Handbook of Clinical Neurology, Vol. 112 (3rd series) Pediatric Neurology Part II O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved Chapter 119 Aseptic meningitis LISE E. NIGROVIC* Department of Medicine, Children’s Hospital Boston and Harvard Medical School, Boston, MA, USA Meningitis refers to inflammation of the cerebrospinal fluid (CSF) and the meninges that surround the brain and spinal cord (Fig.119.1). Aseptic meningitis or viral meningitis cases occur at any age but are most common in infants and young children. Most cases of aseptic meningitis have a benign, self-limited course with maximal symptom duration of 1–2 weeks. The youngest patients, particularly neonates within the first few weeks of life, typically have the most severe symptoms. Meningoencephalitis occurs when infection involves the brain parenchyma as well as the meninges. CLINICAL PRESENTATION Young children and infants with meningitis may present with nonspecific signs: fever, irritability, lethargy, poor feeding, or vomiting (Rittichier et al., 2005). Older children with meningitis may present with fever, photophobia, headache, or stiff neck. Seizures are most common with herpes meningoencephalitis. Physical examination findings such as the Brudzinski sign (active flexion of the neck results in passive flexion of the patient’s hip) and Kernig sign (pain with knee extension when the hip is flexed), although rare, are highly suggestive of meningitis. DIAGNOSIS OF MENINGITIS A lumbar puncture is diagnostic of meningitis and should be performed as soon as the patient’s clinical stability allows. Head computed tomography prior to lumbar puncture need not be performed routinely, but should be considered when the child has evidence of increased intracranial pressure or a fucal neurologic exon because of the risk of subsequent cerebral herniation. Signs of increased intracranial pressure include a bulging fontanel, blurred optic disk margins, or any focal neurological deficit. Antibiotic pretreatment prior to diagnostic evaluation for possible meningitis should lower the clinical threshold to perform a diagnostic lumbar puncture due to the potential of partially treated bacterial meningitis. A case of aseptic meningitis is defined by the presence of CSF pleocytosis (CSF white blood cell (WBC) 10 cells/mm3) with a negative CSF bacterial culture in a patient who has not received prior antibiotics. Bleeding due to traumatic insertion of the lumbar puncture needle complicates the interpretation of the CSF analysis due to the introduction of both red blood cells (RBCs) and WBCs. Although several methods of correcting CSF WBCs for the presence of RBCs have been developed, none of these methods can accurately identify all cases of meningitis (Bonadio et al., 1990). Use of local anesthetic and removal of the catheter stylet after the lumbar puncture needle pierces the skin are modifiable procedural factors that have been shown to reduce the rate of traumatic lumbar puncture (Nigrovic et al., 2007b). MICROBIOLOGY In the era of widespread vaccinations against bacterial pathogens, most cases of meningitis are caused by viral not bacterial infection. Enteroviruses are picornaviruses which are responsible for the vast majority of aseptic meningitis cases (85–95% of cases in which a pathogen is identified; Lee et al., 2006). The picornavirus family includes echovirus, Coxsackie A and B viruses, as well as the polioviruses. Poliovirus, although exceedingly rare due to effective widespread vaccination, results in selective destruction of the motor neurons leading to flaccid paralysis. Enterovirus 71 has been linked to several recent outbreaks of encephalitis with high associated mortality. Although these infections occur year round, peak yearly incidence in temperate climates occurs *Correspondence to: Lise E. Nigrovic, M.D., M.P.H., Assistant Professor of Pediatrics, Department of Medicine, Children’s Hospital Boston and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Tel: þ1-617-355-6363, Fax: þ1-617-730-0335, E-mail: [email protected] 1154 L.E. NIGROVIC Fig.119.1. Cross-sectional anatomy. Meningitis is caused by inflammation of cerebrospinal fluid (CSF) and the meninges that surround the brain and spinal cord. Reprinted with permission from Torpy et al., 2007. Copyright 2007 American Medical Association. during the summer and fall months (June through October). Transmission of the enteroviruses occurs via the fecal–oral route, although inhalation of infected droplets has also been reported. The incubation period is usually 3–6 days. Other less common viral causes include the following: Epstein–Barr virus, herpes simplex, human paraechovirus, mumps, and varicella-zoster virus. Aseptic meningitis may also be caused by nonviral infections (Bartonella henselae (cat