SEMINAKS IN NEUKOl.OGY-VO1,UME
12, NO. 3 SEPTEMBER 1992
Viral Meningitis and Encephalitis
Viral infections of the central nervous system (CNS) are divided into meningitis and encephalitis, with involvement of the meninges in the former and the brain parenchyma in the latter. Although CNS viral infections such as poliomyelitis and rabies have been recognized for centuries, a great deal of' knowledge about the pathogenesis of viral infections of the CNS developed with the use of electron microscopy, immunohistochemistry, cell culture rnetllods, and serologic assays.' T h e availability of new molecular virologic techniques, such as the polymerase chain reaction, will have a significant impact on the diagnosis of CNS viral infections. With the advent of antiviral therapy, increased attention has focused on the prompt diagnosis, pathogenesis, and treatment of CNS viral infectior~s,especially herpes simplex encephalitis.' This article will present an overview of acute meningitis and encephalitis, as well as subacute-chronic encephalitis. We will limit our discussion to the most frequently identified causes of viral meningitis and encephalitis in the United States. Infections caused by the human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1 (I-I'I'LV-I),and the subacute spor~giformencephalopathy agent ("prion") have been covered elsewhere in this issue and in other issues of Snninars.
VIRUS ENTRY AND SPREAD Viruses may initially cause infection by passively en~ e r i n gthrough the skin or the respiratory, gastrointestinal, o r urogenital tract." They generally gain access to the CNS by one of' two routes, hernatogenous or neuronal. Herriatogenous spread is the more common. Primary replication, which usually occurs near the site of entry, results in dissemination of the virus to the reticuloeridothelial system and sometimes to muscle, where further replication occurs. Secondary viremia leads to seeding of other sites, including the CNS.' T h e choroid plexus may provide a route for cerebrospinal fluid (CSF) penetration with subsequent spread to ependyma and ~ of the CNS capillary enbrain p a r e n ~ h y m a .Infection dothelial cells may also allow virus entry.
Viruses can enter the CNS via the olfactory route by infecting the olfactory receptor cells o r the arachnoid cells, either directly or following virernia. This may be one of the routes to the CNS for arbovir-uses and herpes simplex." Viruses may also spread to the CNS through nerve endings by rneans of retrograde transmission via axons (for example, poliovirus, reovirus and rabies, herpes simplex, and varicella-zoster virus [VZV]). Spread of enteric viruses f r o n ~the intestinal tract to the CNS was recently studied in mice using a serotype 3 reovirus strain. It Mias demonstrated that initial spread to the CNS occurred with primary infection of the myenteric plexus neurons followed by infection of the dorsal motor nucleus of the vagus, suggesting retrograde spread of virus along autonomic neural paths. This took place despite the presence of significant quantities of virus in the bloodstream, with no evidence of infection of' enclothelial cells, meninges, choroid plexus, hypothalamus, o r area postrema. Whether poliovirus and other entcric viruses penetrate the CNS by means similar to reovirus awaits further in~estigation.~
VIRAL MENINGITIS Viral meningitis is the most common cause of aseptic meningitis, a self-limited inflammatory disorder involving the leptomeninges without evidence of a bacte. ~h e characteristic features are rial or fungal e t i ~ l o g y T headache, fever, and stiff neck. There is usually no evidence of parenchymal involvement such as depression in the level of' consciousness, focal neurologic signs, o r sei7ures. In 1990, 11,852 cases of aseptic meningitis were reported to the Centers for Disease Control (CDC).' In the majority of cases of aseptic meningitis, a specific diagnosis is not made. Enteroviruses are the most common causes of aseptic meningitis with a known etiologic agent. Figure 1 depicts the incidence of aseptic meningitis by month as reported to the CDC from 1986 to 1990.' Many viruses produce illness primarily during certain seasons of the year, as shown in Table 1;' for example, the summer peaks of disease mainly reflect the seasonal occurrence of enteroviral infections.
Dcpartment of Neurology, University of Chicago, Chicago, Illinois Keprint requests: Dr. Rubeiz, Department of Neurology, Box 425, University of Chicago Medical Center, 5841 South Maryland Ave., Chicago, 11-, 60637 Copyright 0 1992 by Thicme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
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Helene Kubeiz, M.D., and Raymond P. ROO.$, M.L).
SEMINAKS IN NEURO1,OGY
- By month, United States. 1986-1990
CLINICAL MANIFESTATIONS
Figure 1. Reported cases, by month, of aseptic meningitis in the United States per 100,000 population between 1986 and 1990. (Reprinted from Morbidity and Mortality Weekly Reportr81982.)
Table 1. Seasonal Prevalence of Some Viral Agents* Summer and early fall Arboviruses Enteroviruses Fall and winter Lymphocytic choriomeningitis virus Winter and spring Mumps Any season Herpesvirus Epstein-Barr virus Cytorneqalovirus 'Adapted from T ~ l e r . ~
Table 2.
Arbovirus Cytomegalovirus Enterovirus E-B virus Herpes LCM Mumps HIV Measles
166
+
CTFV
Regardless of' the specific virus involved, the symptoms and signs of aseptic meningitis are generally similar. T h e onset of the illness is usually sudden, but may be'gradual. T h c most common symptoms are frontal or retro-orbital headache, fever usually less than 40°C, ancl stiffness of the neck usually on terminal neck flexion. Signs of meningeal irritation are generally less marked than in bacterial meningitis. Other symptonis inclucle malaise, photophobia, tnyalgia, nausea, vomiting, and abdominal pain. Infants may manifest fever and irritability without signs of meningeal irritation.The illness usually lasts 1 to 2 weeks. Specific non-CNS manifestations (Table 2)"can occur, such as the rash of herpes zoster, the vesicular lesions of genital herpes simplex, the parotitis of rnurnps, and a maculopapular, vesicular, or petechial eruption with enteroviral infections."'
