Viral meningitis in children: Clinical features and diagnosis

INTRODUCTION — The etiology, clinical manifestations, diagnosis, and differential diagnosis of viral meningitis in children will be reviewed here. The epidemiology, pathogenesis, management, prognosis, and prevention are discussed separately. (See "Viral meningitis in children: Epidemiology, pathogenesis, and etiology" and "Viral meningitis in children: Management, prognosis, and prevention".)

TERMINOLOGY

●Meningitis – Meningitis is inflammation of the meninges, manifest by cerebrospinal fluid (CSF) pleocytosis (ie, an increased number of white blood cells) [1].

Aseptic meningitis is the clinical syndrome of meningeal inflammation with negative cultures for routine bacterial pathogens in a patient who did not receive antibiotics before lumbar puncture [1-4]. Aseptic meningitis has a number of infectious and noninfectious causes (table 1). Viruses (usually enteroviruses [EVs]) are the most common cause (table 2). Because viruses are the most common cause of aseptic meningitis, the terms aseptic meningitis and viral meningitis are sometimes used synonymously.

●Encephalitis – Encephalitis is inflammation of the brain parenchyma that produces neurologic dysfunction (eg, altered mental status, behavior, or personality; motor or sensory deficits; speech or movement disorders; hemiparesis; and paresthesias) [5]. Encephalitis may occur during or after a viral infection. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis".)

●Myelitis – Myelitis is inflammation of the spinal cord, manifest by weakness, bladder dysfunction, flaccid paralysis, and reduced or absent reflexes. (See "Disorders affecting the spinal cord", section on 'Acute viral myelitis'.)

Abnormal brain function distinguishes encephalitis from meningitis. The distinction between these entities is frequently blurred; however, it is important to try to distinguish between them because the likely causes differ somewhat (table 2).

The discussion that follows will focus on viruses that most often cause meningitis. Viral etiologies of encephalitis are reviewed separately. (See "Acute viral encephalitis in children: Pathogenesis, epidemiology, and etiology", section on 'Etiology'.)

CLINICAL FEATURES — Clinical features of viral meningitis in children vary with age, immune status, and etiologic agent [1,6].

Common features — The manifestations of viral meningitis are generally similar to those of bacterial meningitis but often are less severe [7]. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Clinical features' and "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Presentation'.)

●Infants – Infants may have an abrupt onset of fever accompanied by nonspecific symptoms (eg, irritability, poor feeding, vomiting, diarrhea, rash, respiratory symptoms). Physical findings may include bulging fontanelle and nuchal rigidity. Seizures in the absence of fever and/or cerebrospinal fluid (CSF) pleocytosis are common manifestations of human parechovirus infections in neonates [8]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates'.)

Neurologic manifestations in neonates range from no symptoms to irritability and lethargy to frank nuchal rigidity or bulging fontanelle [1,6,9]. Depending on the etiology, central nervous system (CNS) infection may progress to encephalitis, which may manifest with seizures and/or focal neurologic findings [10]. Neonates with viral meningoencephalitis, particularly when caused by herpes simplex virus (HSV) infection, are at increased risk for severe systemic disease. Systemic manifestations may include pneumonia, hepatitis with necrosis, myocarditis, necrotizing enterocolitis, and a sepsis-like picture [10]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Disseminated disease'.)

●Children and adolescents – Older children typically present with fever, headache, nausea, vomiting, stiff neck, and photophobia [11,12]. Physical findings include nuchal rigidity and manifestations of viral illness (eg, rash, conjunctivitis, herpangina, pharyngitis).

Features associated with specific viruses

Enteroviruses — Enteroviruses (EVs) include poliovirus, coxsackievirus, echovirus, and the numbered EVs. Meningitis due to EV is associated with the acute onset of fever that ranges from 38 to 40ºC in more than 50 percent of cases and is sometimes biphasic [1,9,11-13]. Fever is generally accompanied by nonspecific constitutional symptoms, such as anorexia, nausea, vomiting, exanthem, myalgias, and upper and lower respiratory symptoms [12-14].

