Apr. 24, 2021
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Meningitis refers to inflammation of the meninges and can occur in the setting of infection or, less commonly, autoimmunity (78; 122). Viral causes of meningitis are more common than bacterial etiologies in industrialized countries and more frequently occur in children than in adults. 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 (19; 54; 98). Enteroviruses cause most viral meningitis cases, with up to 19 cases per 100,000 persons annually, followed by herpes viruses, and in some parts of the world, arthropod-borne viruses. West Nile virus can also cause meningitis in addition to other central nervous system complications (119).
• 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 (72; 42).
• 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 less than 300 cells/mm3), a normal glucose concentration, normal or mildly elevated protein concentration, a negative Gram stain, and negative bacterial culture.
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 (92). In 1925 Wallgren recognized viruses as a cause of aseptic meningitis (115). In the early part of the 20th century, it was known that meningeal inflammation occurred 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) (95).
Subsequently, it was recognized that aseptic meningitis was a syndrome that could have multiple causes, both infectious and noninfectious (116; 02; 122). The syndrome consists of symptoms and signs of meningeal irritation, a CSF 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%-100%), temperature greater than 38 C (65%-69%), nausea, vomiting, and neck stiffness (55%-69%) (110; 107). 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 5% and specificity of 95%) (111; 114; 05). Other clinical signs include photophobia (sensitivity of 28% and specificity of 88%) and jolt accentuation of headache (75; 04).
Extraneural manifestations may provide clues to the underlying causative viral infection. The enteroviruses can cause diffuse rashes or more specific syndromes (68; Sinclair et al 2020). 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 (122). The occurrence of parotitis, pancreatitis, and orchitis strongly suggests mumps as the etiology (Davison et al 2020). Indeed, pain in the parotid glands (91%) or swelling of 1 or both (up to 50%) occur in patients with mumps meningitis (38; 122). Other less frequent symptoms are swollen and painful testes (15%), arthralgias, and myalgias (14%-21%) (110; 122).
West Nile virus may present with rash that involves the trunk and limbs, gastrointestinal symptoms, and myalgias. Other symptoms are tremors, parkinsonism, and myoclonus (118; 123). 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 (118) whereas dengue virus causes myalgia, arthralgia, and petechial rash (91; Almeida et al 2019). Ebola virus caused meningitis in a Scottish nurse who assisted during the outbreak in Sierra Leone (50).
Herpesviruses, typically HSV-2, may produce recurrent episodes of meningitis with a gap between episodes of months to up to 10 years (60; 97). HSV can invade the meninges through the cranial nerves (121). Other symptoms associated with herpesvirus are neuropathic pain following a specific dermatomal pattern, hallucinations, arthralgias, and difficulty with micturition (75).
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 can rarely cause CNS inflammation. Associated neurologic syndromes that have been described to date include anosmia, ageusia, encephalopathy, encephalitis, Guillain-Barre syndrome, meningitis, and stroke, among others (64; 67; 69). The first case of meningoencephalitis caused by SARS-CoV-2 was published in May 2020, where the patient developed fever, fatigue followed by altered mental status, seizures, and neck stiffness (76). Polymerase chain reaction from a nasopharyngeal swab was negative for the virus but positive in CSF. 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 (42).
Most patients with viral meningitis recover in 1 to 2 weeks without substantial sequelae (02; 84). 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). Deficits include psychiatric disorders, eg, depression, anxiety and neurocognitive dysfunction, eg, short-term memory, speech difficulties, attention and learning dysfunction (25), lingering malaise and fatigue (Hotopf et al 1996; 71), sleep disorders due to persistent headache (103; 25), limb paralysis, radiculitis, developmental delay, and deafness (81; 47; 66; 96; 49; 70; 03).
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, 60% segmented neutrophils, 35% lymphocytes, and 5% monocytes. Lumbar puncture revealed opening pressure of 35 cm of water, white blood cells 102 cells/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 cytopathic effect consistent with an enterovirus infection (lytic cytopathic effect). Immunofluorescence staining of tissue cultures revealed a 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 infections varies from year to year, depending on epidemic activity, and the highest incidence is in young children. Nonpolio human enteroviruses are the most common cause of viral meningitis, causing 23% to 61% of cases (44; 15). Seventy-five thousand cases caused by enterovirus have been reported per year in the United States, with most infections in the summer and autumn months (72). Other less common pathogens are lymphocytic choriomeningitis virus (LCMV), herpes simplex viruses type 1 and 2, arthropod borne flaviviruses, bunyaviruses and orthobunyavirus (including West Nile virus, Zika virus, Chikungunya virus, dengue virus, Ebola virus, La Crosse 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 varicella-zoster virus and human herpesvirus type 6 (59; 110). Among immunocompromised patients, members of the herpesvirus family (Epstein-Barr virus, cytomegalovirus, varicella zoster), polyomavirus family, and human immunodeficiency virus have been reported (93).
Mumps was a previously common cause of viral meningitis; however, it has markedly decreased in the postvaccination era (02; 73; 63; Centers for Disease Control 1976; 94). Lymphocytic choriomeningitis virus is transmitted thorough inhalation of aerosolized urine and droppings of infected rodents as well as by corneal, liver, and kidney transplantation with fatal outcomes (34; 18; 101; 110). Human parechovirus-3 is an occasional cause of meningitis and sepsis, typically in the first few months of life, and is typically associated with normal CSF leukocyte counts (120; 117; 11; 27). Zika virus, another flavivirus, causes peripheral nervous syndromes in Africa, Asia, South America, and the Caribbean (33; 58). Though infected patients are usually asymptomatic, Zika virus can cause meningoencephalitis (16; 79; 89; 105).