LABORATORY FINDINGS T h e white blood cell counr is usually normal, but nlay be reduced or elevated. T h e differential count is generally nornlal, although a left shift is occasionally observed. Specific laboratory abnormalities are at times seen, suggesting a particular etiologic agent (Table 3)." CSF examination reveals a clear fluid with a nornlal or elevated opening pressure. T h e CSF cell count generally ranges from 10 to 1000/mrr1"but is usually less than 300 ~ e l l s i m m ~ I n. the early phase of the disease, a predominance ot' polymorphonuclear leukocytes occurs in up to 75% of patients. This is followed within 24 to 48 hours by a shift to a mononuclear response. T h e CSF leukocyte count gradually decreases and usually returns towarcl normal within a few days. Occasionally, CSF pleocytosis persists for 1 to 2 months."" For the latter reason, repeating a lumbar puncture on an aseptic men-
Findings Associated with Viral CNS Diseases*t
SLE
SLE
+ (+) HSV
+ +
+ + +
+ + +
+
(+)
+
HSV
VZV
vzv +
+
+
(+)
(+I
(+)
+
CTFV POW
+ +
vzv
SLE
+
CTFV POW
vzv
(+)(+)
+
+
'Adapted from T ~ l e r . ~ t + :present; ( + ) : occasionally present; CTFV: Colorado tick fever virus; SLE: St. Louis encephalitis virus; POW: Powassan virus; HSV: herpes simplex virus; VZV: varicella-zoster virus; LCM: lymphocytic choriomeningitis virus; HIV: human immunodeficiency virus; E-B virus: Epstein-Barr virus.
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ASEPTIC MENlNGtTlS
VOI.UME 12, NUMBER 3 SEPTEMBER 1992
VIKAI, MENINGITIS AND ENCEPHALITI>KUBEIZ, Koos Table 3. Laboratory Study Abnormalities in Viral CNS Diseases'
Leukopenia Thrombocytopenia Atypical lymphocytosis Renal dysfunction Abnormal liver function
lncreased creatine kinase, aldolase lncreased amylase, lipase Hyponatremia
Possible Etiolwies
Lymphocytic choriomeningitis, Colorado tick fever, EpsteinBarr virus Lymphocytic choriorneningitis, Colorado tick fever, St. Louis encephalitis (rare) Epstein-Barr virus, cytomegalovirus St. Louis encephalitis Lymphocytic choriomeningitis, Epstein-Barr virus, cytomegalovirus, arboviruses (some), mumps St. Louis encephalitis Mumps, enteroviruses (rare), lymphocytic choriomeningitis (rare) St. Louis encephalitis
'Adapted from Tyler.=
ingitis patient who is clinically improving may be unnecessary as well as confusing. T h e CSF glucose concentration is usually normal but may be decreased in mumps and lymphocytic choriomeningitis virus infections.12T h e CSF protein is usually normal or mildly elevated, in the range of 50 to 100 mg1100 ml. Unusual CSF findings that are not typical of aseptic meningitis may provide clues to the etiologic agent (Table 4).' T h e CSF-immunoglobulin G (IgG) index may be elevated, and oligoclonal bands may be present."," In general, most viruses commonly associated with viral meningitis can be recovered from (:SF.'" Attempts to isolate virus from feces, urine, and throat washings should also be made (see Table 5).14 Evidence for intrathecal production of specific antil~odyor a fourfold rise in specific antibody in con-
Table 4.
Unusual Cerebrospinal Fluid Findings in Viral CNS Diseases* Diagnosis
Abnormality
Decreased glucose Marked pleocytosis (>I 000 cells) PMNst predominate (after first 48 hours) Red blood cells (nontraumatic tap) Atypical lymphocytes
Mumps, lymphocytic choriomeningitis, herpes simplex (late, rare) Lymphocytic choriomeningitis, Eastern equine encephalitis, California encephalitis, mumps Echovirus (especially E9), Eastern equine encephalitis Herpes simplex, California encephalitis, Colorado tick fever Epstein-Barr virus, cytomegalovirus
'Adapted from Tyler.= tPMNs: polymorphonuclear leucocytes.
DIFFERENTIAL DIAGNOSIS T h e clinical syndrome of headache, fever, and nuchal rigidity is not specific to viral meningitis. Nonviral infections causing aseptic meningitis include partially treated bacterial meningitis, parameningeal infections, Mycoplasma pneumoniae meningitis, leptospirosis, and Lyme disease. 1;ungal and tuberculous meningitides are usually diagnosed on the basis of the clinical picture and special stains and cultures. Aseptic meningitis can be caused by noninfectious processes, including meningeal carcinomatosis, collagen vascular disease, sarcoidosis, certain drugs such as nonsteroidal anti-inflammatory agents,:$.~.r, -antineoplastic agents,'Vmmunosuppressants such as OKT-3," and, occasionally, trimethoprim, either alone or in combination with s ~ l f o n a m i d e s . ' Acute ~~~ meningeal reactions nlay complicate isotope cisternography and myelography.'Themical meningitis is also sometimes caused by intracranial or intraspinal tumors. A history of recurrent bouts of meningitis with a benign clinical picture and without a parameningeal source should suggest the diagnosis of herpes simplex type 2 meningitis, Mollaret's meningitis, o r uveomeningitis.
