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Home , Polio, Viral meningitis

Accurate diagnosis and an extensive work-up can avoid unnecessary treatments. As the season heats up, here’s how to be ready.

iral meningitis is a significant cause of morbidi- nective tissue diseases, partially treated bacterial meningitis, ty and mortality. There are over 100,000 cases of parameningeal and drug-induced meningitis.2 annually in the United Some viral may cause “pure” meningitis in which States.1 The term “aseptic meningitis” refers to the signs of involvement and both infectious and noninfectious causes of are absent. Viral may also result in a combined syn- meningitisV for which no etiology is identified after routine drome of menigoencephalitis or .3 The clini- evaluation and culture of the (CSF). The cal features associated with are often non-spe- differential diagnosis for aseptic meningitis is quite broad. cific, so awareness of epidemiology, including seasonality and Although are the major cause of acute meningitis, the geographic distribution of the various pathogens, becomes clinical presentation and CSF findings are often indistinguish- important in establishing a diagnosis. Given the paucity of able from other causes of aseptic meningitis, presenting a diag- effective for viral meningitis, preventive measures nostic challenge. Therefore, knowledge of unique clinical fea- have an important role in reducing morbidity and mortality. A tures and epidemiology for the causative agents of viral menin- detailed look at the unique characteristics of the common gitis is especially important for diagnosis, treatment and pre- pathogens in viral meningitis will aid in clinical recognition. vention of disease. In this article we have reviewed the major causes of viral meningitis, including diagnosis of and available therapies for these pathogens. Enteroviruses are the most common cause of aseptic meningi- tis for all ages. In the United States, enteroviruses cause over Identifying the 75,000 cases of aseptic meningitis annually.4,5 With the advent The annual number of cases of meningitis due to of polymerase chain reaction (PCR) analysis, detection of viruses surpasses that of all other etiologies of aseptic enteroviral RNA in the CSF has improved dramatically. meningitis. Nevertheless, in addition to viral etiolo- Enteroviruses are classified into five groups: coxsackie A, gies, possible causes of aseptic meningitis include coxsackie B, echoviruses, and the newer, num- bacteria that are not easily detected on Gram’s stain bered enteroviruses. Certain are more strongly asso- or culture such as mycobacteria and spirochetes as ciated with meningitis than others.6 As many as 85 to 95 per- well as fungi, protozoa, helminths, neoplasms, con- cent of acute viral meningitis cases have been attributed to