Older children typically complain of fever, headaches (usually retro-orbital or frontal), and photophobia. More than one-half of adults and children older than one to two years present with nuchal rigidity [1,12,13,15]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

Clinical features suggestive of EV include conjunctivitis, pharyngitis, rash, herpangina, and hand-foot-mouth disease (picture 1A-C). EV-A71, which usually causes hand-foot-mouth disease, also may cause a rhombencephalitis that is associated with cranial nerve palsies, flaccid paralysis, and noncardiac pulmonary edema [16-19]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

The potential association between EV-D68 and polio-like neurologic disease is discussed separately [20]. (See "Acute flaccid myelitis" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Acute paralysis and brainstem encephalitis'.)

Parechoviruses — Most human parechovirus infections occur in infants. The spectrum of clinical manifestations includes neonatal sepsis, meningitis, encephalitis, and paralysis [21-28]. In a retrospective review of 58 cases in which human parechovirus was isolated from the CSF, the mean age was 6.6 weeks and the most common symptoms were irritability, fever, and nonspecific rash (picture 2) [23,29]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates'.)

Herpesviruses

●HSV – HSV infections of the CNS in neonates manifest primarily as encephalitis with or without multiorgan involvement; however, meningitis in this age group also can present with fever as the only manifestation [30]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Central nervous system disease'.)

Older children, teenagers, and adults with primary HSV infection who develop encephalitis generally present with fever, altered mental status, focal neurologic deficits, and seizures. Those with meningitis generally present with fever and classic symptoms of meningitis (eg, fever, stiff neck, headache, photophobia). HSV and other herpesvirus meningitis may be complicated by sacral radiculopathy (manifest by urinary retention, constipation, paresthesia, and motor weakness) [31]. (See "Herpes simplex virus type 1 encephalitis" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)

●Epstein-Barr virus – Epstein-Barr virus can affect virtually any organ system, though it is an uncommon cause of CNS infection in immunocompetent children [32]. Meningoencephalitis, acute encephalitis, acute cerebellitis, and transverse myelitis have been reported [33,34]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)

●Cytomegalovirus (CMV) – In preterm infants, early postnatal CMV infection can have severe multisystem involvement, which may include meningoencephalitis. In term infants and immunocompetent children, CMV infection is rarely severe. However, immunocompromised children are at risk for acquiring serious CMV disease, including CNS infection. (See "Overview of cytomegalovirus infections in children".)

●Human herpesvirus 6 – Meningoencephalitis of variable severity can rarely occur as a complication of roseola or as the primary manifestation of human herpesvirus 6 infection in immunocompetent hosts. (See "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment", section on 'Less common manifestations'.)

Arboviruses — Arboviruses are spread by arthropod or insect vectors (eg, mosquitoes, ticks, sand flies) [14]. In temperate climates, arboviral infections have a seasonal pattern, with most infections occurring in the summer and fall.

The clinical manifestations of meningitis caused by arboviruses are similar to those of other viral pathogens. Most cases are characterized by the acute onset of fever, chills, headaches, nausea, vomiting, and nuchal rigidity in the absence of focal neurologic findings.

●The manifestations of St. Louis encephalitis virus range from a mild "flu-like" illness to fatal encephalitis. (See "St. Louis encephalitis".)

●The manifestations of La Crosse (California) encephalitis, which primarily occurs in children, include fever, focal neurologic signs, and focal seizures that mimic HSV encephalitis [35]. (See "Arthropod-borne encephalitides", section on 'La Crosse encephalitis virus'.)

●West Nile virus is characterized by fever, headache, malaise, back pain, myalgias, and anorexia. A maculopapular rash appears in approximately one-half of patients (picture 3). Some manifestations seen in adults (eg, weakness, peripheral neuropathy, diffuse paralysis) are rare in children. (See "Clinical manifestations and diagnosis of West Nile virus infection".)