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Result
valescent serum supports the etiologic involvement of a particular virus.
SPECIFIC VIRAL INFECTIONS Enteroviruses
Enteroviruses are the most common cause of aseptic nleningitis in which the etiology is found."They belong to the family Picornaviridae and include poliovirus (3 serotypcs), Coxsackieviruses (23 group A and 6 group B serotypes), echoviruses (31 serotypes), and the newer enteroviruses (EV types 68-72)." Some serotypes have a particular propensity to cause aspetic meningitis (echovirus types 6, 9, and 20; Coxsackieviruses A9, B2, B3, and B j ) . W u r i n g large epidemics, multiple enteroviruses are often involved." These agents are worldwide in their distribution. They inhabit the alimentary tract and are spread from host to host by fecal-oral or fecal-handoral transmission, occurring more frequently in young child re^^. Errlerovirus infections have an epidemic seasonal incidence, peaking in summer and early fall; sporadic infections and infections in tropical areas occur at any time during the year.?"." T h e prognosis for cnterovirus aseptic nierringitis is very good. In aseptic meningitis caused by enteroviruses, the CSF pararrleters are usually similar to those found in other causes of viral meningitis." Viral isolation, serologic testing, 01-both confirm the diagnosis. Cultures of CSF, stool, and oropharynx should be performed. T h e stool is the most likely source for virus isolation. Isolation of Coxsackieviruses and echoviruses from the CSF is more conrrnun than with poliovirus, occurrirlg in about 30%)of cases. Acute and convalescent sera should be obtained; however, serologic testing is impractical as the primary diagnostic procedure for the group A Coxsackieviruses and echoviruses because of' the large number of serotypes. An increased (;SF: serum enterovirus antibody ratio may be of'diagnostic value."
167
SEMINARS IN NEIJROLOGY
VOLUME 12, NUMBER 3
SEPTEMBER 1992
Table 5. Specimens for Diagnosis of CNS Viral Infections* Virus
Throat Washinas
Stool
CSF
+++ ++
-
+
++ +
Blood
Urine
Other
Sera
-
++
-
-
t
++
-
+
Enteroviruses Polioviruses Coxsackie viruses Echoviruses
Lymphocytic choriomeningitis virus
-
Arboviruses
-
-
+
Herpesvirus Herpes simplex Type 1 Type 2
-
-
-
-
-
+
+
-
Herpes zoster
-
+
-
-
Epstein-Barr virus Cytomegalovirus
-
-
-
-
+ +
Saliva
+
Brain Vesicular fluid
+ +
Vesicular fluid
+ + +
-
+
(rare) Rabies
-
-
+
-
-
Saliva Brain
+
*Adapted from Johnson.14
Mumps Virus
Mumps meningitis may be associated with hypoglycorrhachia, and 5 to 15% of cases have decreased CSF glucose."." T h e CSF protein is normal or moderately elevated. Murnps-specific oligoclonal IgG may be present."'.?' T h e diagnosis is usually established from the clinical picture of parotitis and by isolation of the virus from the CSF, saliva, arid urine. It is confirmed by demonstrating a fourfold rise in specific antibody in serum, or. eviderlce of intrathecal production of specific antibody.'!'
T h e second most corrimon cause of aseptic mcningitis is mumps virus. Mumps has a worldwide distribution, occurring in epidemics mostly in winter and spring. 'I'he iristitution of a vaccine program has markedly decreased the number of cases in the United States. Mumps virus is a member of the Paramyxoviridac family. It exists as a single serotype, and no immunologic variants have been described." Mumps virus spreads primarily by respiratory droplets or by direct trarisfer of saliva, and usually causes a systemic infection. T h e virus infects glandular tissue such as the par-otids, testes, ovaries, mammary glands, and pancreas, and occasionally Lymphocytic Choriomeningitis Virus other organs, including the CNS."' Parotitis occurs in about 50% of patients with mumps meningitis. Some ob1,ymphocytic choriomeningitis (LCM)virus is a memservers note that meningitis may precedeby 1 week the ber of the Arenaviridae group. LCM virus causes human develo~mentof ~arotitis.but others have stated that infections after contact with infccted rodents, particumeningitis takes place approximately 1 week after the larly mice o r hamsters. I'erson-to-person transmission is development of p a r ~ t i t i s . ~Meningoericephalitis, ".~~ en- not common. Inftctions with LCM virus occur all year cephalitis, and postirifectious encephalomyelitis in addi- round; however, the disease tends to be more corrlmori tion to aseptic rneningitis may appear in the setting of in the winter months. 'I'he latter fact presumably relates mumps i n f e c t i ~ n . ' ~ to human exposure to rodents that enter homes in the Meningitis d u e to mumps is usually a benign, self- winter."' Infections with LCM virus are characterized by a limited disease characterized by the usual clinical manifestations of viral meningitis; persistent sequelae are un- flulike proclromal illness with systemic maniLestations common. Uriilateral and permanent deafness occurs in such as fever, arthralgia, myalgia, and occasionally pneuI to 5% of cases as a result of cochlear inf~ction.'~.'" monitis and alopecia, prior to the onset of meningitic Mumps meningitis in neonates and children is a rare symptoms. Parotitis and orchitis may occur. Coma arld death have rarely been rep~rted."'~'~" Encephalitis is not cause of aqueductal stenosis arid hydrocephal~s.'~,'" In mumps rrieningitis, the spinal fluid typically rare. CSF cell counts are often high (more than 1000 shows mononuclear cells rather than polymorphonu- cellsimm:'), with lymphocytic predominance, arid hypoclear leukocytes, and unlike patients with rrieningitis due glycorrhachia is common.'" T h e diagnosis of LCM can to enteroviruses, only 3 to 7% have a polymorphonu- be established by culturing the virus from blood o r spiclear preclomir~ance in their initial CSF ~arnples.'~'." nal tluid."' More commonly, infections are diagnosed se168
