Epstein-Barr virus infections of the nervous system
Nov. 11, 2023
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Meningitis is an inflammatory condition of the coverings of the brain and spinal cord and can occur in the setting of infection, autoimmune disorders, medications, and neoplasia (116; 60). Viral causes of meningitis are more common than bacterial etiologies in industrialized countries and occur more frequently in children under 5 years of age and in immunocompromised individuals. The annual incidence of viral meningitis is estimated to be between 0.26 and 17 cases per 100,000 persons in the United States, with an annual cost of $200 to $300 million (81; 97). Enteroviruses cause most viral meningitis cases, with up to 19 cases per 100,000 persons annually, followed by herpes simplex virus 2 and varicella zoster virus. West Nile virus can also cause meningitis in addition to other central nervous system complications and is currently the most common cause of summer epidemic viral meningitis in the United States (97).
• The most common symptoms of viral meningitis are acute onset of fever, headache, neck stiffness, and photophobia.
• Adults are more likely to present with meningeal signs than children whereas children more frequently develop respiratory symptoms, fever, and leukocytosis.
• Nonpolio enteroviruses account for most viral meningitis cases in the United States (up to 61% of cases), followed by herpes simplex and varicella zoster virus (40; 116).
• Viral meningitis and bacterial meningitis cannot be reliably differentiated based on symptoms and signs; therefore, cerebrospinal fluid analysis is needed.
• CSF will classically show a lymphocytic pleocytosis (usually fewer than 300 cells/mm3), a normal glucose concentration, normal or mildly elevated protein concentration, a negative Gram stain, and negative bacterial culture.
• A substantial percentage (up to 30%) of acute lymphocytic meningitis cases are never linked to a specific organism despite exhaustive evaluation (62).
In 1890, Heinrich Quincke, a German internist and surgeon, introduced the lumbar puncture as a medical procedure in a patient with suspected meningitis and over a hundred years later this procedure remains the pivotal tool for diagnosis (90). In 1925 Wallgren recognized viruses as a cause of aseptic meningitis (112). In the early part of the 20th century, meningeal inflammation was recognized as part of paralytic poliomyelitis and epidemic parotitis. In the 1930s, filterable agents (viruses) were recovered from the CSF of patients with aseptic meningitis (lymphocytic choriomeningitis virus) (94).
Subsequently, aseptic meningitis was recognized as a syndrome that could have multiple causes, both infectious and noninfectious (113; 02; 117). The syndrome consists of symptoms and signs of meningeal irritation, a CSF white blood cell pleocytosis, and negative stains and cultures for bacteria, fungi, and parasites.
In most cases, the onset of the illness is sudden. In some cases, a prodromal "influenza-like illness" may occur for several days prior to the onset of central nervous system disease. Although the presentation can be variable, the most common symptoms of viral meningitis are headache (97% to 100%), temperature greater than 38°C (65% to 69%), nausea, vomiting, and neck stiffness (55% to 69%) (102; 60). Other less common accompanying syndromes include photophobia, malaise, myalgias, sore throat, chills, diarrhea, abdominal pain, and drowsiness. Unlike cases of bacterial meningitis, these symptoms tend to be self-limiting. The headaches in patients with viral meningitis are described by the patients as intense and either frontal or retro-orbital. Temperatures tend to range from 38°C to 40°C. Physical exam maneuvers to evaluate for meningismus, such as Kernig and Brudzinski signs, may aid in diagnosis, but the absence of these signs does not rule out meningitis (sensitivity of 20% to 30% and specificity of 85% to 95% in all-cause meningitis) (04). Other clinical signs include photophobia (sensitivity of 28% and specificity of 88% in all-cause meningitis) and jolt accentuation of headache (sensitivity of 40% to 60% and specificity of 65% to 75% in all-cause meningitis) (04).
Extraneural manifestations may provide clues to the underlying causative viral infection. The enteroviruses can cause diffuse rashes or more specific syndromes and may be preceded by a respiratory or gastrointestinal prodrome (69; 60). The group A coxsackieviruses often cause hand-foot-and-mouth disease and herpangina, whereas the group B coxsackieviruses characteristically cause pleurodynia and myocarditis or pericarditis. Both coxsackieviruses and echoviruses can also cause conjunctivitis and myopathies (116). The occurrence of parotitis, pancreatitis, and orchitis strongly suggests mumps as the etiology (24). Indeed, pain in the parotid glands (91%) or swelling of one or both (up to 50%) occur in patients with mumps meningitis (116). Other less frequent symptoms are swollen and painful testes (15%), arthralgias, and myalgias (14% to 21%) (116).