By Bevin Sell, MD and Lawrence L. Livornese Jr. MD

June 2007 Practical 45 Viral Meningitis

enteroviral infection.7 The incidence of enteroviral meningitis but available therapies have included immune serum globulin is five to eight times higher in infants than in the adult popu- and pleconaril. Immune serum globulin has been used prima- lation.8 rily in neonates and immunocompromised patients.13,14 In temperate climates, enteroviral infections arise most Pleconaril is an oral antiviral agent that inhibits enteroviral often in the summer and early fall. Sporadic cases, however, replication.9 There is some data to suggest that Pleconaril may may appear at any time of year.9 The typical clinical presenta- reduce the duration of symptoms associated with enteroviral tion of enteroviral meningitis varies with age. Neonates and meningitis. However, the Food and Drug Administration young children will often present with and other non- denied licensure due to equivocal data regarding efficacy and specific findings, while is a prominent complaint concern for drug interactions.15 among adults and older children. , nausea and vomiting are common; however, Arboviruses nuchal rigidity is found in less than 70 percent of patients. In Arboviruses are a commonly recognized cause of some cases, clinical findings can be suggestive of infection with throughout the world. A number of these viruses, including a particular enteroviral . For example, hand-foot- , Tick-borne encephalitis virus, mouth syndrome has been associated with 71 Colorado tick fever virus and , may also cause infection; is typically seen with coxsackie virus A meningitis as a manifestation of disease. Saint Louis infection; a maculopapular rash has been linked to echovirus 9 Encephalitis virus (SLE) is one of the most common causes of infection.3,5 Symptoms will usu- vector-transmitted aseptic menin- ally resolve within a week but Because enteroviruses are gitis in the United States. Cases of can occasionally persist for sev- SLE have been reported from most eral weeks.10 cleared via -mediated of the continental United States, Because enteroviruses are sparing only a few of the north- cleared via antibody-mediated mechanisms, patients with eastern states.16 mechanisms, patients with Birds are the primary reservoir agammaglobulinemia are at agammaglobulinemia are at for infection and mosquitos serve greater risk for developing as the vector for . chronic enteroviral meningoen- greater risk for developing Symptoms of meningitis occur in cephalitis, which may last for approximately 15 percent of symp- several years. The prognosis in chronic enteroviral menin- tomatic individuals.3 Colorado these patients is poor, with five- goencephalitis, which may last tick fever virus (CTFV) is a tick- year mortality rates approach- borne coltivirus that has been iso- ing 50 percent.3,5,9 for several years. The prognosis lated from patients with meningi- Historically, polioviruses tis in the Rocky Mountain region have been an important cause in these patients is poor, with of the United States and Canada. of viral meningitis, with large CTFV can cause a prolonged involving the United five-year mortality rates , lasting up to four States and in the first months.17 half of the . In approaching 50 percent. develops in about five to 10 per- 1988 the World Health cent of infected individuals. Assembly initiated the initiative to eradicate Treatment for SLE and CTFV is primarily supportive, and, the burden of disease was reduced by over 99 per- although there are reports of experimental use of Ribavirin for cent. However, despite worldwide efforts, there CTFV infection.18 Tick-borne encephalitis (TBE) is a flavivirus were still 2,001 cases of polivirus infection in the year 2006.11,12 that is transmitted by ticks and has been increasingly recog- Although the rates of meningitis have decreased nized as an important cause of viral meningitis in Europe and markedly in past years, the burden of disease caused by non- Asia.19 Neurological symptoms of infection can include menin- polio enteroviruses remains considerable. gitis, encephalitis, or a combined syndrome. CSF polymerase chain reaction (PCR) can be used for diag- Meningitis accounts for approximately 50 percent of reported nosis of enteroviral meningitis and has been found to be faster, central disease. There is no known treatment more sensitive and more specific than culture of the CSF. for TBE. An inactivated, whole virus has been used in Treatment for enteroviral meningitis is primarily supportive, some areas, but is not available in the United States.20

