Acute meningitis is a clinical syndrome characterized by the onset of meningeal symptoms over the course of hours up to several days, and is defined by an abnormal number of white blood cells in cerebrospinal fluid [CSF]. The acute meningitis syndrome may be caused by a wide variety of infectious agents and may also be a manifestation of noninfectious diseases. Here, I will concentrate on the more common infectious causes of acute meningitis, with emphasis on the bacteria, viruses, and mycobacteria that most typically cause this syndrome.
ETIOLOGY
Bacterial Meningitis
Bacterial meningitis remains a very important disease worldwide [1,2,3,4]. The overall annual attack rate for bacterial meningitis, as defined by a surveillance study of 27 states in the United States from 1978 through 1981, was approximately 3.0 cases per 100,000 population, although there was variability based on age, race, and sex [1]; the three most common meningeal pathogens [i.e., Haemophilus influenzae, Neisseria meningitides, and Streptococcus pneumoniae] accounted for more than 80% of cases. In a subsequent surveillance study conducted during 1995 in laboratories serving all the acute care hospitals in 22 counties of four states [>10 million population] [3], the incidence of bacterial meningitis decreased dramatically, as a result of a vaccine-related decline in meningitis caused by H. influenzae type b [from 2.9 cases per 100,000 population in 1986 to 0.2 cases per 100,000 population in 1995] such that in the United States, bacterial meningitis is now a disease predominantly of adults rather than infants and children; S. pneumoniae was the most frequent pathogen, accounting for 47% of cases. In a more recent epidemiologic survey, published only in abstract form [4], the incidence of bacterial meningitis declined from 1998 to 2003, with a reduction in pneumococcal meningitis in patients less than 2 years of age.
The isolation frequency of specific pathogens in patients with bacterial meningitis varies depending upon the age of the patient, various predisposing factors, and geographic locale. For example, in neonates, group B streptococcus is the most common etiologic agent. In patients 16 years or older with community-acquired bacterial meningitis [5,6,7], most cases are caused by S. pneumoniae, N. meningitidis, and Listeria monocytogenes. Bacterial meningitis is also a significant problem in hospitalized patients. In one review of 493 episodes of bacterial meningitis in adults 16 years or older at the Massachusetts General Hospital from 1962 through 1988 [5], 40% of episodes were nosocomial in origin, with most cases [38%] caused by gram-negative bacilli. In addition, bacterial meningitis is a major problem in other areas of the world. In the largest review of approximately 4100 cases of bacterial meningitis at Hospital Couta Maia in Salvador, Brazil from 1973 through 1982, the attack rate was 45.8 cases per 100,000 population [8], with H. influenzae, N. meningitidis, and S. pneumoniae accounting for 62% of the cases.
The following sections review the epidemiology and etiology of specific meningeal pathogens.
Streptococcus pneumoniae
S. pneumoniae is now the most frequently observed etiologic agent of community-acquired bacterial meningitis in the United States, accounting for 47% of the total cases and associated with a mortality rate ranging from 19 to 26% [1,2,3]. Patients with pneumococcal meningitis often have contiguous or distant foci of infection such as pneumonia, otitis media, mastoiditis, sinusitis, or endocarditis. Serious infection may be observed in patients with various underlying conditions [e.g., splenectomy or asplenic states, multiple myeloma, hypogammaglobulinemia, alcoholism, malnutrition, chronic liver or renal disease, malignancy, and diabetes mellitus] [9,10]. The pneumococcus is the most common etiologic agent of meningitis in patients who have suffered basilar skull fracture with CSF leak. In children who develop second episodes of pneumococcal meningitis, screening for congenital immunoglobulin deficiencies should be performed [11].