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Mumps virus Adenovirus
VIKAl, MENINGI'I'IS AN11 ENCF:PHALI~'IS-RUREIZ,Roos
Herpes Simplex Virus
cleosis, there are usually atypical lymphocytes, mononuclear cells, elevated proteitr levels, and heterophile antibodies in the CSF."' Aseptic meningitis or- meningoencephalitis can occur during acquired CMV inf'e~tions,:'"~ most cornmonly in organ transplant recipients o r in patients with AIDS.""-" "1 patients with normal irnmune responses, C;NS complications and residual deficits have rarely been reported . r 3 ~ , 5 : i , ~ ,In patients with urlderlyirig defects in cell-mediated immunity, the prognosis is least favorable.":'
Herpes simplex virus (HSV) has been recogriized as a relatively corrlrrlorl CNS patllogerl. HSV types I (HSVI ) and 2 (HSV-2) can be distinguished by differences in capsular antigens. T h e two types arc associated with different diseases; HSV-2 is associated with genital disease and aseptic meningitis,:" whereas HSV-1 has a predilection fbr the organs of'the upper body (oropharynx, eyes, ACUTE VIRAL ENCEPHALITIS AND CNS), and is usually associated with a meningoencephPOSTINFECTIOUS ENCEPHALOMYELITIS alitis. I"."'." HSV-2 is associated with aseptic meningitis ir1 about h:rrcephalitis is defined as inflammation of the brain 0.5 to 3%) of case^."'."^."" T h e HSV-2 meningitis usuallv parenchyma. In most cases, there is also evidence of " af'frcts young, sexually active adults, and more fre- rrierlirlgeal ir~volvernerlt,and irr this situation meningoquently females; the rrlenirlgitis usually occurs during encephalitis may be a more appropriate term. T h e clina primary genital infection. T h e initial contact with ical features include altered state of consciousrless HSV-2 is usually genital or rectal, with virus then spread- accompanied by fever, heaclache, and a variety of assoing to the meninges via the bloods~rearn.Craig ancl ciated neurologic signs. T h e clinical diagnosis of encephNalrtnias" have isolated HSV-2 from the buffr coat and alitis rather than ari uricorr~plicatedaseptic meningitis is vulvar ulcers of paticnts with aseptic rneriingitis. Despite important because of its in~plicationsregarding the etithe virus's relatiorlship to a primary genital infection, ologic agent as well as prognosis. Acute viral encephalitis meningitis may be seen and HSV-2 may be isolated from is predominantly a disease of the gray matter, with perithe CSF in the absence of genital lesions or of a history vascular and parenchyn~alinfiltration of inflammatory of cutaneous lesiorrs.:'"."' A sacral raclic~~litis and low seg- cells and neuronophagia. T h e involvement of brain pamental myelitis can also be seen in association with the rerrchyrna makes encephalitis a more serious condition meningitis and prirr~arygenital o r rectal HSV-2 infec- than aseptic meningitis. t i c ) r r . : ~ : i . : ~ ~ - 4 ~ j Myelitis has been a rare complication in imPostinfectious encephalomyelitis is primarily a dismunocompromised paticnts with AIDS; orre report ease of white matter with perivenular inflammation and notes two patients wiih AIDS who had a myelitis d i e to demyelination." Postinfectious encephalomyelitis is usua mixed infection with HSV-2 and cytornegalovirus ally considered an autoimnrune disease for the following ( C I V I V ) . ~Occasionally, ~.~ recurrent genital episodes are reasons: the clinical disease usually appears relatively associated with recurrent radiculitis o r rneningitis."~~' late iri the virus irifection; virus carlrlot usually be isoCSF pleocytosis, 300 to 2600 cellsln~m~, is noted in lated from the CSF or brain; the pathologic findings reall cases, with lyniphocytes usually predominating. Ele- semble experimental allergic encephalomyelitis, an exvated spinal fluid protein above 110 mgI100 ml is noted perinrerltal autoirnmur~edisease directed against rnyelin in one half of cases. Hypoglycorrhachia has been clocu- proteins; there is evidence of reactivity against myelin rnerl~eci.'~."'l'he disease is benign and self-limited; it re- basic protein irl peripheral blood lymphocytes frorn mits without significant scquelae. T h e diagnosis is estab- postinfectious encephalomyelitis patients."""' lished by either a positive CSP culture o r a fourfold rise In 1990, 134 1 cases of primary encephalitis and 105 in the antibody to HSV-2. There rnay be a future role cases of postinfectious encephalitis were reported to the chain reaction in diagnosis. Isolated CDC.' T h e actual r ~ ~ r r r ~ b are for the polymerase e r s probably higher. Viral . . HSV-2 meningitis requires no specific arrtiviral therapy; encephalitis can be epidemic o r sporadic. Encephalitis however, aseptic meningitis in association with primary due to arboviruses tends to occur in epidemics during genital herpes infection shoulcl be treated with acyclovir, the summer, whereas encephalitis caused by herpessince the d r u g is beneficial for the genital ir~fectiori."~~~' viruses occurs sporadically throughout the year. rl'his review will focus on acute encephalitis caused by herpesviruses, arboviruses, errteroviruses, rrleasles ( ~ ~ ~ s t i r r f e c Other Herpes Viral Meningitides tious encephalomyelitis), and rubella.