46 Practical Neurology June 2007 The West Nile virus (WNV) was first isolated in the West nant water should be avoided as these can serve as a breeding Nile province of Uganda in 1937. The first recognized case in ground for mosquitoes, and a thorough check for ticks should the United States occurred in 1999 after an of be done after time spent outdoors. Finally, local and govern- meningitis and encephalitis in New York City.21 The virus has ment programs for insect control can be helpful in reducing since spread to the Western United States and is now found the risk of exposure. nationwide. WNV is a flavivirus and a member of the Japanese encephalitis virus serocomplex, which contains Japanese Herpes viruses encephalitis, SLE, Murray valley, Kunjin and Usutu viruses.22 types 1 and 2, , Epstein-Barr Transmission to humans occurs most commonly through virus and human herpes virus type 6 have all been associated the bite of an infected culicine mosquito. Birds serve as the nat- with aseptic meningitis. Meningitis due to HSV-1 and HSV-2 ural for the virus. Humans and other mammals typically infection, however, is much more common than that caused by have low-level viremia and, therefore, mammal-to-mammal the other herpes viruses and accounts for approximately one to transmission by mosquitoes is unlikely. Additional modes of three percent of all cases of aseptic meningitis.3 While both transmission include blood transfusion, organ transplantation, HSV-1 and HSV-2 have been reported to cause meningitis, breast-feeding, transplacental and occupational exposure in HSV-2 is a more common cause of pure meningitis, whereas laboratory workers.23 The majority of humans infected with HSV-1 traditionally causes meningoencephalitis.28 WNV are . HSV meningitis is most commonly seen in association with Twenty percent of patients will develop a mild febrile illness genital herpes, although genital do not have to be pres- while only one percent will develop ent at the time of infection. The typical age range for patients involvement. Lymphadenopathy and a maculopapular rash are with herpes meningitis occurs in a bimodal distribution, with prominent among infected patients.22,24 The most common the majority of patients being under 20 or over 50 years old.5 presentation of CNS disease is a meningoencephalitis, but iso- Unlike patients with HSV encephalitis,for which mortality lated meningitis or encephalitis may also occur. The primary rates have been estimated at 70 percent if left untreated, HSV risk factor for developing neurological disease is advanced age.25 meningitis is usually self-limited with a relatively benign clini- Other possible neurological manifestations of disease include cal course in an immunocompetent host.29,30 , acute flaccid , , and In a subset of patients, however, HSV infection can be asso- . Rarely, ataxia, cranial involvement, optic ciated with recurrent episodes of aseptic meningitis, which has neuritis, and polyradiculopathy may occur.23 been referred to as “Mollaret’s meningitis.”31 Diagnosis of HSV The diagnosis of WNV infection can be made by serology, meningitis can be made by detection of HSV DNA in the CSF PCR or isolation of the virus. Detection of serum IgM by by PCR, which is both highly sensitive and specific. The role enzyme immunosorbent assay (EIA) is the primary method of of acyclovir in patients with HSV meningitis is diagnosing WNV infection.26 Flaviviruses are closely related unclear. There is some data to suggest acyclovir may have a role antigenically, therefore false-positive results can occur in in the treatment of immunocompromised patients.32 patients who have been infected by other flaviviruses or have been vaccinated against yellow fever or Japanese encephalitis virus.24 Treatment of WNV infection is largely supportive. Prior to the introduction of the , licensed in the There are case reports of successful treatment with intravenous United States in 1967, mumps was one of the most common immunoglobulin, but more conclusive data is needed. Clinical causes of viral meningitis and encephalitis. The virus is spread, trials for alternate treatments, including interferon and AVI- primarily, through respiratory droplets. In unimmunized pop- 420, a new injectable drug, are currently under way.27 Presently, ulations, mumps most often affects school-age children there is not an approved human vaccine for WNV. However, between the months of January and May. Symptoms will there are a number of in development, two of which develop in approximately 60 to 70 percent of infected individ- have reached phase I clinical trials.22 uals and may include fever, parotitis and epididymo-orchitis. Reducing exposure to ticks and mosquitoes is an important CNS involvement can occur in up to 10 to 30 percent of cases step in decreasing morbidity, mortality and infection rates due and may range from mild aseptic meningitis to fatal encephali- to arbovirus infection. Personal protective measures include tis.33,34 Meningitis is the most common CNS manifestation of covering exposed areas of skin, limiting outdoor activities dur- mumps infection. ing peak mosquito feeding times, avoiding tick infested areas, The clinical course in patients with meningitis from mumps wearing a DEET containing insect repellant and using mosqui- infection is typically benign. In some patients, however, infec- to netting and screens for doors and windows. Areas of stag- tion can involve the eighth cranial nerve with resultant deaf-

June 2007 Practical Neurology 47 Viral Meningitis

ness.35 Of note, cases of aseptic meningitis have been reported as a of the mumps vaccine. This vaccine associ- ated meningitis typically occurs two to four weeks after admin- istration and resolves without neurological sequelae.36

HIV Human virus (HIV) can be a cause of both acute and chronic meningitis.37 HIV meningitis has most com- monly been reported in the setting of primary HIV infection. Up to 17 percent of patients diagnosed with primary HIV have neurological manifestations of infection, including meningitis, encephalitis or meningoencephalitis.38 In patients who present acutely, headache, fever and meningeal signs are common, and typically resolve within 10 days. In patients who develop chronic meningitis, headache and CSF pleocytosis may be present for several months, but meningeal signs are often absent.3 Initiation of or changes to highly active anti- retroviral therapy has been associated with clinical improve- ment in patients with acute HIV-associated CNS abnormali- ties.39