Neisseria meningitidis
N. meningitidis most commonly causes meningitis in children and young adults and is associated with an overall mortality rate of 3 to 13% [1,2,3]. Meningococci of serogroups B, C, and Y account for most of the endemic disease in the United States; during an active and ongoing, laboratory-based, population-based surveillance for meningococcal disease in the United States from 1992-1996, serogroup C caused 35%, serogroup B caused 32%, and serogroup Y caused 26% of cases [12]. In contrast, serogroup B accounted for 75% of isolates in Italy in a recent study [13]. Disease caused by serogroups A and C may occur in epidemics; group Y strains may be associated with pneumonia. Several outbreaks of invasive meningococcal disease caused by serogroup C have been reported in the United States, Canada and Europe, with most caused by one strain of electrophoretic type 37 [ET-37] termed ET-15. Isolates of the ET-37 complex were also responsible for most cases of sporadic serogroup C meningococcal disease in another study [14]. During the outbreak of meningococcal disease coinciding with the Hajj pilgrimage in March 2000, the attack rate of W135 disease was 25 cases per 100,000 pilgrims, with all outbreak-associated isolates of serogroup W135 members of a single clone of the hypervirulent ET-37 complex [15], occurring as a the result of expansion of a clone that had been in circulation since 1970. Respiratory tract infections, with viruses such as influenza virus, may play a role in the pathogenesis of invasive meningococcal disease. Nasopharyngeal carriage of N. meningitidis is an important factor that leads to the development of invasive disease [16]. Patients with deficiencies in the terminal complement components [C5, C6, C7, C8, and perhaps C9], the so-called membrane attack complex, have a markedly increased incidence of neisserial infection [17], including that caused by N. meningitidis, although mortality rates in patients with meningococcal disease are lower than those in patients with an intact complement system. Because meningococcal meningitis occurs in ~39% of persons with late complement component deficiencies and 6% of those with properdin deficiencies, it has been suggested that a screening test for complement function [i.e., CH50] should be performed for all patients who have invasive meningococcal infections, with consideration of direct assessment of terminal complement components and properdin proteins [11].
Listeria monocytogenes
L. monocytogenes causes 8% of cases of bacterial meningitis in the United States and carries a mortality rate of 15 to 29% [1,2,3]; serotypes 1/2b and 4b have been implicated in up to 80% of meningitis cases caused by this organism. Listerial infection is most common in infants younger than 1 month [up to 10% of cases], adults older than 50 years, alcoholics, cancer patients, those receiving corticosteroid therapy, and immunosuppressed adults [e.g., renal transplant recipients] [18,19]. Other predisposing conditions include diabetes mellitus, liver disease, chronic renal disease, collagen-vascular diseases, and conditions associated with iron overload. Although colonization rates are low, pregnant women [who account for 25% of all cases of listeriosis] may harbor the organism asymptomatically in their genital tract and rectum and transmit the infection to their infants. Listeria meningitis is found infrequently in patients with HIV infectiondespite its increased incidence in patients with deficiencies in cell-mediated immunity. Adults less than 50 years of age who present with Listeria meningitis should be screened for HIV infection [11]. Meningitis can also occur in previously healthy adults. Outbreaks of Listeria infection have been associated with the consumption of contaminated cole slaw, raw vegetables, milk, and cheese, with sporadic cases traced to contaminated cheese, turkey franks, alfalfa tablets, and processed meats [20], thus pointing to the intestinal tract as the usual portal of entry.
Streptococcus agalactiae
Group B streptococcus is a common cause of meningitis in neonates, with 52% of all cases in the United States reported during the first month of life [3]; in the United States, the overall mortality rate ranges from 7 to 27% [1,2,3]. Most cases of neonatal meningitis occur after the first week of life. Group B streptococcus has been isolated from the vaginal or rectal cultures of 15 to 35% of asymptomatic pregnant women; the risk of transmission from mother to infant is increased when the inoculum of organisms and the number of sites of maternal colonization are increased and is not related to the route of delivery. Horizontal transmission has also been documented from the hands of nursery personnel to the infant. Risk factors in adults who develop group B streptococcal meningitis include age older than 60 years, diabetes mellitus, pregnancy or the postpartum state, cardiac disease, collagen-vascular diseases, malignancy, alcoholism, hepatic failure, renal failure, previous stroke, neurogenic bladder, decubitus ulcers, and corticosteroid therapy [21,22]; in one review of group B streptococcal meningitis in adults, no underlying illnesses were found in 43% of patients [21].