●Eastern equine encephalitis virus is characterized by sudden onset of headache, high fever, chills, and vomiting. The illness may then progress into disorientation, seizures, or coma. Eastern equine encephalitis is one of the most severe mosquito-transmitted diseases in the United States. (See "Arthropod-borne encephalitides", section on 'Eastern equine encephalitis virus'.)

●Western equine encephalitis virus infection is characterized by headache, vomiting, stiff neck, and backache; restlessness, irritability, and seizures are common in children. Neurologic sequelae are relatively common in infants. (See "Arthropod-borne encephalitides", section on 'Western equine encephalitis virus' and "Viral meningitis in children: Management, prognosis, and prevention", section on 'Prognosis'.)

●Powassan virus infection is characterized by a short prodrome of fever, malaise, headache, and sore throat, followed by progressive neurologic deterioration [36]. (See "Arthropod-borne encephalitides", section on 'Powassan virus'.)

Other viruses

●HIV – Human immunodeficiency virus (HIV) can cause meningitis in the early stage of infection. It is characterized by typical manifestations of viral meningitis (ie, headache, meningismus, photophobia, and a lymphocytic pleocytosis on CSF analysis). (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Neurologic findings'.)

●Influenza – Influenza A and B infections of the CNS are preceded by the classic symptoms of typical influenza infection: fever, coryza, cough, vomiting, headaches, and diarrhea. Neurologic manifestations develop within one to four days after the onset of symptoms [9]. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Central nervous system'.)

●Lymphocytic choriomeningitis virus (LCMV) – LCMV is a human zoonosis that is transmitted through exposure to urine and feces of rodents, including mice, rats, and hamsters. Most LCMV infections are asymptomatic or associated with mild constitutional symptoms [1,37]. Symptomatic infection manifests as a biphasic illness with an initial phase characterized by fever, malaise, photophobia, headache, nausea, vomiting, sore throat, and adenopathy. Signs and symptoms of CNS disease develop in the second phase, which follows resolution of fever.

Congenital infection is characterized by chorioretinitis (affecting more than 90 percent of infants in reported cases); micro- or macrocephaly; and neurologic sequelae including seizures, intellectual disability, and cerebral palsy [38].

Meningitis develops in approximately 15 percent of confirmed cases of LCMV [1]. Encephalitis and meningoencephalitis are rare complications of LCMV [1]. Other complications include transverse myelitis, Guillain-Barré syndrome, myocarditis, pneumonitis, and parotitis.

●Mumps – Mumps infection is frequently accompanied by a nonspecific prodrome consisting of low-grade fever, malaise, headache, myalgias, and anorexia. These symptoms are generally followed within 48 hours by the development of painful parotitis, the hallmark of mumps infection.

Meningitis occurs in approximately 1 to 10 percent of mumps infections [39]. CNS infection usually manifests approximately five days after parotitis, but it may occur as much as two weeks later or one week earlier [40,41]. Mumps meningitis generally has a benign course with full neurologic recovery. (See "Mumps".)

●Rabies – Rabies infection, which is more commonly associated with encephalomyelitis, is heralded by a prodrome of 2 to 10 days of nonspecific symptoms, such as fever, headache, malaise, myalgias, cough, sore throat, nausea, and vomiting [9]. Anxiety, hallucinations, nightmares, and insomnia may occur during this early stage [42]. Rapid and progressive neurologic deterioration occurs in one to two weeks, leading to coma and death, usually by the third week of illness [9]. (See "Clinical manifestations and diagnosis of rabies".)

●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – There are scattered published case reports describing a wide range of neurologic manifestations of SARS-CoV-2 infection, including meningitis and encephalitis [43-45]. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neurologic manifestations'.)

●Zika virus – While meningitis is an uncommon manifestation of Zika infection in children and adults [46], congenital infection is associated with severe neurologic sequelae. (See "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate".)

EVALUATION

Overview — As a general principle, children suspected of having meningitis should be initially presumed to have bacterial meningitis and should be managed accordingly until bacterial meningitis has been excluded (or at least deemed very unlikely) or a specific viral diagnosis has been made. Management includes rapid evaluation and stabilization of cardiorespiratory and hemodynamic status, obtaining initial laboratory studies, and administering empiric antibiotics in a timely manner (table 3). This is discussed separately. (See "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Empiric therapy'.)