12, NO. 3 SEPTEMBER 1992
Viral Meningitis and Encephalitis
Viral infections of the central nervous system (CNS) are divided into meningitis and encephalitis, with involvement of the meninges in the former and the brain parenchyma in the latter. Although CNS viral infections such as poliomyelitis and rabies have been recognized for centuries, a great deal of' knowledge about the pathogenesis of viral infections of the CNS developed with the use of electron microscopy, immunohistochemistry, cell culture rnetllods, and serologic assays.' T h e availability of new molecular virologic techniques, such as the polymerase chain reaction, will have a significant impact on the diagnosis of CNS viral infections. With the advent of antiviral therapy, increased attention has focused on the prompt diagnosis, pathogenesis, and treatment of CNS viral infectior~s,especially herpes simplex encephalitis.' This article will present an overview of acute meningitis and encephalitis, as well as subacute-chronic encephalitis. We will limit our discussion to the most frequently identified causes of viral meningitis and encephalitis in the United States. Infections caused by the human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1 (I-I'I'LV-I),and the subacute spor~giformencephalopathy agent ("prion") have been covered elsewhere in this issue and in other issues of Snninars.
VIRUS ENTRY AND SPREAD Viruses may initially cause infection by passively en~ e r i n gthrough the skin or the respiratory, gastrointestinal, o r urogenital tract." They generally gain access to the CNS by one of' two routes, hernatogenous or neuronal. Herriatogenous spread is the more common. Primary replication, which usually occurs near the site of entry, results in dissemination of the virus to the reticuloeridothelial system and sometimes to muscle, where further replication occurs. Secondary viremia leads to seeding of other sites, including the CNS.' T h e choroid plexus may provide a route for cerebrospinal fluid (CSF) penetration with subsequent spread to ependyma and ~ of the CNS capillary enbrain p a r e n ~ h y m a .Infection dothelial cells may also allow virus entry.
Viruses can enter the CNS via the olfactory route by infecting the olfactory receptor cells o r the arachnoid cells, either directly or following virernia. This may be one of the routes to the CNS for arbovir-uses and herpes simplex." Viruses may also spread to the CNS through nerve endings by rneans of retrograde transmission via axons (for example, poliovirus, reovirus and rabies, herpes simplex, and varicella-zoster virus [VZV]). Spread of enteric viruses f r o n ~the intestinal tract to the CNS was recently studied in mice using a serotype 3 reovirus strain. It Mias demonstrated that initial spread to the CNS occurred with primary infection of the myenteric plexus neurons followed by infection of the dorsal motor nucleus of the vagus, suggesting retrograde spread of virus along autonomic neural paths. This took place despite the presence of significant quantities of virus in the bloodstream, with no evidence of infection of' enclothelial cells, meninges, choroid plexus, hypothalamus, o r area postrema. Whether poliovirus and other entcric viruses penetrate the CNS by means similar to reovirus awaits further in~estigation.~
VIRAL MENINGITIS Viral meningitis is the most common cause of aseptic meningitis, a self-limited inflammatory disorder involving the leptomeninges without evidence of a bacte. ~h e characteristic features are rial or fungal e t i ~ l o g y T headache, fever, and stiff neck. There is usually no evidence of parenchymal involvement such as depression in the level of' consciousness, focal neurologic signs, o r sei7ures. In 1990, 11,852 cases of aseptic meningitis were reported to the Centers for Disease Control (CDC).' In the majority of cases of aseptic meningitis, a specific diagnosis is not made. Enteroviruses are the most common causes of aseptic meningitis with a known etiologic agent. Figure 1 depicts the incidence of aseptic meningitis by month as reported to the CDC from 1986 to 1990.' Many viruses produce illness primarily during certain seasons of the year, as shown in Table 1;' for example, the summer peaks of disease mainly reflect the seasonal occurrence of enteroviral infections.
Dcpartment of Neurology, University of Chicago, Chicago, Illinois Keprint requests: Dr. Rubeiz, Department of Neurology, Box 425, University of Chicago Medical Center, 5841 South Maryland Ave., Chicago, 11-, 60637 Copyright 0 1992 by Thicme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
Helene Kubeiz, M.D., and Raymond P. ROO.$, M.L).
SEMINAKS IN NEURO1,OGY
- By month, United States. 1986-1990
CLINICAL MANIFESTATIONS
Figure 1. Reported cases, by month, of aseptic meningitis in the United States per 100,000 population between 1986 and 1990. (Reprinted from Morbidity and Mortality Weekly Reportr81982.)
Table 1. Seasonal Prevalence of Some Viral Agents* Summer and early fall Arboviruses Enteroviruses Fall and winter Lymphocytic choriomeningitis virus Winter and spring Mumps Any season Herpesvirus Epstein-Barr virus Cytorneqalovirus 'Adapted from T ~ l e r . ~
Table 2.
Arbovirus Cytomegalovirus Enterovirus E-B virus Herpes LCM Mumps HIV Measles
166
+
CTFV
Regardless of' the specific virus involved, the symptoms and signs of aseptic meningitis are generally similar. T h e onset of the illness is usually sudden, but may be'gradual. T h c most common symptoms are frontal or retro-orbital headache, fever usually less than 40°C, ancl stiffness of the neck usually on terminal neck flexion. Signs of meningeal irritation are generally less marked than in bacterial meningitis. Other symptonis inclucle malaise, photophobia, tnyalgia, nausea, vomiting, and abdominal pain. Infants may manifest fever and irritability without signs of meningeal irritation.The illness usually lasts 1 to 2 weeks. Specific non-CNS manifestations (Table 2)"can occur, such as the rash of herpes zoster, the vesicular lesions of genital herpes simplex, the parotitis of rnurnps, and a maculopapular, vesicular, or petechial eruption with enteroviral infections."'