Haemophilus influenzae
H. influenzae was previously isolated in 45 to 48% of all cases of bacterial meningitis in the United States; this organism is now isolated in only 7% of cases [3]; the overall mortality rate is 3 to 6% [1,2,3]. Most episodes of meningitis previously occurred in infants and children with a peak incidence of 6 to 12 months of age, with 90% of cases caused by capsular type b strains. Isolation of this organism in older children and adults should suggest the presence of certain underlying conditions, including sinusitis, otitis media, epiglottitis, pneumonia, diabetes mellitus, alcoholism, splenectomy or asplenic states, head trauma with CSF leak, and immune deficiency [e.g., hypogammaglobulinemia] [23,24]. Recently, a profound reduction in the incidence of invasive infections [including bacterial meningitis] caused by H. influenzae type b in the United States and Western Europe has been seen. This decrease in infection is attributed to the widespread use of conjugate vaccines against H. influenzae type b that have been licensed for routine use in all children beginning at 2 months of age. The benefits of vaccination have also been observed in the developing world. In one trial in The Gambia [25], the annual incidence of H. influenzae type b meningitis before use of the vaccine was 200 cases per 100,000 children less than 1 year of age compared to no cases in 2002.
Aerobic Gram-Negative Bacilli
Aerobic gram-negative bacilli [e.g., Klebsiella spp., Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Salmonella spp.] have become increasingly important as etiologic agents in patients with bacterial meningitis [26,27]. These agents may be isolated from the CSF of patients after head trauma or neurosurgical procedures and may also be found in neonates, the elderly, immunosuppressed patients, and patients with gram-negative septicemia. Some cases have been associated with disseminated strongyloidiasis in the hyperinfection syndrome, a condition in which meningitis caused by enteric bacteria results from seeding of the meninges during persistent or recurrent bacteremias associated with the migration of infective larvae. Alternatively, the larvae may carry enteric organisms on their surfaces or within their own gastrointestinal tracts as they exit the intestine and subsequently invade the meninges.
Staphylococci
Meningitis caused by Staphylococcus aureus is usually found in early postneurosurgical or post-trauma patients and in those with CSF shunts; other underlying conditions include diabetes mellitus, alcoholism, chronic renal failure requiring hemodialysis, injection drug use, and malignancies [28,29]. Thirty-five percent of cases are observed in the setting of head trauma or after neurosurgery, and an additional 20% of patients have underlying infective endocarditis or paraspinal infection. Other sources of community-acquired S. aureus meningitis include patients with sinusitis, osteomyelitis, and pneumonia. Mortality rates have ranged from 14 to 77% in various series. Coagulase-negative staphylococci [e.g., Staphylococcus epidermidis] are the most common causes of meningitis in patients with CSF shunts.
Viral Meningitis
Viruses are the major cause of the acute aseptic meningitis syndrome, a term used to define any meningitis [infectious or noninfectious], particularly one with a lymphocytic pleocytosis, for which a cause is not apparent after initial evaluation and routine stains and cultures of CSF [30]. Common viral etiologic agents that cause the acute aseptic meningitis syndrome are discussed in the following sections.
Enteroviruses
Enteroviruses are currently the leading recognizable cause of aseptic meningitis syndrome, accounting for 85 to 95% of all cases in which a pathogen is identified [30]. Estimates from the Centers for Disease Control and Prevention [CDC] indicate that 30,000 to 75,000 cases of enteroviral meningitis occur annually in the United States. However, these figures are most likely an underestimation of the true incidence because of underreporting of enteroviral cases from state laboratories to the CDC. Enteroviruses are worldwide in distribution. In temperate climates they appear with a marked summer/fall seasonality, although in tropical and subtropical areas a high year-round incidence is observed. Periods of warm weather and wearing sparse clothing may facilitate the fecal-oral spread of these organisms. In the United States, the 14 most commonly occurring enteroviral serotypes account for more than 80% of isolates [31]. In addition, the newly numbered enteroviruses 70 and 71 have been reported to commonly cause central nervous system [CNS] disease [32,33,34]. Infants and young children are the primary victims of enteroviral meningitis because they are the most susceptible host population [i.e., absence of previous exposure and immunity] within the community. More than one episode of enteroviral meningitis may develop, although the same enteroviral serotype has not been implicated more than once in any immunocompetent patient. Enteroviruses are also the most common causes of aseptic meningitis in adults [35]. Immunodeficiency [specifically congenital or acquired impaired humoral immunity] may predispose to enteroviral meningitis. Cases of enteroviral meningoencephalitis have also been seen in patients treated with the chimeric anti-CD20 monoclonal antibody rituximab [36].