West Nile virus is a common cause of meningitis during the summer months and may present with rash that involves the trunk and limbs, gastrointestinal symptoms, and myalgias. West Nile virus can cause meningitis in any age group, whereas encephalitis typically occurs in people older than 65 years. Common symptoms of CNS involvement, particularly when the brain parenchyma is affected, are tremors, parkinsonism, and myoclonus (118). Chikungunya virus is present in rainy seasons throughout the tropics and subtropics (Africa, Pacific Islands, Latin America, and the Caribbean). It is typically associated with severe joint pain of hands and feet as well as maculopapular rash and conjunctivitis. Zika virus is usually associated with myalgia, rash, and conjunctivitis. Zika virus, which is found in equatorial countries worldwide, is usually associated with myalgia, rash, and conjunctivitis (114), whereas dengue virus, which is now found on all continents except Antarctica, causes myalgia, arthralgia, and petechial rash (65; 06). Ebola virus caused meningitis in a Scottish nurse who assisted during the outbreak in Sierra Leone (49).
Herpesvirus (HSV) 1 more frequently causes encephalitis, whereas HSV-2 typically causes meningitis. HSV-2 meningitis may occur with or without evidence of concomitant genital infection. This virus may produce recurrent episodes of meningitis, with a gap between episodes of months up to 10 years, and it is one of the causes of Mollaret meningitis (96). HSV can invade the meninges through the cranial nerves (116). Other symptoms associated with HSV-1 and HSV-2 infections are neuropathic pain following a specific dermatomal pattern, hallucinations, arthralgias, and difficulty with micturition (105).
In December 2019, a novel coronavirus subsequently termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified and declared the cause of a global pandemic in March 2020. Although the virus is not typically neuroinvasive, in rare cases it may enter into and directly cause CNS pathology. Even when evidence of entry into the CNS is absent, SARS-CoV-2 infection may be associated with CNS inflammation. Associated neurologic syndromes that have been described to date include anosmia, ageusia, encephalopathy, encephalitis, Guillain-Barre syndrome, meningitis, and stroke, among others (68; 70). The first case of meningoencephalitis caused by SARS-CoV-2 was reported in May 2020, where the patient developed fever and fatigue followed by altered mental status, seizures, and neck stiffness (75). Polymerase chain reaction was positive in CSF, a very uncommon finding. MRI of the brain demonstrated hyperintensity of the right lateral ventricle, mesial temporal lobe, and hippocampus.
After the first few days of illness, the course of viral meningitis is typically one of slowly progressive improvement. The duration may be between 7 to 18 days and treatment, aside from herpes viruses for which acyclovir is administered, is primarily supportive (40).
Most patients with viral meningitis recover in 1 to 2 weeks without substantial sequelae (116). Recovery usually begins after several days of illness, and most patients feel normal within a week. The fatality rate is less than 1% and about 10% of patients report sequelae. However, these values may vary depending on the virus involved (03). Serious complications include the syndrome of inappropriate hormone ADH release (SIADH), cerebral edema, or seizures. Long-term deficits include psychiatric disorders, eg, depression and anxiety, and neurocognitive dysfunction, eg, short-term memory, speech difficulties, and attention and learning dysfunction (48), lingering malaise and fatigue (40), sleep disorders due to persistent headache (23), limb paralysis, radiculitis, developmental delay, and deafness (03; 48).
A 13-year-old teenager developed fever, sore throat, and headache. The following day, the patient developed chills, nausea, photophobia, and neck pain, which prompted a visit to the local hospital emergency room. Examination revealed an oral temperature of 101°F, pulse of 90, respiratory rate of 20, blood pressure of 120/80, and nuchal rigidity. The neurologic examination was otherwise normal. Family history was positive for fever, sore throat, and a rash (vesicles) on the hands and feet and in the mouth of a 9-year-old sibling 1 week prior to the patient’s admission.