scratch disease), Borrelia burgdorferi (Lyme disease), Cryptococcus, Mycobacterium tuberculosis (Mollaret’s meningitis), Rickettsia species, Mycoplasma pneumoniae) or noninfectious entities (drugs, autoimmune/collagen vascular diseases, Kawasaki disease). DISTINGUISHING ASEPTIC FROM BACTERIAL MENINGITIS Definitive discrimination between aseptic and bacterial meningitis depends on the results of the CSF culture; it takes 2–3 days to exclude bacterial growth reliably. Meningeal signs (defined by the presence of neck stiffness, Kernig’s or Brudinski’s sign, or bulging fontanelle in an infant) are associated with the presence of bacterial meningitis but also aseptic meningitis, pneumonia, deep neck-space infections, as well as other self-limiting diseases such as myalgias or torticollis. Clinicians use CSF results to distinguish bacterial from aseptic meningitis. CSF Gram stain is the best single predictor with a sensitivity of approximately 65% depending on the bacterial pathogen and the colony count. Other CSF parameters such as WBC count, glucose, or protein have a wide zone of overlap between bacterial and aseptic meningitis. Biomarkers such as C-reactive protein or CSF lactate may not show elevation early in bacterial disease and may also be elevated in patients with viral infections. Recent studies suggest that procalcitonin (which is in widespread clinical usage in Europe but not the USA) may have a role in discriminating between aseptic and bacterial meningitis, although further investigations are needed (Dubos et al., 2006a). Enteroviral polymerase chain reaction (EV-PCR), however, provides a means to identify positively cases of viral meningitis. A new commercially available PCR testing platform can provide clinicians with EV-PCR results within a few hours, having the potential to affect management decisions about antibiotic administration and disposition (Ramers et al., 2000; Archimbaud et al., 2009). Multivariate clinical prediction rules combine readily available clinical and laboratory parameters to distinguish cases of bacterial from aseptic meningitis. One meningitis prediction rule (the Bacterial Meningitis Score) was validated on a large multicenter cohort in the era of widespread conjugate pneumococcal vaccination. This prediction rule identifies a group of patients at very low risk of bacterial meningitis if they lack all of the high-risk criteria (Table 119.1; Nigrovic et al., 2002, 2007a) and has now been validated in eight published studies (Nigrovic et al., 2012). Application of a validated meningitis decision rule has the potential to help clinicians improve the care of children with CSF pleocytosis ASEPTIC MENINGITIS Table 119.1 Bacterial Meningitis Score: five high-risk criteria Positive CSF Gram stain CSF absolute neutrophil count (ANC) 1000 cells/mm3 CSF protein 80 mg/dL Peripheral blood ANC 10 000 cells/mm3 Presence of a seizure at or prior to presentation From Nigrovic et al. (2007a). by identifying a subset of patients at very low risk of bacterial meningitis who could, in the appropriate clinical context, be managed as outpatients after strong consideration of administration of a long-acting parenteral antibiotic (Dubos et al., 2006b, 2008). Meningitis clinical prediction rules should be applied cautiously to the youngest infants ( 2 months of age), who are most likely to be misclassified and who are the most difficult to evaluate clinically. Clinicians also need to be aware that these prediction models do not identify patients at risk of other treatable types of central nervous system infections such as Lyme meningitis or herpes encephalitis. PRETREATED MENINGITIS Administration of antibiotics prior to lumbar puncture may render CSF culture results falsely negative, making the determination of the appropriate duration of antibiotics more difficult (Kanegaye et al., 2001). When bacterial meningitis is clinically suspected, however, empirical antibiotics should be started without delay even if the diagnostic lumbar puncture is to be deferred. Antibiotic pretreatment has also been shown to affect CSF profiles by decreasing CSF protein and increasing CSF glucose without significant effects on CSF cell counts (Nigrovic et al., 2008). Therefore, clinical prediction rules for bacterial meningitis should not be applied to patients pretreated with antibiotics. CSF latex agglutination tests detect the presence of bacterial antigens in the CSF but have low sensitivity and limited clinical utility. TREATMENT Viral meningitis is treated with supportive measures alone. Inpatient care is required only for intravenous hydration and pain control. No currently available antiviral agents have activity against enteroviruses. Definitive exclusion of bacterial infections depends on bacterial culture results, which