitis can be predicted based on the age of the patient, predisposing factors, and underlying conditions. The most common causative organisms of community-acquired bacterial meningitis in adults ages 15 to 50 years are S. pneumoniae and N. meningitidis. The most important antecedent illnesses for pneumococcal meningitis are pneumonia, acute otitis media, and acute sinusitis. Several Case year-old man presents to the emergency department in early June complaining of 6 hours of fever, headache, and pain on flexion of his neck. He underwent renal transplantation 1 year ago. On examination he is febrile and has meningismus. There is a slight erythematous maculopapular rash on his chest. The neurological examination is normal with the exception of meningismus. Blood cultures are obtained. The 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. cyclovir 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 320 mm H 2 O, 1000 white blood cells per mm 3 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. mpicillin, acyclovir, and 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. mpicillin 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. s 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.

3 factors predispose to pneumococcal meningitis, including complement deficiency, hypogammaglobulinemia, splenectomy, head trauma with basilar skull fracture and CSF rhinorrhea, alcoholism, diabetes, sickle cell disease, thalassemia major, and multiple myeloma (Musher, 1992). Less common causative organisms of bacterial meningitis in adults in this age range are L. monocytogenes, staphylococci, enteric gram-negative bacilli including Escherichia coli, Klebsiella species, Enterobacter, and Pseudomonas aeruginosa, and rarely H. influenzae. S. pneumoniae is the most common cause of meningitis following traumatic head injury in association with the formation of a dural sinus fistula. N. meningitidis initially colonizes the nasopharynx. The risk of invasive disease following nasopharyngeal colonization depends on both the virulence of the organism and host immune-defense mechanisms. Host defense against invasive meningococcal disease depends on the presence of serum bactericidal antibodies and an intact complement system. In addition, deficiency or dysfunction in the properdin (ie, alternate) pathway may also result in invasive or severe infections due to N. meningitidis. Properdin promotes activation of the alternate pathway of complement (Overturf, 2003). The most common organisms causing meningitis in a patient who has undergone a neurosurgical procedure, with the exception of a shunting procedure, are gram-negative bacilli and staphylococci. Coagulase negative staphylococci and Staphylococcus aureus are the most common pathogens causing CSF shunt infections and meningitis that occur as a complication of the use of a subcutaneous Ommaya reservoir for the administration of intrathecal chemotherapy. The causative organism of bacterial meningitis in an immunocompromised patient can be predicted based on the patient s type of immune abnormality and the duration of immunosuppression. Patients with defects in cell-mediated immunity are most susceptible to central nervous system infections by microorganisms that are intracellular parasites, the eradication of which depends on an intact T- lymphocyte macrophage system. L. monocytogenes is the most common cause of bacterial meningitis in patients with defective cell-mediated immunity. This includes patients with hematological malignancies, pregnancy, organ transplantation, cancer and cancer chemotherapy, HIV infection, and chronic corticosteroid therapy (rmstrong and Wong, 1982). Patients with defective humoral immunity are unable to mount an antibody response to a bacterial infection, and they are therefore unable to control infection caused by polysaccharide-encapsulated bacteria such as S. pneumoniae and N. meningitidis. Young age, old age, and congenital or acquired immunodeficiency states are associated with antibody deficiency or dysfunction. Congenital or acquired splenic dysfunction or a complement deficiency or dysfunction increases the risk of infection caused by polysaccharide-encapsulated pathogens (Overturf, 2003). Recurrent bacterial meningitis occurs in patients with previous head trauma and a skull fracture or dural CSF leak, those who have had a splenectomy, those with congenital defects such as meningomyelocele, those with deficiencies of any of the complement components or hypogammaglobulinemia (Case 1-2), and those with a parameningeal focus of infection. cute meningitis may be due to a virus. Enteroviruses are the most common cause of viral meningitis. The enteroviruses include the coxsackieviruses, KEY POINTS: Host defense against meningitis due to polysaccharideencapsulated bacteria such as S. pneumoniae and N. meningitidis depends on the presence of serum bactericidal antibodies and an intact complement system. The most common organisms causing meningitis in a patient who has undergone a neurosurgical procedure, with the exception of a shunting procedure, are gram-negative bacilli and staphylococci. Enteroviruses are the most common cause of viral meningitis. 15