Arboviruses
The most common arthropod-transmitted cause of aseptic meningitis in the United States, until 2002, was St. Louis encephalitis virus, a flavivirus. Aseptic meningitis accounts for about 15% of all symptomatic cases of St. Louis encephalitis and may be as high as 35 to 60% in children, although in patients older than 60 years, encephalitis is the more common finding. These infections are more frequent in warmer months when contact with the insect vector is more likely; vector exposure is more likely to occur indoors than outside because poorly sealed residences appear to be a risk factor. Other arboviruses reported to cause aseptic meningitis include the California encephalitis group of viruses [e.g., La Crosse, Jamestown Canyon, and snowshoe hare viruses, which are bunyaviruses] and the agent of Colorado tick fever, a coltivirus seen in the mountainous and western regions of the United States and Canada. West Nile virus may also cause aseptic meningitis or asymmetric flaccid paralysis, indistinguishable from poliomyelitis, although encephalitis is the most common manifestation [37].
Mumps Virus
In an unimmunized population, mumps is one of the most common causes of aseptic meningitis and encephalitis; symptomatic meningitis is estimated to occur in 10 to 30% of mumps patients overall, and is usually a benign and self-limited process [38]. CNS disease caused by mumps virus can occur in patients without evidence of parotitis; 40 to 50% of patients with mumps meningitis have no evidence of salivary gland enlargement. Meningitis is the most common neurologic manifestation of infection with mumps virus. Males are affected two to five times more often than females, and the peak incidence is in children aged 5 to 9 years. Cases of vaccine-associated mumps meningitis have also been reported.
Herpesviruses
Herpesviruses include herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesviruses 6, 7, and 8. Although neurologic complications are known to occur with these viruses, complications associated with herpes simplex viruses are of the most significance. Overall, herpes simplex viruses account for approximately 0.5 to 3% of all cases of aseptic meningitis [39]. In patients beyond the neonatal period, it is critical to differentiate between herpes simplex encephalitis, a potentially fatal form of encephalitis, and herpes simplex meningitis, a self-limited syndrome. The syndrome of herpes simplex virus aseptic meningitis is most commonly associated with primary genital infection with herpes simplex virus type 2, developing in 36% of women and 13% of men concomitant with primary infection in one study [40]. Meningitis is less likely with recurrences of genital herpes [41]. Primary genital infection with herpes simplex virus type 1 and nonprimary genital infection with herpes simplex virus of either type rarely result in meningitis. Acute aseptic meningitis has also been associated with herpes zoster in patients with or without typical skin lesions [42], the latter known as zoster sine herpete. Cases of Mollaret's recurrent meningitis have been associated with herpes simplex virus type 1, herpes simplex virus type 2 [43,44,45] and Epstein-Barr virus [46]. Human herpesvirus 6 has also been associated with meningitis in conjunction with roseola infantum; however, this virus can exhibit persistence in the CNS and has been demonstrated in the CSF of asymptomatic persons [47]. Cytomegalovirus and Epstein-Barr virus may cause aseptic meningitis in association with a mononucleosis syndrome, particularly in immunocompromised patients.
Human Immunodeficiency Virus
Human immunodeficiency virus [HIV] can cross the meninges early and persist in the CNS after initial infection [48,49]. Meningitis associated with HIV may occur as part of the primary infection or occur in an already infected patient; HIV has been isolated from the CSF in some of these cases. However, acute meningitis does not occur in every individual who becomes infected and can be silent. Retrospective studies have noted that an acute meningoencephalitis is observed in 5 to 10% of HIV-infected patients during or after the mononucleosis-like syndrome that heralds the initial infection.