Lymphocytic Choriomeningitis Virus Lymphocytic choriomeningitis virus (LCMV) is an arenavirus. Transmission to humans occurs after inhalation, or direct contact with the virus, which is found in the , urine and of infected rodents. The majority of infected humans are either mildly ill or asymptomatic. Approximately 15 percent, however, will have clinical symptoms consistent with aseptic meningitis.3 Predominant symptoms include fever, headache and severe . Patients may also develop lymphadenopathy and an erythematous eruption on the face and trunk that may desquamate.1 CSF findings suggestive of LCMV infection, versus other causes of viral meningitis, include a marked CSF pleocytosis and hypoglycorrhachia.40 Fatalities and permanent neurologic sequelae are rare, but have been reported.41 There are no approved treatments for LCMV. Pregnant and immunocom- promised individuals should take precautions to avoid contact with rodents, including pest control measures, if mice are sus- pected in the home. A number of other viruses have rarely been associated with meningitis, including , adenovirus, , parain- fluenza, rhabdovirus, parvovirus B-19, , nipah and hendra viruses.3,5,46

Making the Diagnosis The diagnosis of viral meningitis can be challenging. The clin- ical presentation is often non-specific and no single CSF or blood parameter has been able to differentiate viral meningitis from other causes. Procalcitonin and C-reactive protein levels have shown some value in distinguishing between viral and Summary bacterial etiologies, with higher levels being suggestive of a bac- Viruses are the leading cause of meningitis. The enteroviruses terial cause.42-44 Additionally, more severe presentation and CSF are the most commonly identified cause of viral meningitis. neutrophil count above 1000x106/l are suggestive of a bacter- Other clinically important causes of meningitis include Herpes ial cause, but are not definitive.45 viruses, arboviruses, mumps, HIV and LCMV. With improve- Typical CSF findings include mild to moderate pleocytosis ments in diagnostic methods, such as PCR, viral etiologies are with a lymphocytic or mononuclear predom- being recognized with increased frequency. inance, normal to slightly low levels and normal to Despite the lack of approved treatments for many of the slightly elevated protein. Some exceptions include West Nile viral causes of meningitis, accurate diagnosis remains impor- meningoencephalitis, which has been associated with a persist- tant. When are able to identify a causative viral ent polymorphonuclear predominance, and LCMV and agent, our patients may avoid unnecessary , diagnos- mumps meningitis, which have been associated with more pro- tic tests and prolonged hospital stays. Knowledge of the epi- nounced hypoglycorrhachia.1,13 Travel history, season, animal demiology and risk factors for these viral pathogens is impor- exposure, exposure to mosquitoes or ticks, sexual history, intra- tant for clinicians, not only for diagnosis and treatment, but venous drug use and presence of a rash or recent illness are all also for the prevention of disease. PN important points to clarify in the history of a patient with sus- pected viral meningitis. In patients with a negative CSF Gram’s Bevin Sell, MD is an Infectious Diseases Fellow at Thomas Jefferson University in Philadelphia. stain, as well as clinical and CSF findings consistent with viral meningitis, workup should include: CSF PCR for enterovirus Lawrence L. Livornese Jr. MD is Clinical Assistant Professor of Medicine at and HSV, CSF IgM for WNV. Additional testing may be Drexel University College of Medicine in Philadelphia and on staff in the Division of Infectious Diseases at Lankenau Hospital in Wynnewood, PA. added based on clinical suspicion for other pathogens.