take several days to reliably exclude bacterial growth. Empirical antibiotics should be initiated early for all patients with a clinical concern for bacterial meningitis. For these patients, antibiotics should be selected to have a broad antimicrobial spectrum that covers the likely bacterial pathogens and 1155 known resistance patterns. The duration of antibiotics should be determined by a combination of clinical presentation, viral diagnostics, and bacterial culture results. MENINGOENCEPHALITIS Children with meningoencephalitis present with acute onset of altered mental status, focal neurological deficits, ataxia, aphasia, or focal seizures. Most children will also have an associated fever. Examination of the CSF typically reveals a mild pleocytosis with a lymphocytic predominance. Herpes simplex virus (HSV) is the most commonly identified cause of encephalitis and occurs in patients of all ages. Neonates are particularly susceptible to HSV infection, with most cases transmitted peripartum (although in utero and postnatal transmission are also reported). Neonatal HSV meningitis often occurs without cutaneous findings and typically presents within the first 2 weeks of life. If HSV infection is suspected, CSF should be obtained for PCR detection as well as routine studies. Abnormalities in the temporal lobe region on neuroimaging suggest HSV encephalitis, although the viral tropism is not specific enough to enable definite identification of the infecting virus. Aciclovir therapy should be initiated pending diagnostic test results. Children with proven HSV encephalitis should be treated with intravenous aciclovir for 21 days as well as long-term suppressive therapy (Kimberlin et al., 2011). Even after appropriate diagnosis and treatment, children with HSV encephalitis can have significant associated morbidity and mortality. Arthropod-borne viruses cause epidemic encephalitis. Because the mosquito is the most common vector, most cases occur during the summer months when insect activity is the highest. West Nile encephalitis was first reported in the West Nile district of Uganda in the 1930s. Now, West Nile virus has been detected in 46 of the states (concentrated in the East and South) as well as throughout Europe. Other causes of arborviral encephalitis in the USA include: eastern equine, La Crosse, St. Louis, and western equine viruses. Therapy for arborvirus infection is largely supportive, although empirical acyclovir should be considered until HSV infection can be definitely excluded. Most patients make a complete recovery, although some patients with arborviral encephalitis are left with seizure disorder or persistent neurological deficits. Influenza virus infection (particularly type A) has also been rarely associated with encephalitis. The incidence of neurological complications is highest in children under 5 years of age. Viral transmission occurs person to person through respiratory secretions with a peak incidence during the winter months (January through February). 1156 L.E. NIGROVIC NONINFECTIOUS CAUSES Aseptic meningitis can result from noninfectious causes such as medications. Drugs that have been implicated as possible causes of aseptic meningitis include nonsteroidal anti-inflammatory drugs (NSAIDs), sulfa drugs, and intravenous immunoglobulin (IVIG). Medicationinduced aseptic meningitis must remain a diagnosis of exclusion after other more common infectious causes have been effectively excluded. RECURRENT ASEPTIC MENINGITIS Recurrent or Mollaret meningitis is an extremely rare clinical entity defined as three or more episodes of aseptic meningitis. Patients present with fever and meningismus lasting several days followed by spontaneous resolution. There is considerable patient-to-patient variability in the time between episodes (weeks to years). The CSF reveals a mild pleocytosis with a lymphocytic predominance. Most commonly, these episodes are caused by HSV (type 1 or 2) infection identified by PCR testing of the CSF. Patients often do not have a history of genital lesions. Noninfectious causes of Mollaret meningitis, such as an epidermoid cyst, must also be considered. CONCLUSIONS Aseptic meningitis is a common but typically benign childhood infection. The incidence is highest in infants and during the summer months. Affected children typically make a complete recovery with supportive care alone. Because of the overlap between the clinical and laboratory features of patients with aseptic and bacterial meningitis, many patients with aseptic meningitis are treated with empirical antibiotics while awaiting bacterial culture results. Viral diagnostics allow for more rapid exclusion of bacterial infection as well as initiation of specific therapy when available. 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