Viral meningitis may be suspected on the basis of epidemiologic data, clinical features, and initial cerebrospinal fluid (CSF) studies (table 4), but clinical features can overlap with bacterial meningitis (table 5) and it can be difficult to exclude bacterial meningitis with certainty based on initial testing [14,47]. Clinical prediction tools can be used in children with CSF pleocytosis to help distinguish bacterial meningitis from viral meningitis while awaiting more definitive test results (algorithm 1). (See 'Clinical prediction rules' below and "Viral meningitis in children: Management, prognosis, and prevention", section on 'Assessing risk of bacterial meningitis'.)

Ultimately, a confirmed diagnosis of viral meningitis requires negative bacterial cultures and positive identification of a viral pathogen from CSF. Detection of virus in other samples (eg, blood, urine, throat swab, or stool or rectal swab) also supports the diagnosis. However, because enteroviruses and parechoviruses are shed from the throat and gastrointestinal tract, the finding of these viruses in these sites in less supportive than in blood or urine.

Nonviral etiologies should be considered in children with negative CSF cultures for routine bacterial pathogens and negative polymerase chain reaction (PCR) studies for enterovirus (EV) and herpes simplex virus (HSV), particularly in patients with an atypical presentation, immunodeficiency, or specific exposures (eg, tuberculosis, ticks, rodents) (table 1). (See 'Differential diagnosis' below.)

History — Information from the history helps prioritize among the possible causes of meningitis and aseptic meningitis (table 1). Important aspects of the history in a child with suspected viral meningitis include [4,14,48]:

●Presence of classic symptoms (fever, stiff neck, headache, photophobia) but without the presence of severe systemic disease (except for the neonate).

●Symptoms of encephalitis (eg, altered mental status, behavior, or personality; motor or sensory deficits; speech or movement disorders; hemiparesis; and paresthesias).

●Symptoms associated with specific viruses (eg, rash, sore throat, vomiting, diarrhea, genitourinary symptoms) (table 2).

●Preceding illness (pneumonia or respiratory illness may indicate Mycoplasma pneumoniae).

●Exposure in preceding two to three weeks to: ill contacts; ticks, mosquitoes, or other animals, including pet rodents; water potentially contaminated with rodent droppings or urine; uncooked meat; swimming in hot springs (associated with primary amebic meningoencephalitis).

●Prenatal and perinatal history in the neonate and young infant (<3 months), particularly related to congenital infection. (See "Overview of TORCH infections", section on 'Clinical features of TORCH infections'.)

●Previous episodes (consider HSV-2, epidermoid cyst).

●Sexual history and risk factors for HIV or HSV infection.

●Immunization history.

●Recent injections and/or medications, including antibiotics, nonsteroidal antiinflammatory drugs, immunoglobulin.

●Outbreaks of human or animal disease in the community, particularly by season (eg, EVs, parechovirus, influenza, West Nile virus, measles, rabies, St. Louis encephalitis, etc).

Examination — The examination of the patient with suspected viral meningitis centers on assessment of meningeal inflammation, brain function (to exclude encephalitis), and clues to specific viral etiologies. Important aspects of the examination include [4,14]:

●Signs of meningeal inflammation (nuchal rigidity, Kernig and Brudzinski signs) (movie 1A-B).

●Assessment of mental status (Glasgow coma scale (table 6)) and presence of focal neurologic signs (suggestive of encephalitis).

●Findings associated with EV infection (eg, conjunctivitis, pharyngitis, rash, herpangina, hand-foot-mouth disease (picture 1A-C)). (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

●Findings associated with other potential causes of viral meningitis (eg, generalized lymphadenopathy, suggestive of Epstein-Barr or HIV infection; oral or genital ulcers, suggestive of HSV infection; rash, suggestive of varicella (picture 4); parotid swelling, suggestive of mumps (picture 5) or lymphocytic choriomeningitis virus [LCMV]; palmar-plantar erythema suggestive of human parechovirus type 3 infection (picture 2) [29]).