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

5 Patients with viral meningitis have fever, headache, photophobia, nuchal rigidity, and chills. Constitutional signs and symptoms of viral infection may also be present, including nausea and vomiting, anorexia, rash, diarrhea, cough and upper respiratory symptoms, and myalgias (Rotbart, 2000). Patients with viral meningitis may have lethargy or drowsiness, but a more profound alteration in consciousness such as stupor or coma does not occur and, if present, is suggestive of bacterial meningitis. Focal neurological deficits and seizure activity also do not occur in viral meningitis with the exception of febrile seizures, which may complicate viral meningitis in children. The classic signs of meningeal irritation are nuchal rigidity and Brudzinski s and Kernig s signs. Today, both Brudzinski s sign and Kernig s sign are elicited with the patient in a supine position. Brudzinski s sign is positive when passive flexion of the neck results in flexion of the hips and knees. To elicit Kernig s sign, the thigh is flexed on the abdomen, and with the knee flexed, the leg is then passively extended. When meningeal inflammation is present, the patient resists leg extension. The presence of a diffuse erythematous maculopapular rash with symptoms of meningitis suggests that either the causative organism is an enterovirus or the rash may be an early manifestation of meningococcemia. The lesions of meningococcemia rapidly become purpuric or petechial. Petechiae are found on the trunk and lower extremities, in the mucous membranes and conjunctiva, and occasionally on the palms and soles. Petechiae can occur, but rarely, in H. influenzae, pneumococcal, and staphylococcal meningitis. Coxsackievirus and enterovirus 71 can cause vesicular lesions on the hands and feet and in the oropharynx (hand-foot-mouth). Identification of genital vesicular lesions or complaints of urinary retention or radicular symptoms in association with headache, fever, and mild photophobia are typical of HSV meningitis. t least 50% of patients with acute bacterial meningitis develop neurological complications, including cerebral edema, hydrocephalus, septic venous sinus thrombosis, arteritis, seizures, cranial nerve palsies (most commonly hearing impairment due to purulent labyrinthitis), septic shock, disseminated intravascular coagulation, renal failure, syndrome of inappropriate antidiuretic hormone secretion, or rarely, central diabetes insipidus and cerebral salt wasting syndrome, and adult respiratory distress syndrome. DIFFERENTIL DIGNOSIS The differential diagnosis of a clinical presentation of fever, headache, and stiff neck is bacterial or viral meningitis, fungal meningitis, tuberculous meningitis, drug-induced hypersensitivity meningitis, carcinomatous or lymphomatous meningitis, meningitis associated with inflammatory disorders (eg, sarcoidosis, systemic lupus erythematosus, Behçet s disease, Sjögren syndrome), and subarachnoid hemorrhage (Case 1-3). When an altered level of consciousness, new-onset seizure activity, or focal neurological deficits are added to the classic triad, the differential diagnosis includes viral encephalitis, tick-borne bacterial infections (ie, Rocky Mountain spotted fever and ehrlichia infections), fungal meningitis, brain abscess, epidural abscess, subdural empyema, and venous sinus thrombosis. DIGNOSIS When the signs and symptoms suggest bacterial meningitis, blood cultures KEY POINT: Patients with viral meningitis may have lethargy or drowsiness, but a more profound alteration in consciousness such as stupor or coma does not occur and, if present, is suggestive of bacterial meningitis. Focal neurological deficits and seizure activity also do not occur in viral meningitis with the exception of febrile seizures, which may complicate viral meningitis in children. 17