Tuberculous Meningitis
Virtually all tuberculous infections of the CNS are caused by the human tubercle bacillus, Mycobacterium tuberculosis. Much of the data on the incidence of CNS tuberculosis was obtained in the first half of the 20th century, when approximately 5-15% of individuals exposed to tuberculosis developed symptomatic disease; of this number, 5-10% of patients ultimately had CNS involvement [50]. Tuberculous meningitis accounts for approximately 15% of extrapulmonary cases or about 0.7% of all clinical tuberculosis in the United States. Factors such as advanced age, immunosuppressive drug therapy, transplantation, lymphoma, gastrectomy, pregnancy, diabetes mellitus, and alcoholism are known to compromise the immune response in patients with smoldering chronic organ tuberculosis, leading to reactivation of latent foci and progression to the clinical syndrome of late generalized tuberculosis [51,52]. The advent of HIV infection has also influenced the epidemiology of tuberculosis in the United States [53]. Although the majority of tuberculosis cases in HIV-infected patients are pulmonary, extrapulmonary tuberculosis [including CNS disease] occurs in more than 70% of patients with the acquired immunodeficiency syndrome [AIDS] or AIDS discovered soon after the diagnosis of tuberculosis, but in only 24-45% of patients with tuberculosis and less advanced HIV infection [54]; this suggests that extrapulmonary tuberculosis appears to be more common in patients with more severe HIV-induced immunosuppression.
CLINICAL MANIFESTATIONS
Bacterial Meningitis
Patients with bacterial meningitis classically present with fever, headache, meningismus, and signs of cerebral dysfunction [i.e., confusion, delirium, or a declining level of consciousness ranging from lethargy to coma] [9,55]. In a review of 493 cases of acute bacterial meningitis in adults [5], however, the triad of fever, nuchal rigidity, and change in mental status was found only in two thirds of patients, although all patients had at least one of these findings. The meningismus may be subtle, marked, or acccompanied by Kernig's, Brudzinski's, or both signs [56]. However, in a recent prospective study that examined the diagnostic accuracy of meningeal signs in adults with suspected meningitis, the sensitivity of these findings were only 5% for Kernig’s sign, 5% for Brudzinski’s sign, and 30% for nuchal rigidity [57], indicating that they did not accurately distinguish patients with meningitis from those without meningitis, and the absence of these findings did not rule out the diagnosis of bacterial meningitis. Cranial nerve palsies [especially those involving cranial nerves III, IV, VI, and VII] and focal cerebral signs are seen in 10 to 20% of cases. Seizures occur in about 30% of patients. Focal neurologic deficits and seizures arise from cortical and subcortical ischemia, which results from inflammation and thrombosis of blood vessels, often within the subarachnoid space. Papilledema is seen in less than 5% of cases early in infection, and its presence at the time of clinical presentation should suggest an alternative diagnosis. With disease progression, signs of increased intracranial pressure may develop, including coma, hypertension, bradycardia, and palsy of cranial nerve III.
To further characterize the accuracy and precision of the clinical examination in adult patients with acute meningitis, patient data on 845 episodes of acute meningitis [confirmed by lumbar puncture or autopsy] in patients aged 16-95 years were reviewed [58]; the majority of patients in this review had acute bacterial meningitis, although 62 had tuberculous or “aseptic” meningitis. The results demonstrated that individual items of the clinical history [i.e., headache, nausea, and vomiting] had a low accuracy for the diagnosis of acute meningitis in adults. However, on review of the accuracy of physical examination findings, the absence of fever, neck stiffness, and altered mental status effectively eliminated the likelihood of acute meningitis; the sensitivity was 99-100% for the presence of one of these findings in the diagnosis of acute meningitis. Despite these findings, physicians should have a low threshold for performance of lumbar puncture in patients at high risk for bacterial meningitis, given the serious nature of this disease.