LABORATORY FINDINGS T h e white blood cell counr is usually normal, but nlay be reduced or elevated. T h e differential count is generally nornlal, although a left shift is occasionally observed. Specific laboratory abnormalities are at times seen, suggesting a particular etiologic agent (Table 3)." CSF examination reveals a clear fluid with a nornlal or elevated opening pressure. T h e CSF cell count generally ranges from 10 to 1000/mrr1"but is usually less than 300 ~ e l l s i m m ~ I n. the early phase of the disease, a predominance ot' polymorphonuclear leukocytes occurs in up to 75% of patients. This is followed within 24 to 48 hours by a shift to a mononuclear response. T h e CSF leukocyte count gradually decreases and usually returns towarcl normal within a few days. Occasionally, CSF pleocytosis persists for 1 to 2 months."" For the latter reason, repeating a lumbar puncture on an aseptic men-
Findings Associated with Viral CNS Diseases*t
SLE
SLE
+ (+) HSV
+ +
+ + +
+ + +
+
(+)
+
HSV
VZV
vzv +
+
+
(+)
(+I
(+)
+
CTFV POW
+ +
vzv
SLE
+
CTFV POW
vzv
(+)(+)
+
+
'Adapted from T ~ l e r . ~ t + :present; ( + ) : occasionally present; CTFV: Colorado tick fever virus; SLE: St. Louis encephalitis virus; POW: Powassan virus; HSV: herpes simplex virus; VZV: varicella-zoster virus; LCM: lymphocytic choriomeningitis virus; HIV: human immunodeficiency virus; E-B virus: Epstein-Barr virus.
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ASEPTIC MENlNGtTlS
VOI.UME 12, NUMBER 3 SEPTEMBER 1992
VIKAI, MENINGITIS AND ENCEPHALITI>KUBEIZ, Koos Table 3. Laboratory Study Abnormalities in Viral CNS Diseases'
Leukopenia Thrombocytopenia Atypical lymphocytosis Renal dysfunction Abnormal liver function
lncreased creatine kinase, aldolase lncreased amylase, lipase Hyponatremia
Possible Etiolwies
Lymphocytic choriomeningitis, Colorado tick fever, EpsteinBarr virus Lymphocytic choriorneningitis, Colorado tick fever, St. Louis encephalitis (rare) Epstein-Barr virus, cytomegalovirus St. Louis encephalitis Lymphocytic choriomeningitis, Epstein-Barr virus, cytomegalovirus, arboviruses (some), mumps St. Louis encephalitis Mumps, enteroviruses (rare), lymphocytic choriomeningitis (rare) St. Louis encephalitis
'Adapted from Tyler.=
ingitis patient who is clinically improving may be unnecessary as well as confusing. T h e CSF glucose concentration is usually normal but may be decreased in mumps and lymphocytic choriomeningitis virus infections.12T h e CSF protein is usually normal or mildly elevated, in the range of 50 to 100 mg1100 ml. Unusual CSF findings that are not typical of aseptic meningitis may provide clues to the etiologic agent (Table 4).' T h e CSF-immunoglobulin G (IgG) index may be elevated, and oligoclonal bands may be present."," In general, most viruses commonly associated with viral meningitis can be recovered from (:SF.'" Attempts to isolate virus from feces, urine, and throat washings should also be made (see Table 5).14 Evidence for intrathecal production of specific antil~odyor a fourfold rise in specific antibody in con-
Table 4.
Unusual Cerebrospinal Fluid Findings in Viral CNS Diseases* Diagnosis
Abnormality
Decreased glucose Marked pleocytosis (>I 000 cells) PMNst predominate (after first 48 hours) Red blood cells (nontraumatic tap) Atypical lymphocytes
Mumps, lymphocytic choriomeningitis, herpes simplex (late, rare) Lymphocytic choriomeningitis, Eastern equine encephalitis, California encephalitis, mumps Echovirus (especially E9), Eastern equine encephalitis Herpes simplex, California encephalitis, Colorado tick fever Epstein-Barr virus, cytomegalovirus
'Adapted from Tyler.= tPMNs: polymorphonuclear leucocytes.
DIFFERENTIAL DIAGNOSIS T h e clinical syndrome of headache, fever, and nuchal rigidity is not specific to viral meningitis. Nonviral infections causing aseptic meningitis include partially treated bacterial meningitis, parameningeal infections, Mycoplasma pneumoniae meningitis, leptospirosis, and Lyme disease. 1;ungal and tuberculous meningitides are usually diagnosed on the basis of the clinical picture and special stains and cultures. Aseptic meningitis can be caused by noninfectious processes, including meningeal carcinomatosis, collagen vascular disease, sarcoidosis, certain drugs such as nonsteroidal anti-inflammatory agents,:$.~.r, -antineoplastic agents,'Vmmunosuppressants such as OKT-3," and, occasionally, trimethoprim, either alone or in combination with s ~ l f o n a m i d e s . ' Acute ~~~ meningeal reactions nlay complicate isotope cisternography and myelography.'Themical meningitis is also sometimes caused by intracranial or intraspinal tumors. A history of recurrent bouts of meningitis with a benign clinical picture and without a parameningeal source should suggest the diagnosis of herpes simplex type 2 meningitis, Mollaret's meningitis, o r uveomeningitis.
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Result
valescent serum supports the etiologic involvement of a particular virus.