6 "CUTE MENINGITIS 18 KEY POINT: cranial CT scan is not required prior to lumbar puncture in every patient. Cranial CT scanning should be obtained prior to lumbar puncture in the patient with suspected bacterial meningitis and any of the following: focal neurological deficit, new-onset seizure, altered level of consciousness, papilledema, or an immunocompromised state. Case year-old woman 1 year after diagnosis with breast cancer complains of headache, fever, and stiff neck. She lives on a farm in the Midwest, and her husband complains there are far too many animals in the house. She has been taking nonsteroidal anti-inflammatory agents to treat her headaches and tamoxifen for breast cancer. Therapy is initiated with dexamethasone, cefepime, vancomycin, ampicillin, and acyclovir. Spinal fluid analysis demonstrates a normal opening pressure, a lymphocytic pleocytosis of 340 cells/mm 3, a normal glucose concentration, and an increased protein concentration of 100 mg/dl. Gram s stain and bacterial culture are negative. Dexamethasone and the antibiotics are discontinued. cyclovir is continued pending the results of CSF varicella-zoster virus IgM and PCR. India ink and fungal culture are negative. CSF smear for acid-fast bacilli is negative. Mycobacterium tuberculosis culture is pending. CSF broad-range PCR for bacterial nucleic acid is negative. CSF RT-PCR for enteroviruses is negative as is viral culture. No varicella-zoster virus antibodies are detected in CSF. PCR for varicella-zoster virus nucleic acid is negative. CSF cytology is negative. Serology for lymphocytic choriomeningitis virus is positive, and the patient admits to recently acquiring a hamster. Comment. The clinical presentation and the CSF formula suggest that this is a viral meningitis, although in a patient with a history of breast cancer, carcinomatous meningitis is also a possibility. In carcinomatous meningitis, the opening pressure is typically elevated, the protein concentration is moderately to markedly increased, and the glucose concentration is either normal or decreased. L. monocytogenes and 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/mm 3, 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. 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 antimicrobial and adjunctive therapy begun prior to lumbar puncture and before the patient is sent to the CT scanner. cranial CT scan is not required prior to lumbar puncture in every patient. The recommended criteria for patients with suspected bacterial meningitis who should undergo CT scanning prior to lumbar puncture are as follows: (1) focal neurological deficit; (2) new-onset seizure; (3) papilledema; (4) abnormal level of consciousness; and (5) immunocompromised state (Tunkel et al, 2004). The practice of obtaining CSF prior to the initiation of antimicrobial therapy is strongly discouraged. The yield of CSF Gram s stain and culture may be diminished by antimicrobial therapy given

7 for several hours prior to lumbar puncture, but antimicrobial therapy will not affect the CSF white blood cell count and glucose concentration such that bacterial meningitis is not suspected. In addition, antimicrobial therapy will not affect the result of the PCR, which detects nucleic acid of bacteria in CSF. In bacterial meningitis, cranial CT cannot reliably predict who will and who will not herniate from lumbar puncture. In patients with either an altered level of consciousness or papilledema and suspected increased intracranial pressure, a bolus dose of mannitol 1 gm/kg of body weight can be given intravenously and lumbar puncture performed 20 minutes later. lternatively, the patient can be intubated and hyperventilated in addition to being treated with mannitol. If the clinician is concerned about a risk of herniation with lumbar puncture, lumbar puncture can be delayed while the patient is being treated with empiric antimicrobial therapy until either the patient stabilizes enough that lumbar puncture is safe or the organism is identified by blood culture. The CSF abnormalities characteristic of bacterial meningitis include an opening pressure greater than 180 mm/h 2 O, a polymorphonuclear leukocytosis, a decreased glucose concentration, and an increased protein concentration. Normal uninfected CSF does not contain polymorphonuclear leukocytes; however, following centrifugation, an occasional polymorphonuclear leukocyte may be seen. The presence of more than five white blood cells per mm 3 in CSF is abnormal in individuals aged 8 weeks and older. The normal CSF glucose concentration is between 45 mg/dl and 80 mg/dl with a serum glucose of 70 mg dl to 120 mg/dl or approximately 65% of the serum glucose. CSF glucose concentrations below 40 mg/dl are abnormal. s serum hyperglycemia may increase the CSF glucose concentration, the CSF glucose concentration is best determined by the CSF serum glucose ratio in the presence of hyperglycemia. The CSF glucose concentration is low when the CSF blood glucose ratio is less than 0.6. CSF blood glucose ratio of 0.40 or less is highly predictive of bacterial meningitis. The question often arises as to how to interpret the CSF glucose concentration when an ampule of D50 (50 ml of 50% glucose) has been given en route to or on arrival in the emergency department. It takes at least 30 minutes and more likely