●Weakness or paralysis, which may occur with poliovirus, EV-D68, EV-A71 and, occasionally, other EVs.

Laboratory evaluation — The initial laboratory evaluation of a child with suspected meningitis includes blood tests and lumbar puncture. Further testing may be necessary to exclude nonviral causes, particularly in patients with an atypical presentation, immunodeficiency, or specific exposures (eg, tuberculosis, ticks, rodents). (See 'Detection of virus' below and 'Differential diagnosis' below.)

For febrile infants younger than three months, additional evaluation may be warranted as part of the fever evaluation. This is discussed separately. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

Blood tests — Initial blood tests for a child with suspected meningitis should include [7,14]:

●Blood cultures

●Complete blood count with differential and platelet count

●Inflammatory markers (eg, C-reactive protein, procalcitonin), which can help distinguish viral from bacterial meningitis

●Coagulation studies (prothrombin time, activated partial thromboplastin time), particularly in patients with petechiae or purpuric lesions

●Serum electrolytes, blood urea nitrogen, creatinine, and glucose

When used in isolation, the sensitivity and specificity of C-reactive protein and procalcitonin levels are insufficient to accurately discriminate between viral and bacterial meningitis. However, these tests can be helpful when used in conjunction with other variables (eg, as part of a clinical prediction rule, as discussed below). (See "Viral meningitis in children: Management, prognosis, and prevention", section on 'Assessing risk of bacterial meningitis'.)

Additional studies may be indicated if there are clinical clues suggestive of particular infections. These may include HSV whole-blood PCR and serum alanine aminotransferase (ALT) for infants <6 weeks of age with suspected disseminated HSV infection and serologic testing for measles, mumps, arboviruses, varicella, Epstein-Barr virus, LCMV, HIV, syphilis, and Lyme disease [49].

Cerebrospinal fluid studies — Examination of the CSF is necessary to establish a diagnosis of meningitis and to make a provisional diagnosis of bacterial, viral, or unclear etiology. Lumbar puncture also may provide symptom relief in patients with viral meningitis [50].

CSF should be sent for:

●Gram stain and bacterial culture

●Cell count and differential

●Glucose and protein

●Viral PCR studies, as discussed below (see 'Detection of virus' below)

Interpretation of CSF parameters is discussed below. (See 'Cerebrospinal fluid interpretation' below.)

Additional testing for unusual pathogens may be warranted in special circumstances (eg, in immunocompromised hosts) [4]. It is helpful to reserve a tube of CSF for further testing, which may be necessary if the patient fails to improve as expected.

Detection of virus — In most patients with suspected viral meningitis, samples of CSF should be sent for EV reverse-transcription polymerase chain reaction (RT-PCR), which can be accomplished with a targeted specific EV RT-PCR test or as part of a multiplex PCR panel that simultaneously tests for EV and other viral, bacterial, and fungal pathogens. In the appropriate settings, PCR for HSV and West Nile virus may also be warranted. Multiplex PCR testing is less sensitive for HSV-1 and HSV-2 than standard HSV PCR assays, and, therefore, it may be necessary to test specifically for HSV when clinical suspicion for HSV infection is high [51]. If HSV infection is suspected in an infant <6 weeks old, other specimens in addition to CSF should be tested (eg, surface cultures and blood or plasma HSV PCR) [49]. The evaluation of suspected neonatal HSV infection is discussed separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV'.)

The decision to perform additional testing for other viral pathogens depends upon the clinical scenario and suspected viral pathogen.

PCR has largely replaced viral culture and serologic testing for the diagnosis of viral meningitis [52-56]. PCR is highly sensitive and specific, and results are available sooner than viral culture.

Multiplex or panel-based PCR tests are available that test for multiple viral and bacterial pathogens simultaneously in a single CSF sample (eg, FilmArray meningitis/encephalitis panel [BioFire]) [51,57,58]. These tests are highly sensitive and specific, though false-positive and false-negative results can occur. (See "Molecular diagnosis of central nervous system infections", section on 'Viruses'.)