1. DeBiasi RL, Tyler KL. Viral meningitis and Clin Infect Dis 1995;20(5):1201-6. 26. Haley M, Retter AS, Fowler D, Gea-Banacloche J, cine in UK children. Lancet 1993;341(8851):979-82. encephalitis. Continuum: Lifelong Learning in O'Grady NP. The role for intravenous immunoglobulin Neurology 2002;8:59-88. 15. Desmond RA, Accortt NA, Talley L, Villano SA, in the treatment of west nile virus encephalitis. Clin 37. Post MJ, Tate LG, Quencer RM, et al. CT, MR, and Soong SJ, Whitley RJ. Enteroviral meningitis: Natural Infect Dis 2003;37(6):e88-90. pathology in HIV encephalitis and meningitis. AJR Am 2. Mandell GL, Bennett JE, Dolin R. Principles and history and outcome of pleconaril therapy. Antimicrob J Roentgenol 1988;151(2):373-80. practice of infectious DIseases: Fifth edition. Vol. 2. Agents Chemother 2006;50(7):2409-14. 27. Clinical trials for treating west nile virus disease 2000:960-961. [homepage on the Internet]. . 2007 02/28/07. 38. Newton PJ, Newsholme W, Brink NS, Manji H, 16. Human saint louis encephalitis cases by state, Available from: Williams IG, Miller RF. Acute meningoencephalitis and 3. Rotbart HA. Viral meningitis. Semin Neurol 1964-2005 [homepage on the Internet]. . 2007 2/2/07. 2000;20(3):277-92. www.cdc.gov/ncidod/dvbid/arbor/images/SLE1964- http://www.cdc.gov/ncidod/dvbid/westnile/clinicalTria meningitis due to primary HIV infection. BMJ 2005.jpg. ls.htm. 2002;325(7374):1225-7. 4. Rotbart HA, Brennan PJ, Fife KH, et al. Enterovirus meningitis in adults. Clin Infect Dis 1998;27(4):896-8. 17. Attoui H, Mohd Jaafar F, de Micco P, de 28. Rathore MH, Mercurio K, Halstead D. Herpes sim- 39. Wendel KA, McArthur JC. Acute meningoen- Lamballerie X. Coltiviruses and seadornaviruses in plex virus type 1 meningitis. Pediatr Infect Dis J cephalitis in chronic human immunodeficiency virus 5. Chadwick DR. Viral meningitis. Br Med Bull north america, europe, and asia. Emerg Infect Dis 1996;15(9):824-8. (HIV) infection: Putative central nervous system 2005;75-76:1-14. 2005;11(11):1673-9. 29. Yap E, Ellis-Pegler R. in herpes escape of HIV replication. Clin Infect Dis 6. Atkinson PJ, Sharland M, Maguire H. Predominant 18. Gunther G, Haglund M. Tick-borne simplex type 2 meningitis. J Infect 2006;53(2):e75-7. 2003;37(8):1107-11. enteroviral serotypes causing meningitis. Arch Dis : Epidemiology, diagnosis, treat- Child 1998;78(4):373-4. 30. Simko JP, Caliendo AM, Hogle K, Versalovic J. 40. Rousseau MC, Saron MF, Brouqui P, Bourgeade A. ment and prevention. CNS Drugs 2005;19(12):1009- Differences in laboratory findings for cerebrospinal Lymphocytic choriomeningitis virus in southern 7. Rotbart HA, Webster AD, Pleconaril Treatment 32. fluid specimens obtained from patients with meningi- france: Four case reports and a review of the literature. Registry Group. Treatment of potentially life-threaten- 19. Hansmann Y, Pierre Gut J, Remy V, Martinot M, tis or encephalitis due to (HSV) Eur J Epidemiol 1997;13(7):817-23. ing enterovirus infections with pleconaril. Clin Infect Allard Witz M, Christmann D. Tick-borne encephalitis documented by detection of HSV DNA. Clin Infect Dis Dis 2001;32(2):228-35. in eastern france. Scand J Infect Dis 2006;38(6- 2002;35(4):414-9. 41. Barton LL, Hyndman NJ. Lymphocytic chori- 8. Abzug MJ, Cloud G, Bradley J, et al. Double blind 7):520-6. omeningitis virus: Reemerging central nervous sys- 31. Tyler KL. Herpes simplex virus infections of the tem pathogen. Pediatrics 2000;105(3):E35. placebo-controlled trial of pleconaril in infants with 20. Kunze U, Asokliene L, Bektimirov T, et al. Tick- central nervous system: Encephalitis and meningitis, enterovirus meningitis. Pediatr Infect Dis J borne encephalitis in childhood--consensus 2004. including mollaret's. Herpes 2004;11 Suppl 2:57A- 42. Simon L, Gauvin F, Amre DK, Saint-Louis P, 2003;22(4):335-41. Wien Med Wochenschr 2004;154(9-10):242-5. 