as long as 4 hours for the glucose concentration to reach equilibrium between blood and CSF. Therefore, an ampule of D50 will not influence the CSF glucose concentration until at least 30 minutes after it has been given. In clinical practice, in patients with acute bacterial meningitis, the CSF glucose concentration is often very low and may even be 0. Gram s stain is positive in identifying the organism in 60% to 90% of cases of bacterial meningitis. The probability of detecting bacteria on a Gram s stain specimen depends on the number of organisms present. The higher the CSF bacterial concentration, the more likely the smear is to be positive. CSF culture is positive in 80% of untreated patients. Latex particle agglutination tests that detect antigens of N. meningitidis, S. pneumoniae, H. influenzae, and Streptococcus agalactiae can provide diagnostic confirmation, but they are not routinely available. Increasingly, laboratories are offering a broad range PCR that can detect small numbers of viable and nonviable organisms in CSF. When the broadrange PCR is positive, a PCR that uses specific bacterial primers to detect the nucleic acid of S. pneumoniae, KEY POINT: In bacterial meningitis, the presence or absence of abnormalities on cranial CT cannot reliably predict who will and who will not herniate from lumbar puncture. 19

8 "CUTE MENINGITIS 20 KEY POINT: Definitive diagnosis of an arboviral meningitis requires either the detection of viral IgM in CSF, the detection of viral nucleic acid in CSF or a fourfold or greater increase in serum antibody titer between acute and convalescent sera, or the isolation of the virus from the brain or spinal cord. Case year-old girl presents with complaints of sore throat, painful nodes in her neck, headache, and fever. Therapy is initiated with dexamethasone, cefepime, vancomycin, and acyclovir. Examination of the CSF demonstrates a lymphocytic pleocytosis, a normal glucose concentration, and a normal protein concentration. Gram s stain is negative. Dexamethasone, cefepime and vancomycin are discontinued. CSF RT-PCR for enteroviruses is negative. CSF-PCR for HSV DN is negative. HIV serology is negative. ntiviral capsid antigen (VC) IgG titers are 1:320, and Epstein-Barr virus VC IgM antibody is positive. nti Epstein-Barr (virus) nuclear antigen (EBN) IgG is negative. EBV DN is detected in CSF by PCR assay. The diagnosis is meningitis due to acute EBV infection. Comment. cute EBV infection is confirmed by the detection of VC IgG titers of 1:320 or higher, positive IgM antibody titers to the VC (EBV VC IgM antibody), and the absence of antibodies to virus-associated nuclear antigen (anti-ebn IgG). In subsequent serum specimens a fourfold decrease should occur in the IgG antibody titer to VC and a 16-fold increase in anti-ebn IgG (Connelly and DeWitt, 1994). N. meningitidis, E. coli, L. monocytogenes, H. influenzae, and S. agalactiae should be done. In viral meningitis there is typically a lymphocytic pleocytosis, a normal or mildly decreased glucose concentration, and a normal or mildly increased protein concentration. Rarely, polymorphonuclear leukocytes may predominate in the first 48 hours of the illness, especially in patients with meningitis due to echovirus 9, West Nile virus, eastern equine encephalitis virus, or mumps. In patients with suspected viral meningitis, viral cultures, viral antibodies, and the PCR assay should be performed on CSF. Enteroviruses can be grown in culture of CSF, and enteroviral RN can be detected with the reverse transcriptase (RT)-PCR assay. Enteroviruses can be isolated from throat and stool cultures. Isolation of an enterovirus from a throat or stool culture in the setting of fever, headache, stiff neck, and CSF lymphocytic pleocytosis is presumptive evidence of enteroviral meningitis, but it is not diagnostic. In cases of suspected arboviral meningitis, virus immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody titers should be sent on serum and CSF, and CSF should be sent for the detection of viral nucleic acid to West Nile virus. Definitive diagnosis of an arboviral meningitis requires either the detection of viral IgM in CSF, the detection of viral nucleic acid in CSF or a fourfold or greater increase in serum antibody titer between acute and convalescent sera, or the isolation of the virus from brain or spinal cord. diagnosis of meningitis due to HSV-2 can be made by detecting HSV DN in CSF. Meningitis due to HIV-1 can be diagnosed by detecting HIV-1 RN in CSF but in addition requires the exclusion of other infections. HIV-1 RN can be detected in CSF routinely in patients with HIV infection. The diagnosis of meningitis due to Epstein-Barr virus is made by a combination of the CSF- PCR assay and serology (Case 1-4). Epstein-Barr virus DN is found in peripheral blood mononuclear cells and can contaminate the CSF if the lumbar puncture is traumatic. CSF studies that can rapidly differentiate bacterial from viral meningitis