SPECIFIC VIRAL INFECTIONS Enteroviruses
Enteroviruses are the most common cause of aseptic nleningitis in which the etiology is found."They belong to the family Picornaviridae and include poliovirus (3 serotypcs), Coxsackieviruses (23 group A and 6 group B serotypes), echoviruses (31 serotypes), and the newer enteroviruses (EV types 68-72)." Some serotypes have a particular propensity to cause aspetic meningitis (echovirus types 6, 9, and 20; Coxsackieviruses A9, B2, B3, and B j ) . W u r i n g large epidemics, multiple enteroviruses are often involved." These agents are worldwide in their distribution. They inhabit the alimentary tract and are spread from host to host by fecal-oral or fecal-handoral transmission, occurring more frequently in young child re^^. Errlerovirus infections have an epidemic seasonal incidence, peaking in summer and early fall; sporadic infections and infections in tropical areas occur at any time during the year.?"." T h e prognosis for cnterovirus aseptic nierringitis is very good. In aseptic meningitis caused by enteroviruses, the CSF pararrleters are usually similar to those found in other causes of viral meningitis." Viral isolation, serologic testing, 01-both confirm the diagnosis. Cultures of CSF, stool, and oropharynx should be performed. T h e stool is the most likely source for virus isolation. Isolation of Coxsackieviruses and echoviruses from the CSF is more conrrnun than with poliovirus, occurrirlg in about 30%)of cases. Acute and convalescent sera should be obtained; however, serologic testing is impractical as the primary diagnostic procedure for the group A Coxsackieviruses and echoviruses because of' the large number of serotypes. An increased (;SF: serum enterovirus antibody ratio may be of'diagnostic value."
167
SEMINARS IN NEIJROLOGY
VOLUME 12, NUMBER 3
SEPTEMBER 1992
Table 5. Specimens for Diagnosis of CNS Viral Infections* Virus
Throat Washinas
Stool
CSF
+++ ++
-
+
++ +
Blood
Urine
Other
Sera
-
++
-
-
t
++
-
+
Enteroviruses Polioviruses Coxsackie viruses Echoviruses
Lymphocytic choriomeningitis virus
-
Arboviruses
-
-
+
Herpesvirus Herpes simplex Type 1 Type 2
-
-
-
-
-
+
+
-
Herpes zoster
-
+
-
-
Epstein-Barr virus Cytomegalovirus
-
-
-
-
+ +
Saliva
+
Brain Vesicular fluid
+ +
Vesicular fluid
+ + +
-
+
(rare) Rabies
-
-
+
-
-
Saliva Brain
+
*Adapted from Johnson.14
Mumps Virus
Mumps meningitis may be associated with hypoglycorrhachia, and 5 to 15% of cases have decreased CSF glucose."." T h e CSF protein is normal or moderately elevated. Murnps-specific oligoclonal IgG may be present."'.?' T h e diagnosis is usually established from the clinical picture of parotitis and by isolation of the virus from the CSF, saliva, arid urine. It is confirmed by demonstrating a fourfold rise in specific antibody in serum, or. eviderlce of intrathecal production of specific antibody.'!'
T h e second most corrimon cause of aseptic mcningitis is mumps virus. Mumps has a worldwide distribution, occurring in epidemics mostly in winter and spring. 'I'he iristitution of a vaccine program has markedly decreased the number of cases in the United States. Mumps virus is a member of the Paramyxoviridac family. It exists as a single serotype, and no immunologic variants have been described." Mumps virus spreads primarily by respiratory droplets or by direct trarisfer of saliva, and usually causes a systemic infection. T h e virus infects glandular tissue such as the par-otids, testes, ovaries, mammary glands, and pancreas, and occasionally Lymphocytic Choriomeningitis Virus other organs, including the CNS."' Parotitis occurs in about 50% of patients with mumps meningitis. Some ob1,ymphocytic choriomeningitis (LCM)virus is a memservers note that meningitis may precedeby 1 week the ber of the Arenaviridae group. LCM virus causes human develo~mentof ~arotitis.but others have stated that infections after contact with infccted rodents, particumeningitis takes place approximately 1 week after the larly mice o r hamsters. I'erson-to-person transmission is development of p a r ~ t i t i s . ~Meningoericephalitis, ".~~ en- not common. Inftctions with LCM virus occur all year cephalitis, and postirifectious encephalomyelitis in addi- round; however, the disease tends to be more corrlmori tion to aseptic rneningitis may appear in the setting of in the winter months. 'I'he latter fact presumably relates mumps i n f e c t i ~ n . ' ~ to human exposure to rodents that enter homes in the Meningitis d u e to mumps is usually a benign, self- winter."' Infections with LCM virus are characterized by a limited disease characterized by the usual clinical manifestations of viral meningitis; persistent sequelae are un- flulike proclromal illness with systemic maniLestations common. Uriilateral and permanent deafness occurs in such as fever, arthralgia, myalgia, and occasionally pneuI to 5% of cases as a result of cochlear inf~ction.'~.'" monitis and alopecia, prior to the onset of meningitic Mumps meningitis in neonates and children is a rare symptoms. Parotitis and orchitis may occur. Coma arld death have rarely been rep~rted."'~'~" Encephalitis is not cause of aqueductal stenosis arid hydrocephal~s.'~,'" In mumps rrieningitis, the spinal fluid typically rare. CSF cell counts are often high (more than 1000 shows mononuclear cells rather than polymorphonu- cellsimm:'), with lymphocytic predominance, arid hypoclear leukocytes, and unlike patients with rrieningitis due glycorrhachia is common.'" T h e diagnosis of LCM can to enteroviruses, only 3 to 7% have a polymorphonu- be established by culturing the virus from blood o r spiclear preclomir~ance in their initial CSF ~arnples.'~'." nal tluid."' More commonly, infections are diagnosed se168