Stool (or rectal swab) and throat swabs can be sent for viral culture to maximize detection since EV RT-PCR is not always positive. Serologies may be obtained for the less common etiologies of viral meningitis; for some pathogens (eg, West Nile virus), specific antibody determinations for immunoglobulins G and M (IgG and IgM) also may be performed on CSF. In addition, samples of blood and urine should be sent for viral studies when viral meningitis is suspected in immunocompromised children.

Details of diagnostic testing for specific causes of viral meningitis are provided separately:

●EVs. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Laboratory diagnosis'.)

●HSV infection. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

●Arboviruses – Arboviruses are usually diagnosed serologically. (See "Arthropod-borne encephalitides" and "St. Louis encephalitis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of West Nile virus infection", section on 'Approach to diagnosis'.)

●LCMV infection – Diagnosis of LCMV infection can be achieved by isolation of the virus, serology testing, and RNA detection by PCR. Only serologic testing is widely available. The immunofluorescent antibody test for IgG and IgM has a better sensitivity than complement fixation or neutralizing antibody tests [37,38]. An enzyme-linked immunosorbent assay (ELISA) test for both IgG and IgM is available only at the Centers for Disease Control and Prevention. PCR testing is not commercially available.

●Rabies. (See "Clinical manifestations and diagnosis of rabies".)

●Influenza. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Diagnosis'.)

Neuroimaging — Neuroimaging is not a routine part of the evaluation for suspected viral meningitis. It is reserved for children with concerning clinical findings, such as focal neurologic deficits, depressed mental status, or other signs of increased intracranial pressure. When these findings are present, neuroimaging should be performed prior to lumbar puncture. However, these findings are rare in patients with uncomplicated viral meningitis and, if present, they should raise concern for another etiology, such as bacterial meningitis or acute encephalitis. Indications for neuroimaging are summarized in the table and are discussed separately (table 3). (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Neuroimaging' and "Acute viral encephalitis in children: Clinical manifestations and diagnosis", section on 'Neuroimaging'.)

DISTINGUISHING VIRAL FROM BACTERIAL MENINGITIS — Viral meningitis may be suspected on the basis of epidemiologic data, clinical features, and initial cerebrospinal fluid (CSF) studies (table 4), but the clinical features can overlap with bacterial meningitis (table 5) and it can be difficult to exclude bacterial meningitis with certainty based on initial testing [14,47]. Ultimately, the diagnosis of viral meningitis requires negative bacterial cultures and positive identification of a viral pathogen from CSF. While awaiting definitive test results, clinical prediction tools can be used in conjunction with clinical judgement to help identify patients with a low risk of bacterial meningitis (algorithm 1).

Cerebrospinal fluid interpretation — The initial CSF studies may help distinguish between viral and bacterial meningitis (table 4). However, CSF analysis is not always predictive of viral or bacterial infection, since there is considerable overlap in the respective findings (table 5) [14,47,59,60]. In addition, CSF findings can vary widely depending on the specific viral etiology (table 7) and there can be considerable variation during an outbreak of a single enterovirus (EV) serotype [12,13,61,62].

●Findings suggestive of viral meningitis – The CSF findings in viral meningitis typically include (table 4):

•Cell count – White blood cell count typically ranges from 10 to 500 cells/microL (higher values can be seen with some viruses). Normal CSF white blood cell counts can be seen in EV and parechovirus meningitis (particularly in young infants) and, more rarely, with herpes simplex virus (HSV) meningoencephalitis early in the course of infection [1,63-66].

•Differential – There is a predominance of mononuclear cells in most cases of viral meningitis, although a polymorphonuclear neutrophil (PMN) predominance has been described early (the first 24 to 48 hours) in the course of EV meningitis caused by the most common serotypes [47,67-69]. Neither the presence nor quantity of bands (immature neutrophils) in the CSF helps to distinguish viral from bacterial meningitis [70].