CT scan of the brain was normal. Complete blood count was normal with a white blood cell count of 6600/mm3, 60% segmented neutrophils, 35% lymphocytes, and 5% monocytes. Lumbar puncture revealed opening pressure of 35 cm of water, white blood cells 102/mm3 with 90% mononuclear cells, protein concentration 66 mg/dL, and glucose concentration 70 mg/dL. Throat, stool, blood, and CSF samples were sent for virus isolation, and serum and CSF were sent for antibody testing. On the third day of admission, cultures of throat, stool, and CSF developed a lytic cytopathic effect consistent with an enterovirus infection. Immunofluorescence staining of tissue cultures revealed group A coxsackievirus on the next day. The patient was treated with intravenous fluids for hydration, analgesics for headache, and antipyretics for fever. Over the next 5 days, the patient’s symptoms dissipated, and the patient was discharged home on the eighth day of hospitalization.
The frequency of viral meningitis varies from year to year, depending on epidemic activity, and the highest incidence is in young children (41).
Nonpolio human enteroviruses are the most common cause of viral meningitis, causing 23% to 61% of cases (43; 15). Seventy-five thousand cases caused by enterovirus are reported per year in the United States, with most infections in the summer and autumn months (72). Patients, often children, present with concomitant respiratory and gastrointestinal symptoms. Most cases are self-limited, but severe illness may occur in immunocompromised populations. The closely related parechoviruses, which, along with enteroviruses, belong to the picornavirus family, are an increasingly recognized cause of meningitis in neonates and very young infants (25; 108). Notably, in many cases of parechoviral meningitis there is no CSF white blood cell pleocytosis, potentially confounding the diagnosis (14).
In contrast to HSV-1, HSV-2 typically causes meningitis, often in younger women (50). Around 85% of patients with HSV-2 meningitis present with genital lesions, and these usually precede the central nervous system symptoms by about a week. Severe disease is seen in immunocompromised patients (59). HSV-2 is identified as the cause of some cases of recurrent benign lymphocytic meningitis, also known as Mollaret meningitis.
West Nile virus is the leading cause of mosquito-transmitted flavivirus in the United States (26). Meningitis can occur in any age group, whereas encephalitis typically affects people older than 65 years or immunocompromised individuals.
La Crosse virus is a mosquito-borne infection commonly seen in the upper Mississippi River Valley area and can cause meningitis in the late summer. Patients typically present with seizures and focal neurologic findings. The disease is self-limited and rarely causes long-term sequelae (45).
Lymphocytic choriomeningitis virus was first reported in humans in the 1960s after documented disease in laboratory personnel working with rodents (39). It is transmitted through inhalation of aerosolized urine and droppings of infected rodents as well as by corneal, liver, and kidney transplantation, and it can cause death (107). The infection is most common during the winter and presents acutely or subacutely with a viral prodrome. Lymphocytic choriomeningitis virus is of particular importance in pregnancy because it has been associated with congenital hydrocephalus, mental retardation, and chorioretinitis.
Mumps was a previously common cause of viral meningitis; however, the incidence has markedly decreased in the postvaccination era (02; 73; 93). Unfortunately, the virus has reemerged given the recent decrease in vaccination rates. In contrast to other viruses, mumps meningitis is associated with low CSF glucose.
Varicella zoster virus typically causes a mild, self-resolving infection in children. However, varicella zoster virus can emerge from the dorsal root ganglia following establishment of latency and cause meningitis. Patients may present with or without rash. Dissemination is common in immunocompromised patients who may also develop stroke due to varicella zoster virus vasculitis (09).
Zika virus, another flavivirus, causes peripheral nervous syndromes in Africa, Asia, South America, and the Caribbean (31; 61). Although infected patients are usually asymptomatic, Zika virus can cause meningoencephalitis (17; 77).
In rare instances, severe acute respiratory syndrome coronavirus 2 has also been associated with meningitis. Other less common pathogens are arthropod borne flaviviruses, bunyaviruses and orthobunyavirus (including Chikungunya virus, dengue virus, Ebola virus, Jamestown Canyon virus, St. Louis encephalitis virus, Powassan virus, Eastern equine encephalitis virus, and Cache Valley virus), measles virus, and herpesvirus other than HSV, such as human herpesvirus type 6 (62; 107; 116). Among immunocompromised patients, meningitis caused by members of the herpesvirus family (Epstein-Barr virus, cytomegalovirus, varicella zoster, HHV-6/HHV-7), polyomavirus family, and human immunodeficiency virus have been reported (91).