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Mumps virus Adenovirus
VIKAl, MENINGI'I'IS AN11 ENCF:PHALI~'IS-RUREIZ,Roos
Herpes Simplex Virus
cleosis, there are usually atypical lymphocytes, mononuclear cells, elevated proteitr levels, and heterophile antibodies in the CSF."' Aseptic meningitis or- meningoencephalitis can occur during acquired CMV inf'e~tions,:'"~ most cornmonly in organ transplant recipients o r in patients with AIDS.""-" "1 patients with normal irnmune responses, C;NS complications and residual deficits have rarely been reported . r 3 ~ , 5 : i , ~ ,In patients with urlderlyirig defects in cell-mediated immunity, the prognosis is least favorable.":'
Herpes simplex virus (HSV) has been recogriized as a relatively corrlrrlorl CNS patllogerl. HSV types I (HSVI ) and 2 (HSV-2) can be distinguished by differences in capsular antigens. T h e two types arc associated with different diseases; HSV-2 is associated with genital disease and aseptic meningitis,:" whereas HSV-1 has a predilection fbr the organs of'the upper body (oropharynx, eyes, ACUTE VIRAL ENCEPHALITIS AND CNS), and is usually associated with a meningoencephPOSTINFECTIOUS ENCEPHALOMYELITIS alitis. I"."'." HSV-2 is associated with aseptic meningitis ir1 about h:rrcephalitis is defined as inflammation of the brain 0.5 to 3%) of case^."'."^."" T h e HSV-2 meningitis usuallv parenchyma. In most cases, there is also evidence of " af'frcts young, sexually active adults, and more fre- rrierlirlgeal ir~volvernerlt,and irr this situation meningoquently females; the rrlenirlgitis usually occurs during encephalitis may be a more appropriate term. T h e clina primary genital infection. T h e initial contact with ical features include altered state of consciousrless HSV-2 is usually genital or rectal, with virus then spread- accompanied by fever, heaclache, and a variety of assoing to the meninges via the bloods~rearn.Craig ancl ciated neurologic signs. T h e clinical diagnosis of encephNalrtnias" have isolated HSV-2 from the buffr coat and alitis rather than ari uricorr~plicatedaseptic meningitis is vulvar ulcers of paticnts with aseptic rneriingitis. Despite important because of its in~plicationsregarding the etithe virus's relatiorlship to a primary genital infection, ologic agent as well as prognosis. Acute viral encephalitis meningitis may be seen and HSV-2 may be isolated from is predominantly a disease of the gray matter, with perithe CSF in the absence of genital lesions or of a history vascular and parenchyn~alinfiltration of inflammatory of cutaneous lesiorrs.:'"."' A sacral raclic~~litis and low seg- cells and neuronophagia. T h e involvement of brain pamental myelitis can also be seen in association with the rerrchyrna makes encephalitis a more serious condition meningitis and prirr~arygenital o r rectal HSV-2 infec- than aseptic meningitis. t i c ) r r . : ~ : i . : ~ ~ - 4 ~ j Myelitis has been a rare complication in imPostinfectious encephalomyelitis is primarily a dismunocompromised paticnts with AIDS; orre report ease of white matter with perivenular inflammation and notes two patients wiih AIDS who had a myelitis d i e to demyelination." Postinfectious encephalomyelitis is usua mixed infection with HSV-2 and cytornegalovirus ally considered an autoimnrune disease for the following ( C I V I V ) . ~Occasionally, ~.~ recurrent genital episodes are reasons: the clinical disease usually appears relatively associated with recurrent radiculitis o r rneningitis."~~' late iri the virus irifection; virus carlrlot usually be isoCSF pleocytosis, 300 to 2600 cellsln~m~, is noted in lated from the CSF or brain; the pathologic findings reall cases, with lyniphocytes usually predominating. Ele- semble experimental allergic encephalomyelitis, an exvated spinal fluid protein above 110 mgI100 ml is noted perinrerltal autoirnmur~edisease directed against rnyelin in one half of cases. Hypoglycorrhachia has been clocu- proteins; there is evidence of reactivity against myelin rnerl~eci.'~."'l'he disease is benign and self-limited; it re- basic protein irl peripheral blood lymphocytes frorn mits without significant scquelae. T h e diagnosis is estab- postinfectious encephalomyelitis patients."""' lished by either a positive CSP culture o r a fourfold rise In 1990, 134 1 cases of primary encephalitis and 105 in the antibody to HSV-2. There rnay be a future role cases of postinfectious encephalitis were reported to the chain reaction in diagnosis. Isolated CDC.' T h e actual r ~ ~ r r r ~ b are for the polymerase e r s probably higher. Viral . . HSV-2 meningitis requires no specific arrtiviral therapy; encephalitis can be epidemic o r sporadic. Encephalitis however, aseptic meningitis in association with primary due to arboviruses tends to occur in epidemics during genital herpes infection shoulcl be treated with acyclovir, the summer, whereas encephalitis caused by herpessince the d r u g is beneficial for the genital ir~fectiori."~~~' viruses occurs sporadically throughout the year. rl'his review will focus on acute encephalitis caused by herpesviruses, arboviruses, errteroviruses, rrleasles ( ~ ~ ~ s t i r r f e c Other Herpes Viral Meningitides tious encephalomyelitis), and rubella.