9 TBLE 1-1 Recommended Cerebrospinal Fluid Routine Studies for cute Meningitis " Opening pressure " Cell count and chemistries Cell count with differential Glucose and protein concentration " Stain and culture Gram s stain and bacterial culture India ink and fungal culture Viral culture cid fast smear and Mycobacterium tuberculosis culture " ntigens Cryptococcal polysaccharide antigen Histoplasma polysaccharide antigen " ntibodies Complement fixation antibody titers for Coccidioides immitis Viral-specific IgM antibodies " Polymerase chain reaction Broad range PCR for bacterial nucleic acid Bacterial-specific PCR Reverse transcriptase PCR for enteroviruses PCR for West Nile virus RN PCR for herpes simplex virus type 2 DN PCR for Epstein-Barr virus DN PCR for human immunodeficiency virus type 1 RN IgM = immunoglobulin M; PCR = polymerase chain reaction. in the initial hours of the illness are important. The best test, of course, is the Gram s stain. The CSF lactate concentration is, in general, nonspecific but does appear to be valuable for the diagnosis of bacterial meningitis in postoperative neurosurgical patients. In the postoperative neurosurgical patient, empiric antimicrobial therapy for bacterial meningitis should be initiated if the CSF lactate concentration is 4.0 mmol/l or greater (Tunkel et al, 2004). Measurement of C-reactive protein may be helpful in patients with CSF TBLE 1-2 Diagnostic Studies in ddition to Cerebrospinal Fluid for cute Meningitis " C-reactive protein " Plasma procalcitonin " Cultures Blood cultures Throat and stool cultures for enteroviruses " Serology Paired acute and convalescent sera for IgG antibodies Enteroviruses rthropod-borne viruses Virus-specific IgM antibodies Human immunodeficiency virus serology ntiviral capsid antigen (VC) titer (Epstein-Barr virus acute infection) Epstein-Barr virus VC IgM antibodies nti Epstein-Barr virus nuclear antigen IgG antibodies (past infection or latent infection) IgG = immunoglobulin G; IgM = immunoglobulin M. 21

10 "CUTE MENINGITIS TBLE 1-3 Recommendations for Specific ntibiotic Therapy in Bacterial Meningitis Microorganism ntibiotic Streptococcus pneumoniae Penicillin susceptible Penicillin tolerant (MIC 0.1 mg/ml to 1.0 mg/ml) Penicillin resistant (MIC greater than 1 mg/ml) Neisseria meningitidis Penicillin G or ceftriaxone (or cefotaxime or cefepime) Ceftriaxone (or cefotaxime or cefepime) or meropenem Cefepime* (or ceftriaxone or cefotaxime) plus vancomycin Penicillin G* or ampicillin* Ceftriaxone or cefotaxime for penicillin-resistant strains Listeria monocytogenes mpicillin* mpicillin plus gentamicin for critically ill patient Streptococcus agalactiae (group B streptococci) Gram-negative Enterobacteriaceae (ie, Klebsiella, Escherichia coli, Proteus) Pseudomonas aeruginosa mpicillin* or penicillin G or cefotaxime Ceftriaxone* or cefotaxime* or cefepime* Meropenem* or cefepime Staphylococcus aureus 22 Methicillin susceptible Methicillin resistant Staphylococcus epidermidis Haemophilus influenzae *Recommended antibiotic. MIC = minimum inhibitory concentration. Nafcillin* or oxacillin* Vancomycin* Vancomycin* or Linezolid Ceftriaxone* or cefotaxime* or cefepime* findings consistent with meningitis based on the data that a normal C- reactive protein has a high negative predictive value in the diagnosis of bacterial meningitis (Tunkel et al, 2004). Plasma procalcitonin is helpful in the differential diagnosis of meningitis due to either bacteria or viruses (Viallon et al, 1999). Procalcitonin is a polypeptide that increases in patients with severe bacterial infections and can be useful in differentiating bacterial from viral meningitis. Table 1-1 lists the recommended CSF routine studies for acute meningitis. Table 1-2 lists diagnostic studies in addition to CSF for acute meningitis. TRETMENT Once the bacterial pathogen is isolated and the sensitivity of the organism to the antibiotic is confirmed by in