The pathogenesis of each agent or family of viruses that causes viral meningitis varies. However, the occurrence of viral meningitis is an uncommon complication of common systemic infections. Viruses initially enter the host through the respiratory tract, gastrointestinal tract, urogenital tract, or breaks in the skin. Most viruses replicate near the entry site (primary replication) and gain access to the CNS by the more common hematogenous route or through neural pathways (peripheral nerves). After primary replication, the virus spreads to lymphatic tissue and into the bloodstream, causing a “primary viremia.” The virus may enter the CNS during the primary viremia or, more likely, during a “secondary viremia,” after amplification at secondary sites such as muscle, skin, internal organs, and fat. The virus then enters the CNS across the choroid plexus or by infection of capillary endothelial cells (106; 78; 116). Some viruses (rabies, herpes simplex virus, varicella zoster virus, and poliovirus) can utilize the neural route entering the CNS through axonal transport from mucosa, muscle, or neuromuscular junctions (72). Viruses entering the CNS across the choroid plexus are more likely to cause viral meningitis, whereas the other pathways are more likely to be utilized by viruses causing encephalitis or myelitis.
Once the virus reaches the choroid plexus, it usually replicates there, resulting in spread throughout the CSF, and allowing the virus to reach meningeal and ependymal cells. The ensuing inflammation primarily consists of neutrophils, monocytes, and CD8+ T lymphocytes, with focal destruction of the ependymal lining, fibrotic basal leptomeninges, and inflammation of the choroid plexus (89; 30; 57). Perivascular cuffing in superficial layers of the cortex can occasionally be observed, and proinflammatory cytokines, eg, interleukin 1, interleukin 6, and interferon gamma, can be elevated in the serum and CSF (64; 16). The combination of the meningeal and ependymal cell destruction and the subsequent inflammatory response is likely responsible for the clinical manifestations of fever, neck stiffness, headache, and photophobia. In most cases (but not all), the immune system inflammatory response limits the amount of viral replication and the length of the viral meningitic syndrome.
Viral meningitis has the greatest prevalence of all causes of meningitis in the developed world (80). In the United States, the incidence of viral meningitis was estimated to be 36,000 persons per year from 1988 to 1999 (56; 72). Viral meningitis typically peaks in the summer and fall in temperate regions but continues to occur year-round and causes meningitis cases in the winter (18; 55; 103). Transmission is typically via the fecal-oral route, and less commonly respiratory secretions (43). Notably, an increasing number of meningitis cases are recognized as being caused by enteroviruses, likely as a result of vaccine-related reductions in other bacterial and viral causes, better diagnostics for enteroviral infections, and decreased seroprevalence to enteroviruses in the general population resulting in a lack of protective maternal antibodies transferred to newborns (46). Although enterovirus and arbovirus infections (eg, La Crosse virus) occur mainly in the summer and early fall, mumps and lymphocytic choriomeningitis virus occur primarily in the winter. The various herpes virus infections (herpes simplex virus type 2, Epstein-Barr virus, cytomegalovirus, varicella zoster virus) and HIV occur at a relatively constant rate year-round.
Active immunizations for mumps and measles (MMR), influenza, and varicella has significantly decreased the incidence of these viruses as etiologic agents of viral meningitis. Enteroviruses are spread by fecal-hand-oral contamination, and this spread can be limited by good hand hygiene. Unfortunately, because young children are a major source of spread, this task is often difficult to accomplish. Lymphocytic choriomeningitis virus, now a very infrequent cause, is spread through rodent excreta and, thus, keeping the home clean and clear of mice is an effective measure of prevention.
Arbovirus infections are prevented by controlling the vector population, whereas herpes simplex virus type 2 and HIV occurrence can be decreased by practicing protected sex. Because varicella zoster virus, Epstein-Barr virus, and cytomegalovirus infections are usually spread by respiratory droplets or in saliva, they are less amenable to prevention. A double-blind randomized trial of oral valacyclovir 500 mg twice daily for 1 year after HSV-2 meningitis did not reduce the risk of recurrent meningitis (08).