A specific etiologic diagnosis in patients with bacterial meningitis may be suggested by certain symptoms or signs [55]. About 50% of patients with meningococcemia, with or without meningitis, present with a prominent rash located principally on the extremities. Early in the course of illness, the rash is typically erythematous and macular, but it quickly evolves into a petechial phase with further coalescence into a purpuric form. The rash often matures rapidly, with new petechial lesions appearing during the physical examination. In one review of the clinical features of 255 patients with acute meningococcal meningitis [59], a petechial rash was observed in three quarters of the patients, and was more commonly seen in children and adults younger than 30 years [81%] than in patients 30 years of age and older [62%]. In patients who have suffered a basilar skull fracture in which a dural fistula is produced between the subarachnoid space and nasal cavity, paranasal sinuses, or middle ear, rhinorrhea or otorrhea may be present secondary to a CSF leak [29]; in these patients, meningitis may be recurrent and is most commonly caused by S. pneumoniae. Patients with L. monocytogenes meningitis have an increased tendency to have seizures and focal deficits early in the course of infection, and some patients may present with ataxia, cranial nerve palsies, or nystagmus secondary to rhombencephalitis [18,19]. In a large review of 367 episodes of CNS infections caused by L. monocytogenes [19], the most frequent findings were fever [92%] and altered sensorium [65%], with headache reported in only about 50% of patients.
Some categories of patients may not manifest many of the classic symptoms and signs of bacterial meningitis [55]. For example, neonates with bacterial meningitis usually do not have meningismus [60]; in this patient population, clinical clues to the presence of meningitis are temperature instability [hypothermia or hyperthermia], listlessness, high-pitched crying, fretfulness, lethargy, refusal to feed, weak suck, irritability, jaundice, vomiting, diarrhea, or respiratory distress. A change in the child's affect or state of alertness is one of the most important signs of meningitis; seizures are observed in 40% of cases. A bulging fontanelle [seen in one third of cases] usually occurs late during the course of illness. In children 1 to 4 years of age, fever [94%], vomiting [82%], and nuchal rigidity [77%] are the most common initial symptoms [61]. Elderly patients, especially those with underlying conditions [e.g., diabetes mellitus or cardiopulmonary disease], may present insidiously with lethargy or obtundation, no fever, and variable signs of meningeal inflammation [62]. In one review [63], confusion was very common in elderly patients on initial examination and occurred in 92% and 78% of those withpneumococcal and gram-negative bacillary meningitis, respectively. The diagnosis of bacterial meningitis in neutropenic patients requires a high index of suspicion because symptoms and signs may initially be subtle because of the impaired ability of the patient to mount a subarachnoid space inflammatory response [64]. In patients with head trauma, the symptoms and signs of meningitis may be present as a result of the underlying injury and not meningitis. In all of these subgroups of patients, altered or changed mental status should not be ascribed to other causes until bacterial meningitis has been excluded by CSF examination.
Viral Meningitis
Enteroviruses
The clinical manifestations of enteroviral meningitis depend on host age and immune status [31,65]. In neonates [2 weeks of age or younger] with proven enteroviral meningitis, fever is a ubiquitous finding and is usually accompanied by any combination of vomiting, anorexia, rash, and upper respiratory symptoms and signs. Neurologic involvement may be associated with nuchal rigidity and a bulging anterior fontanelle, although infants younger than 1 year are less likely to demonstrate meningeal signs. Mental status may be altered, but focal neurologic signs are uncommon. With disease progression, a sepsis-like syndrome characterized by multiorgan involvement, disseminated intravascular coagulation, and cardiovascular collapse may develop. Lack of humoral antibody may contribute to the severity of neonatal infection.
In patients with enteroviral meningitis beyond the neonatal period [older than 2 weeks of age], severe disease and poor outcome are rare. In this patient population the onset of illness is usually sudden, with fever present in 76 to 100% of patients; the fever may be biphasic, initially appearing with nonspecific constitutional symptoms, disappearing, and then reappearing with the onset of meningeal signs; more than half of patients have nuchal rigidity. In adults with enteroviral meningitis, headache [often severe and frontal in location] is nearly always present and photophobia is common. Nonspecific symptoms and signs include vomiting, anorexia, rash, diarrhea, cough, upper respiratory findings [especially pharyngitis], and myalgias. Other clues to the presence of enteroviral disease, in addition to the time of year and known epidemic disease in the community, include the presence of exanthems, myopericarditis, conjunctivitis, and specifically recognizable enteroviral syndromes such as pleurodynia, herpangina, and hand-foot-and-mouth disease [30]. Specific clinical stigmata may also be associated with certain enteroviral serotypes [65] – echovirus 9 is associated with scattered maculopapular rashes, herpangina [in particular the finding of painful vesicles on the posterior oropharynx] is associated with coxsackievirus A, and the presence of pericarditis or pleurisy may identify coxsackievirus B.