11 TBLE 1-4 Recommended Doses for the ntibiotics Commonly Used in the Treatment of Bacterial Meningitis ntibiotic gent mpicillin Cefepime Cefotaxime Ceftriaxone Gentamicin Meropenem Nafcillin Penicillin G Rifampin Vancomycin* y Total Daily Dosage (Dosing Interval in Hours) Neonate: 150 mg/kg/d (every 8 hours) Infants and children: 300 mg/kg/d (every 6 hours) dult: 12 g/d (every 4 to 6 hours) Infants and children: 150 mg/kg/d (every 8 hours) dult: 6 g/d (every 8 hours) 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) dult: 8 g/d to 12 g/d (every 4 to 6 hours) Infants and children: 80 mg/kg/d to 100 mg/kg/d (every 12 hours) dult: 4 g/d (every 12 hours) Neonate: 5 mg/kg/d (every 12 hours) Infants and children: 7.5 mg/kg/d (every 8 hours) dult: 5 mg/kg/d (every 8 hours) Infants and children: 120 mg/kg/d (every 8 hours) dult: 6 g/d (every 8 hours) Neonates: 75 mg/kg/d (every 8 to 12 hours) Infants and children: 200 mg/kg/d (every 6 hours) dult: 9 g/d to 12 g/d (every 4 hours) 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) dult: 24 mu/d (every 4 to 6 hours) Infants and children: 10 mg/kg/d to 20 mg/kg/d (every 12 to 24 hours) dults: 600 mg/d to 1200 mg/d (every 12 hours) 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) dults: 2 g/d to 3 g/d (every 6 to 12 hours) 23 *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. y Intraventricular vancomycin administration: children 1 mg/d to 2 mg/d, adults 10 mg/d to 20 mg/d.

12 "CUTE MENINGITIS 24 KEY POINTS: Dexamethasone exerts its beneficial effect by inhibiting the synthesis of the inflammatory cytokines and by decreasing CSF outflow resistance and stabilizing the blood-brain barrier. Dexamethasone should be administered either before or with the first dose of antibiotic. Patients with clinically suspected meningococcal meningitis must be isolated for the first 24 hours after initiation of antibiotic therapy. vitro testing, antimicrobial therapy is modified accordingly. Table 1-3 lists the recommended antibiotic therapy based on meningeal pathogen. Table 1-4 lists the recommended doses for the antibiotics commonly used in the treatment of bacterial meningitis. The results of a prospective, randomized, multicenter, double-blind trial of adjunctive dexamethasone therapy for bacterial meningitis in 301 adults in five European countries over a period of 9 years demonstrated that dexamethasone improves the outcome in adults with acute bacterial meningitis and reduces mortality (de Gans et al, 2002). The benefits were most striking in the patients with pneumococcal meningitis. Dexamethasone was administered in a dose of 10 mg 15 to 20 minutes before or with the first dose of antibiotic and given every 6 hours for 4 days. Previously, the efficacy of dexamethasone had been demonstrated in animal models of bacterial meningitis and in childhood bacterial meningitis if begun with or before antibiotics. In bacterial meningitis, it is not the pathogen itself that causes the neurological complications: it is the inflammatory response that is initiated by the lysis of bacteria with the release of bacterial cell wall components in the subarachnoid space that leads to the neurological complications. Components of bacterial cell walls, such as lipopolysaccharide molecules (endotoxin), a cell wall component of gramnegative bacteria, and teichoic acid and peptidoglycan cell wall components of the pneumococcus induce meningeal inflammation by stimulating the production of inflammatory cytokines and chemokines by microglia, astrocytes, monocytes, microvascular endothelial cells, and white blood cells in the CSF space. number of pathophysiological consequences result from the formation of the inflammatory cytokines, including an increased permeability of the blood-brain barrier that allows for the leakage of serum proteins into the CSF, resulting in the formation of a purulent exudate, obstructive and communicating hydrocephalus, vasogenic, cytotoxic and interstitial cerebral edema, cerebrovascular complications, seizures, and coma. Dexamethasone exerts its beneficial effect by inhibiting the synthesis of the inflammatory cytokines and by decreasing CSF outflow resistance and stabilizing the blood-brain barrier. Dexamethasone should be administered either before or with the first dose of antibiotic. Bacterial meningitis due to S. pneumoniae, H. influenzae, and group B streptococci is usually treated with intravenous antibiotics for 10 to 14 days. Meningitis due to N. meningitidis is treated for 5 to 7 days. Patients with clinically suspected meningococcal meningitis must be isolated for the first 24 hours after initiation of antibiotic therapy and treated with rifampin 600 mg every 12 hours for 2 days after they finish a course of intravenous antimicrobial therapy to eradicate nasopharyngeal colonization. Meningitis due to L. monocytogenes and Enterobacteriaceae is treated for 3 to 4 weeks. Gentamicin is added to ampicillin in critically ill patients with L. monocytogenes meningitis. Current recommendations are that all patients with pneumococcal meningitis have CSF reexamined 48 hours after antimicrobial therapy has been initiated to determine that the CSF culture is negative. The CSF white blood cell count and glucose concentration will still be abnormal and are not used to monitor therapy. Meropenem is the preferred antibiotic for P. aeruginosa meningitis. Intraventricular vancomycin is safe and can be used for patients who are not responding to parenteral vancomycin.