The clinical syndrome of headache, fever, and neck stiffness is not specific for viral meningitis. Any inflammatory condition in the subarachnoid space can present with similar clinical manifestations. Because viral meningitis most frequently causes a lymphocytic meningeal reaction with a normal CSF glucose concentration, other conditions that result in a similar CSF analysis must be considered in the differential diagnosis (36; 58; 72).
Nonviral causes of the aseptic meningitic picture include partially treated bacterial meningitis, brucellosis, listeria, Mycoplasma pneumoniae, spirochete infections (syphilis, leptospirosis, Lyme disease) (101; 15), rickettsial infections, parameningeal infections, tuberculosis, fungal infections, and parasites. Early in the course of viral meningitis, a neutrophilic predominance can be seen, raising the possibility of bacterial meningitis (72), although the glucose is usually decreased in bacterial meningitis (13).
Syphilitic meningitis may present with malaise, disseminated rash, and headaches in association with lymphocytic pleocytosis and elevated protein. Lyme meningitis usually occurs over the same time periods that enteroviral meningitis reaches its peak incidence (summer/fall). Patients present with headache, neck stiffness, and photophobia. The diagnosis is facilitated by the presence of erythema migrans.
Two major fungal organisms that should be in the differential are cryptococcus and coccidioidomycosis. Cryptococcus neoformans meningitis typically presents in an indolent fashion with fever, malaise, and headaches. Neck stiffness, photophobia, and vomiting are seen in only 25% to 33% of patients (115; 32). The most common complication of cryptococcal meningitis is elevated intracranial pressure due to CSF outflow obstruction, likely related to the osmotic effects of the cryptococcal polysaccharide capsule (67; 95). CSF white blood cell count is typically low (< 50/ul), with mononuclear predominance and slightly abnormal protein and glucose. Coccidioides spp are endemic to the Western United States and Central and South America, with meningitis as the most common CNS manifestation of disease. A CSF eosinophilia is often present, and protein is typically elevated with profoundly low glucose.
Aseptic meningitis can also be caused by many noninfectious processes (58; 116). These include vasculitis, neurosarcoidosis, collagen vascular diseases, meningeal carcinomatosis, leukemias and lymphomas, neuro-Behçet disease, rheumatoid arthritis, systemic lupus erythematosus, Vogt-Koyanagi-Harada syndrome, Kawasaki disease, and anti-GFAP astrocytopathy-associated meningitis (02; 116). Subarachnoid blood can cause meningeal irritation. Mollaret meningitis is a benign recurrent aseptic meningitis. Herpes simplex virus type 2 DNA is isolated from the cerebrospinal fluid of some patients with Mollaret meningitis (117). Periodic rupture of an intracranial or intraspinal epidermoid cyst is implicated in several cases of recurrent aseptic meningitis (01; 21; 34).
Meningeal signs may also be present when a tumor invades the leptomeninges. Patients develop headaches, nausea, vomiting, and symptoms of intracranial hypertension. The diagnosis requires cytologic or flow cytometric identification of malignant cells within the cerebrospinal fluid. The CSF profile may show lymphocytic pleocytosis and elevated protein.
Lastly, drug-induced meningitis is an unusual cause of aseptic meningitis that is typically a diagnosis of exclusion (53). The following drugs have been reported to cause aseptic meningitis: nonsteroidal anti-inflammatory agents; antineoplastic agents; immunosuppressants, such as Muromonab-CD3 (OKT-3) or other anti-CD3 antibodies; antibiotics (eg, amoxicillin, trimethoprim-sulfamethoxazole) (76; 27); intravenous immunoglobulin (110; 42); lamotrigine (79; 12; 38); adalimumab (52); and, interestingly, valacyclovir (83). The presumed mechanisms include a delayed hypersensitivity type reaction or direct meningeal irritation. CSF analysis shows that neutrophilic pleocytosis and symptoms improve shortly after drug discontinuation.