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 (109; 80; 122). 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 (102; 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 virus apparently replicates in these cells, causing cell destruction and inciting inflammation. The inflammation consists primarily of neutrophils, monocytes, and CD8+ T lymphocytes, with focal destruction of the ependymal lining, fibrotic basal leptomeninges, and inflammation of the choroid plexus (90; 32; 56). Occasionally, perivascular cuffing in superficial layers of the cortex is seen and proinflammatory cytokines, eg, interleukin 1, 5, and 6, interferon gamma, and tumor necrosis factor alpha are often observed (36; 62). The combination of the meningeal and ependymal cell destruction and the subsequent inflammatory response apparently is 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 (83). In the United States, the incidence of viral meningitis is estimated between 1 to 17 cases per 100,000 people (55; 72). Because enteroviruses are responsible for most cases and enterovirus activity is maximal in the late spring to early fall, this time is the peak occurrence period for viral meningitis. However, it is now recognized that enteroviruses can remain active year-round and also cause meningitis cases in the winter (20; 54). Transmission is typically via the fecal-oral route, and less commonly respiratory secretions (44). 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 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 (39; 57; 72).
Nonviral causes of the aseptic meningitic picture include partially treated bacterial meningitis, brucellosis, listeria, Mycoplasma pneumoniae, spirochete infections (syphilis, leptospirosis, Lyme disease) (30; 106; 15), rickettsial infections, parameningeal infections, tuberculosis, fungal infections, and parasites. The last 3 usually lower the CSF glucose concentration. Early in the course of viral meningitis, a neutrophilic predominance can be seen, making bacterial meningitis a possibility (07; 72), although the glucose is usually decreased in bacterial meningitis (13).
Aseptic meningitis can also be caused by many noninfectious processes (Rubeiz and Roos 1992; 57; 122). 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; 122). 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 (88; 122), and periodic rupture of an intracranial or intraspinal epidermoid cyst is implicated in several cases (01; 23; 37). The following drugs have been reported to cause aseptic meningitis: nonsteroidal anti-inflammatory agents, antineoplastic agents, immunosuppressants such as Muromonab-CD3 (OKT-3), antibiotics (eg, amoxicillin, trimethroprim-sulphamethoxazole), anti-CD3 monoclonal antibody (Rubeiz and Roos 1992; 77; 28), intravenous immunoglobulin (113; 43), lamotrigine (82; 12; 41), adalimumab (52), and, interestingly, valacyclovir (85).
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. For each hour of delay in performing a lumbar puncture, the chance of pathogen detection decreases by approximately 1% (14). 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; 104; 65). The CSF glucose is usually normal but is depressed in 5% to 15% of cases of mumps meningitis (31). Rarely, the glucose is decreased in isolated cases of viral meningitis caused by other viruses (21; 110). 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 (40).
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 (108). Neither serum procalcitonin level nor C-reactive protein unequivocally distinguish bacterial from viral meningitis (100). 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 gadolinium MRI scans. 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 in case clinical signs of brain edema or shift are present, including papilledema, focal neurologic signs, or uncontrolled seizures (42).
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 specific antibody in the convalescent serum specimen, presence of IgM antibodies, or demonstration of the intrathecal production of specific IgG antibody supports 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 (42). 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 (48; 22; 72). Nonetheless, 1 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 newer molecular diagnostic tools are being brought to bear in cases of suspected encephalitis. The BioFire FilmArray Meningitis/Encephalitis PCR panel is a 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 (61; 87). A cohort study suggested that the use of FilmArray has a positive impact on the number of hospital days and treatment duration (24). In addition, a prospective Ethiopian study showed that the use of this tool reduces antibiotic usage in suspected meningitis cases (09). 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 (35). 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 and thus results should be interpreted with caution.
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 (42). In cases of meningitis due to herpes simplex virus-2, antiviral therapy may shorten the duration of viral shedding, but it is not required. 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 complications such as SIADH, cerebral edema, or seizures. 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 cultures are reported to be negative. Of note, TB 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, famciclovir, or valacyclovir. The use of a 7- to 10-day course of antiviral therapies in immunocompromised patients reduces sequelae. However, the concomitant use of corticosteroids has not revealed benefits (53; 122). The Infectious Disease Society of America suggests the use of adjunctive corticosteroids for selected viral pathogens (varicella zoster and Epstein-Barr virus), though there is not enough support to use these medications routinely (112; 122).
The outcome of viral meningitis is usually good. Children may have symptoms for more than 1 week but normally fully recover. Adults with enterovirus meningitis frequently develop milder symptoms than children and prognosis is also favorable. Neurologic sequelae occur in fewer than 10% of individuals (71).
There is a paucity of information regarding treatment of viral meningitis during pregnancy. In 1 case of a 36-year-old woman with HIV and varicella zoster meningitis, the patient was treated with intravenous antiviral therapy at the onset of clinical suspicion for viral meningitis until complete resolution of her symptoms. Although strong consideration should be given to treating pregnant women with suspicion of meningitis with antiviral medications to decrease potential maternal and fetal sequelae, the optimal treatment duration is unknown (51).
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 viral meningitis (enteroviruses, mumps, measles, cytomegalovirus, herpes simplex virus type 2, varicella zoster virus, lymphocytic choriomeningitis virus) can infect the fetus and cause congenital malformations (45; 29). Notably, Zika virus infection may cause microcephaly, hearing loss, developmental delay, and seizures in newborns (99; 10). In addition, a study revealed that 1 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 (Viskari et al 2000; 46).
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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