13 Linezolid is a newer antimicrobial agent with activity against penicillin-susceptible and penicillin-resistant S. pneumoniae, methicillin-susceptible and methicillinresistant S. aureus, and vancomycinsusceptible and vancomycin-resistant Enterococcus faecalis and Enterococcus faecium. The usual dose of linezolid is 600 mg every 12 hours. dverse effects include bone marrow suppression with thrombocytopenia, rash, liver function abnormalities, and renal insufficiency. The emergence of linezolid resistance in both E. faecium and methicillin-resistant S. aureus has been reported. Patients with viral meningitis often have transient relief of their headache with lumbar puncture. The headache returns and often persists for months. Nonsteroidal anti-inflammatory agents and amitriptyline are the best combination to manage these headaches. Pleconaril is an antipicornavirus agent that blocks the viral encoding process by binding to the virus protein capsid, thus blocking the release of viral DN. Pleconaril looks promising for reducing the duration of headache in patients with enteroviral meningitis, but it is not yet readily available. For meningitis associated with a primary HSV-2 infection, valacyclovir 1000 mg orally 2 times daily or famciclovir 500 mg 3 times daily is given for a 10-day course of therapy. Some insurance companies only pay for acyclovir. The dose of acyclovir is 200 mg orally 5 times daily, which is usually poorly tolerated by the patient. For meningitis associated with recurrent genital herpes, valacyclovir 1000 mg orally 2 times daily or famciclovir 500 mg 3 times daily or acyclovir 200 mg orally 5 times daily is recommended for 5 days. Patients with HIV meningitis should receive potent antiretroviral therapy. Meningitis due to varicellazoster virus is treated the same as the treatment of acute herpes zoster with either valacyclovir 1000 mg 3 times daily or famciclovir 500 mg 3 times daily for 7 to 10 days. cyclovir can be used, but the dose is 800 mg 5 times daily for 7 to 10 days. PREVENTION The pneumococcal polysaccharide vaccine is recommended for individuals over age 65, those with asplenia, and immunocompetent persons older than age 2 who are at risk for pneumococcal disease due to chronic illness. Most adults have protective antibody levels for 5 years, but antibody concentrations should be monitored in patients with recurrent bacterial meningitis. The dvisory Committee on Immunization Practices recommends vaccination with the meningococcal conjugate vaccine (groups, C, Y, and W-135) prior to entry into high school. The hope is to soon vaccinate adolescents aged 11 to 12 in order to reduce the incidence of meningococcal meningitis. 25 REFERENCES " rmstrong D, Wong B. Central nervous system infections in immunocompromised hosts. nnu Rev Med 1982;33: lthough 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.

14 "CUTE MENINGITIS " Connelly KP, DeWitt LD. Neurologic complications of infectious mononucleosis. Pediatr Neurol 1994;10: n 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 dulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347: 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. nalysis of ENV V3 sequences from HIV-1-infected brain indicates restrained virus expression throughout the disease. J Med Virol 1996;49: 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: 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: Look for antibody and complement deficiencies in every patient with bacterial meningitis, even those who have no known predisposing immunodeficiency. " Rotbart H. Viral meningitis. Semin Neurol 2000;20: This is a classic paper on viral meningitis. " Tunkel R, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39: These are the practice guidelines for bacterial meningitis of the Infectious Diseases Society of merica. 26 " Viallon, Zeni F, Lambert C, et al. High sensitivity and specificity of serum procalcitonin levels in adults with bacterial meningitis. Clin Infect Dis 1999;28: Procalcitonin is a polypeptide that increases in patients with severe bacterial infections.