•Glucose – Normal or slightly reduced but usually ≥40 percent of the serum value. A notable exception to this is meningoencephalitis due to mumps, in which hypoglycorrhachia has been reported.

•Protein – Normal to slightly elevated but usually <150 mg/dL. The exception is West Nile virus, in which the CSF protein can be as high as 900 mg/dL.

●Findings suggestive of bacterial meningitis – The CSF findings in bacterial meningitis typically include (see "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation'):

•White blood cell count >1000 cells/microL with a predominance of neutrophils (PMN)

•Glucose <40 mg/dL (2.2 mmol/L)

•Protein between 100 and 500 mg/dL

•Positive Gram stain or positive PCR/multiplex for a bacterial pathogen

Details of the interpretation of the CSF profiles of children who have received antibiotics before lumbar puncture or had a traumatic lumbar puncture are provided separately. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation'.)

Clinical prediction rules — In patients with CSF pleocytosis, clinical prediction rules can be used in conjunction with clinical judgment to identify patients with a very low risk of bacterial meningitis. The approach is summarized in the algorithm and discussed in greater detail separately (algorithm 1). (See "Viral meningitis in children: Management, prognosis, and prevention", section on 'Assessing risk of bacterial meningitis'.)

DIAGNOSIS — The diagnosis of viral meningitis is confirmed by negative bacterial cultures and detection of a viral pathogen in the cerebrospinal fluid (CSF). Detection of virus in other samples (eg, blood, urine, throat swab, or stool or rectal swab) also supports the diagnosis. However, because enteroviruses and parechoviruses are shed from the throat and gastrointestinal tract, the finding of these viruses in these sites in less supportive than in blood or urine.

DIFFERENTIAL DIAGNOSIS

Bacterial meningitis — Bacterial meningitis is an important consideration in the differential diagnosis of viral meningitis. The clinical and laboratory features may point to a viral or bacterial etiology (table 4); however, clinical features often overlap and it can be difficult to exclude bacterial meningitis with certainty based on initial testing (table 5). The approach to differentiating viral meningitis from bacterial meningitis is discussed above. (See 'Distinguishing viral from bacterial meningitis' above.)

Lyme meningitis — Lyme disease, which may cause meningitis, occurs during the same season as enterovirus (EV) infections, the most common cause of culture-negative (aseptic) meningitis. Lyme disease usually occurs in older children and has a longer duration of symptoms than EV infection. Additional features suggestive of Lyme meningitis include erythema migrans (picture 6A-C), cranial nerve palsies (especially facial palsy), papilledema, and cerebrospinal fluid (CSF) neutrophil count <10 percent. (See "Lyme disease: Clinical manifestations in children", section on 'Meningitis'.)

Viral encephalitis — Viral encephalitis is a febrile illness in which signs and symptoms of neurologic dysfunction indicate parenchymal brain involvement. Manifestations of encephalitis include: altered mental status, behavior, or personality; motor or sensory deficits; speech or movement disorders; hemiparesis; and paresthesias. The prognosis for viral encephalitis is usually worse than that for viral meningitis. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis", section on 'Clinical features'.)

Autoimmune encephalitis — Autoimmune encephalitis syndromes have a wide clinical spectrum (table 8) and are increasingly recognized as causes of encephalitis in children. Affected patients typically present with complex neuropsychiatric symptoms, such as deficits of memory or cognition, psychosis, seizures, abnormal movements, or coma. These features help to distinguish autoimmune encephalitis from acute viral meningitis, though ultimately viral and autoantibody testing are required to make the distinction. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

Tuberculous meningitis — Features that may help distinguish tuberculous meningitis from viral meningitis include subacute presentation, epidemiologic factors (history of prior tuberculosis infection or disease, known or possible tuberculosis exposure, and/or past or present residence in or travel to an area where tuberculosis is endemic), and CSF findings (table 5). The diagnosis of tuberculosis meningitis can be confirmed with CSF acid-fast bacilli smear and culture and/or polymerase chain reaction (PCR). (See "Tuberculous meningitis: Clinical manifestations and diagnosis".)