The duration of illness in enteroviral meningitis is usually less than 1 week, with many patients reporting improvement after lumbar puncture, presumably as a result of a reduction in intracranial pressure. In contrast, during an outbreak of enterovirus 71 infection in Taiwan in patients 3 months to 8.2 years of age, the chief neurologic complaint was rhombencephalitis [seen in 90% of children], which carried a case fatality rate of 14% [33]. In another outbreak in young children of enterovirus 71 infection in Perth, Western Australia [34], neurologic syndromes included aseptic meningitis, Guillain-Barre syndrome, acute transverse myelitis, acute cerebellar ataxia, opso-myoclonus syndrome, benign intracranial hypertension, and febrile convulsions.
In persons who are agammaglobulinemic, a chronic enteroviral meningitis or meningoencephalitis may develop and last several years, often with a fatal outcome [31,65]. This syndrome has been designated chronic enteroviral meningoencephalitis in agammaglobulinemia [CEMA], a constellation of neurologic symptoms that includes headache, seizures, hearing loss, lethargy/coma, weakness, ataxia, parethesias, and loss of cognitive skills.
Mumps Virus
In patients with mumps, CNS symptoms usually follow the onset of parotitis, when present, by about 5 days; salivary gland enlargement is present in only about 50% of patients. The most frequent clinical manifestation of mumps CNS infection is the triad of fever, vomiting, and headache [38]. The fever is usually high and lasts for 72 to 96 hours. Other findings include neck stiffness, lethargy or somnolence, and abdominal pain. Most patients have signs of meningitis, but no evidence of cortical dysfunction. Defervescence is usually accompanied by clinical recovery, with the total duration of illness is usually 7 to 10 days in uncomplicated cases. Mumps may rarely cause encephalitis, seizures, polyradiculitis, polyneuritis, cranial nerve palsies, myelitis, Guillain-Barré syndrome, and fatality.
Herpesviruses
Meningitis associated with herpes simplex virus type 2 is usually characterized by stiff neck, headache, and fever [40]. In one review of 27 patients with herpes simplex virus type 2 meningitis 419], neurologic complications were found in 37% of cases and consisted of urinary retention, dysesthesias, paresthesias, neuralgia, motor weakness, paraparesis, concentration difficulties of about 3 months' duration, and impaired hearing. All complications, however, subsided within 6 months in all patients, although recurrent meningitis was documented in five patients. A diffuse vesiculopustular rash may be seen in meningitis caused by varicella-zoster virus. The presence of pharyngitis, lymphadenopathy, and splenomegaly should suggest Epstein-Barr virus infection.
Human Immunodeficiency Virus
HIV-infected patients may present with a typical aseptic meningitis syndrome associated with acute infection [48,49]. Other patients may present with an atypical aseptic meningitis that is often chronic, tends to recur, and often includes cranial neuropathies [usually cranial nerves V, VII, and VIII] or long-tract findings. The most common features are headache, fever, and meningeal signs. The illness is self-limited or recurrent rather than progressive.
Tuberculous Meningitis
The clinical picture of tuberculous meningitis is quite variable [50]. Children commonly develop nausea, vomiting, and behavioral changes, with headache is seen in fewer than 25% of cases. Seizures are infrequent [seen in 10-20% of children prior to hospitalization], although more than 50% of patients may develop seizures during hospitalization. In adults, the clinical presentation of tuberculous meningitis tends to be more indolent [50,66,67], with an insidious prodrome characterized by malaise, lassitude, low-grade fever, intermittent headache, and changing personality ensues. Within 2-3 weeks, there is development of a meningitic phase manifested as protracted headache, meningismus, vomiting, and confusion. In some adults, the initial prodromal stage may take the form of a slowly progressive dementia over several months or years characterized by personality changes, social withdrawal, and memory deficits. In contrast, patients may also present with a rapidly progressive meningitis syndrome indistinguishable from pyogenic bacterial meningitis [51]. A history of prior clinical tuberculosis is infrequent [