The clinical presentation is necessary but not sufficient to establish the etiology of meningitis. In the appropriate clinical setting, the CSF examination is the most important test to establish a definitive diagnosis of viral meningitis and is best performed early. A study has suggested that for each hour of delay in performing a lumbar puncture, the chance of pathogen detection decreases by approximately 1% (71). The CSF in viral meningitis is usually clear, with a normal to moderately elevated opening pressure. The cell count ranges from 10 to 1000 cells/mm3 but is usually less than 300 cells/mm3 (74; 72). A mononuclear lymphocytic cellular response predominates. However, during the first 12 to 48 hours, there may be a predominance of polymorphonuclear leukocytes (07; 100; 66). The CSF glucose is usually normal but is depressed in 5% to 15% of cases of mumps meningitis (29). Rarely, the glucose is decreased in isolated cases of viral meningitis caused by other viruses (19; 107). The CSF protein is usually normal to mildly elevated in the 50 to 100 mg/dL range. A Spanish study of infants younger than 3 months of age who presented with fever of unknown source found that 4.8% had enteroviral meningitis and 60% of those diagnosed did not have a CSF pleocytosis (37).
The peripheral white blood cell count is usually normal in patients with viral meningitis, but may be increased or decreased, and a left shift may be seen. In bacterial meningitis, the peripheral white blood cell count and serum C-reactive protein are usually markedly elevated (104). Neither serum procalcitonin level nor C-reactive protein unequivocally distinguish bacterial from viral meningitis (99). Atypical lymphocytes in peripheral blood occur with Epstein-Barr virus infections and at times with cytomegalovirus infections. Abnormal liver function tests most often occur during infections caused by lymphocytic choriomeningitis virus, Epstein-Barr virus, cytomegalovirus, mumps, and some arboviruses. Increased amylase and lipase occur mainly with mumps and thrombocytopenia with lymphocytic choriomeningitis virus. CT and MRI scans are usually normal, although meningeal enhancement may be seen with T1-weighted MRI scans after administration of gadolinium contrast. In a study of patients with West Nile virus meningitis, 14% had leptomeningeal or periventricular enhancement on MRI (05). Neuroimaging before lumbar puncture is associated with delay in treatment and, thus, is not strictly necessary. However, CT scan should be performed before lumbar puncture if clinical signs of brain edema or shift are present, including papilledema, focal neurologic signs, or uncontrolled seizures (40).
Unfortunately, a distinction between the many viruses causing viral meningitis cannot be made on the basis of either the clinical syndrome or the CSF profile. Therefore, viral isolation, PCRs, antibody studies, extraneural manifestations of the illness (including abnormal blood tests noted above), and the epidemiologic features are important for determining the cause. Many viruses causing viral meningitis can be isolated from the CSF (15). A 4-fold rise in concentration of specific antibody in a convalescent serum specimen, presence of IgM antibodies in CSF, or demonstration of intrathecal production of specific IgG antibody support the diagnosis (72). However, the gold standard for diagnosis of most causes of viral meningitis is cerebrospinal fluid polymerase chain reaction that uses pathogen specific nucleic acid sequence to detect the virus with high sensitivity (40). Throat, nasopharyngeal, and stool swabs are also useful for detecting enteroviruses if the CSF PCR is negative. For enteroviruses, PCR assays are about twice as likely as cell culture to be positive (47; 20; 72). Nonetheless, one study of an outbreak of pediatric enterovirus 71 CNS infections found positive enterovirus CSF PCR in only 31% of cases, with higher yield from PCR of respiratory tract specimens (86).
Several molecular diagnostic tools are being brought to bear in cases of suspected encephalitis. The BioFire FilmArray Meningitis/Encephalitis PCR panel is a multiplex PCR assay that allows the identification of 14 viral, bacterial, and fungal organisms that may potentially cause meningitis or encephalitis with high specificity and sensitivity (63; 88). A cohort study suggested that the use of FilmArray has a positive impact on the number of hospital days and treatment duration (22). In addition, a prospective Ethiopian study showed that the use of this tool reduces antibiotic usage in suspected meningitis cases (10). Metagenomic next-generation sequencing may diagnose a spectrum of potential causes – viral, bacterial, fungal, and parasitic – in a single assay via high-resolution sequencing techniques (33). A multicenter study revealed that metagenomic next-generation sequencing assay can potentially identify more pathogens than conventional tests. Notably, both false positives (eg, Streptococcal species and HHV-6) and false negatives (including HSV, enteroviruses, and cryptococcal species) have been reported for both BioFire FilmArray and Metagenomic NGS and, thus, results should be interpreted with caution and confirmed by other means (111).