64A. Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: A systematic 9. Redington JJ, Tyler KL. Viral infections of the nerv- 21. Centers for Disease Control and Prevention 32. Mommeja-Marin H, Lafaurie M, Scieux C, Galicier ous system, 2002: Update on diagnosis and treatment. L, Oksenhendler E, Molina JM. Herpes simplex virus review and meta-analysis. Clin Infect Dis Arch Neurol 2002;59(5):712-8. (CDC). Outbreak of west nile-like -- new york, 1999. MMWR Morb Mortal Wkly Rep type 2 as a cause of severe meningitis in immunocom- 2004;39(2):206-17. 10. Sawyer MH. Enterovirus infections: Diagnosis and 1999;48(38):845-9. promised adults. Clin Infect Dis 2003;37(11):1527- 33. 43. Sormunen P, Kallio MJ, Kilpi T, Peltola H. C-reac- treatment. Pediatr Infect Dis J 1999;18(12):1033,9; tive protein is useful in distinguishing gram stain-neg- quiz 1040. 22. Dauphin G, Zientara S. West nile virus: Recent trends in diagnosis and vaccine development. Vaccine 33. Kanra G, Isik P, Kara A, Cengiz AB, Secmeer G, ative bacterial meningitis from viral meningitis in chil- 11. Wild poliovirus weekly update [homepage on the 2006. Ceyhan M. Complementary findings in clinical and dren. J Pediatr 1999;134(6):725-9. Internet]. . 2007 03/20/07. Available from: epidemiologic features of mumps and mumps menin- http://www.polioeradication.org/casecount.asp. 23. Sampathkumar P. West nile virus: Epidemiology, goencephalitis in children without mumps vaccina- 44. Gendrel D, Raymond J, Assicot M, et al. clinical presentation, diagnosis, and prevention. Mayo tion. Pediatr Int 2004;46(6):663-8. Measurement of procalcitonin levels in children with 12. Pallansch MA, Sandhu HS. The eradication of Clin Proc 2003;78(9):1137,43; quiz 1144. bacterial or viral meningitis. Clin Infect Dis polio--progress and challenges. N Engl J Med 34. Peltola H. Mumps vaccination and meningitis. 1997;24(6):1240-2. 2006;355(24):2508-11. 24. Asnis DS, Conetta R, Waldman G, Teixeira AA. The Lancet 1993;341(8851):994-5. west nile virus encephalitis outbreak in the united 45. Brivet FG, Ducuing S, Jacobs F, et al. Accuracy of 13. Nowak DA, Boehmer R, Fuchs HH. A retrospective states (1999-2000): From flushing, new york, to 35. Nascimento-Carvalho CM, Moreno-Carvalho OA. clinical, laboratory and outcome analysis in 43 cases beyond its borders. Ann N Y Acad Sci 2001;951:161- Frequency of lymphocytic meningitis associated with clinical presentation for differentiating bacterial from of acute aseptic meningitis. Eur J Neurol 71. mumps before and after a mass campaign for mumps viral meningitis in adults: A multivariate approach. 2003;10(3):271-80. vaccination in children from salvador, northeast brazil. Intensive Care Med 2005;31(12):1654-60. 25. Brilla R, Block M, Geremia G, Wichter M. Clinical Arq Neuropsiquiatr 2003;61(3B):728-30. 14. Abzug MJ, Keyserling HL, Lee ML, Levin MJ, and neuroradiologic features of 39 consecutive cases 46. Wong CJ, Price Z, Bruckner DA. Aseptic meningi- Rotbart HA. Neonatal enterovirus infection: , of west nile virus meningoencephalitis. J Neurol Sci 36. Miller E, Goldacre M, Pugh S, et al. Risk of asep- tis in an infant with rotavirus . Pediatr serology, and effects of intravenous immune globulin. 2004;220(1-2):37-40. tic meningitis after measles, mumps, and vac- Infect Dis 1984;3(3):244-6.

June 2007 Practical Neurology 49