Unusual pathogens — Other unusual pathogens that should be considered, particularly in immunocompromised hosts, include unusual bacteria (nontuberculous mycobacteria, Bartonella sp, Leptospira sp), fungi (eg, Cryptococcus), and parasites (table 1).

Distinguishing between viral and nonviral causes — Among nonviral causes of mononuclear-predominant CSF pleocytosis, the CSF glucose concentration helps narrow the differential diagnosis [71]:

●Normal CSF glucose concentration – Syphilis, Lyme disease, leptospirosis, Rocky Mountain spotted fever, ehrlichiosis, Kawasaki disease, postinfectious encephalomyelitis, and drugs (nonsteroidal antiinflammatory drugs, trimethoprim-sulfamethoxazole) [72]

●Decreased CSF glucose concentration – Partially treated bacterial meningitis, Listeria monocytogenes, M. tuberculosis, fungal infections, primary amebic meningoencephalitis

As described above, the Bacterial Meningitis Score (BMS) and other predictions tools can help distinguish bacterial meningitis from aseptic meningitis. (See 'Bacterial meningitis' above.)

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SUMMARY AND RECOMMENDATIONS

●Clinical features

•Findings attributable to meningitis – The manifestations of viral meningitis are generally similar to those of bacterial meningitis but are usually less severe. Infants may present with abrupt onset of fever accompanied by nonspecific symptoms (eg, irritability, poor feeding, vomiting, diarrhea, rash, respiratory symptoms). Physical findings may include bulging fontanelle and nuchal rigidity. Older children typically present with fever, headache, nausea, vomiting, stiff neck, and photophobia. (See 'Clinical features' above.)

•Other findings attributable to viral illness – Enterovirus (EV) infection, which is the most common cause of viral meningitis, is typically associated with conjunctivitis, pharyngitis, rash, herpangina, and/or hand-foot-mouth disease (picture 1A-C). In temperate climates, EV outbreaks in the community tend to occur in late summer/early fall. (See 'Enteroviruses' above and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

●Laboratory evaluation – The initial laboratory evaluation of a child with suspected meningitis includes (see 'Evaluation' above):

•Blood tests (see 'Blood tests' above):

-Blood cultures

-Complete blood count with differential and platelet count

-Inflammatory markers (eg, C-reactive protein, procalcitonin), which can help distinguish viral from bacterial meningitis

-Prothrombin time, activated partial thromboplastin time (particularly in patients with petechiae or purpura)

-Serum electrolytes, blood urea nitrogen, creatinine, and glucose

•Cerebrospinal fluid (CSF) studies (see 'Cerebrospinal fluid studies' above):

-Gram stain and bacterial culture

-Cell count

-Glucose and protein

-Polymerase chain reaction (PCR) studies (see 'Detection of virus' above)

●Distinguishing viral from bacterial meningitis – Viral meningitis may be suspected on the basis of epidemiologic features (eg, season, exposure to sick contacts), clinical features, and initial CSF studies (table 4), but clinical and laboratory features often overlap with bacterial meningitis and it can be difficult to exclude bacterial meningitis with certainty based on initial testing. (See 'Distinguishing viral from bacterial meningitis' above.)

As a general principle, children suspected of having meningitis should be initially presumed to have bacterial meningitis and should be managed accordingly until bacterial meningitis has been excluded or deemed very unlikely (table 3). (See "Bacterial meningitis in children older than one month: Treatment and prognosis".)

Clinical prediction rules can be used in conjunction with clinical judgment to identify patients at low risk of bacterial meningitis (algorithm 1). (See 'Clinical prediction rules' above.)

●Diagnosis – The diagnosis of viral meningitis is confirmed by negative bacterial cultures and detection of a viral pathogen in the CSF. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of viral meningitis includes bacterial meningitis, Lyme meningitis, viral encephalitis, autoimmune encephalitis, and other unusual pathogens (table 1). (See 'Differential diagnosis' above.)