The treatment of viral meningitis is supportive with the use of analgesics, fluids, and antipyretics. The use of specific antiviral treatments in meningitis, in contrast with encephalitis, does not have FDA approval (40). In cases of meningitis due to herpes simplex virus-2, antiviral therapy may shorten the duration of viral shedding, but the benefit is not clearly established, particularly for immunocompetent individuals. Hospitalization may be needed for management of severe headache, fever, and dehydration from nausea and vomiting. Hospitalization is also encouraged for further workup when the CSF profile is atypical or to manage serious complications. If the glucose concentration is low, or if there is a preponderance of polymorphonuclear leukocytes, acute bacterial meningitis is a worrisome possibility. In these cases, patients should be hospitalized and treated with broad-spectrum antibiotics until CSF studies and blood culture results are negative. Of note, tuberculous meningitis can present with a lower CSF cell count and a higher percentage of lymphocytes than acute bacterial meningitis, thus, potentially mimicking the CSF profile of viral meningitis.
In the case of viral meningitis with a CSF polymorphonuclear pleocytosis, a lumbar puncture can be repeated in 8 to 12 hours and can show a significant decrease in the number of polymorphonuclear leukocytes and a shift to mononuclear cells. Specific antiviral therapy may be indicated for potentially life-threatening complications, which are more likely to occur in newborns, infants, and the immunocompromised. If herpes simplex virus is suspected, consideration should be given to empiric treatment with acyclovir (10 mg/kg intravenously three times daily, adjusted for renal function). There is no consensus on the length of treatment nor on whether and when to transition to famciclovir or valacyclovir (1 g orally twice daily). The use of a 10- to 14-day course of antiviral therapies in immunocompromised patients likely improves outcomes (82). However, the concomitant use of corticosteroids has not revealed benefits (54; 116). The Infectious Disease Society of America (IDSA) recommends treating patients with varicella zoster virus meningitis with acyclovir 15 mg/kg three times daily (assuming normal renal function) for 10 to 14 days. The IDSA also suggests the use of adjunctive corticosteroids for selected viral pathogens (varicella zoster and Epstein-Barr virus), although there is not enough support to use these medications routinely (109; 116). An attempt to treat West Nile virus meningitis with intravenous immunoglobulin had no reported benefit (35). Intravenous immunoglobulin has been used to treat enterovirus meningitis in Asia, though benefits are uncertain (84).
The outcome of viral meningitis is typically considered to be good. Children may have symptoms for more than 1 week but often fully recover. Adults with enterovirus meningitis frequently develop milder symptoms than children, and prognosis is also generally favorable. However, some patients will experience poor outcomes. A nationwide Danish population-based study found that at 30 days post discharge, up to 20% of individuals had some degree of moderate to severe disability regardless of viral etiology and that women were more likely to have an unfavorable outcome (87). In a UK study, those with viral meningitis had a mean loss of 0.2 quality-adjusted life-years in the first year compared with an age-matched population (71).
There is a paucity of information regarding treatment of viral meningitis during pregnancy. Pregnant women suspected of having infectious meningitis should be treated with acyclovir at a dose of 10 mg/kg every 8 hours (assuming normal renal function) for 14 to 21 days to decrease potential maternal and fetal sequelae (51). The teratogenic potential of acyclovir is not clear, but small studies have suggested it is safe in pregnancy (92; 85).
No data are available to indicate that pregnancy is a risk factor for viral meningitis or that viral meningitis is more severe in pregnant women. However, several viruses causing meningitis (enteroviruses, mumps, measles, cytomegalovirus, herpes simplex virus type 2, varicella zoster virus, lymphocytic choriomeningitis virus, Zika) can infect the fetus and cause congenital malformations (44; 28). Notably, Zika virus infection may cause microcephaly, hearing loss, developmental delay, and seizures in newborns (98; 11). In addition, a study revealed that one possible explanation to the increasing of newborn cases from enterovirus meningitis in the postvaccinal era is a greater number of pregnant women who have not developed immunity against enterovirus and cannot passively transfer antibody transplacentally to the fetus (46).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Christina M Marra MD
Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.See Profile
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