Aseptic Meningitis 

Aseptic Meningitis – 17 Interesting Facts

1. Meningitis refers to inflammation of the meningeal membrane layers surrounding the brain and spinal cord
2. Aseptic meningitis is defined as an acute community-acquired meningitis syndrome with cerebrospinal fluid pleocytosis in the absence of a positive cerebrospinal fluid Gram stain and cerebrospinal fluid or blood culture, without a parameningeal focus or a systemic illness, and (typically) with a good clinical outcome
3. No specific etiology of aseptic meningitis is identified in up to half or more of reported cases. When a specific etiology is found, viral etiologies are most common, with Enteroviruses the leading viral cause
4. In addition to viruses, various nonviral infectious (eg, bacteria, mycobacteria, fungi, parasites, spirochetes) and noninfectious (eg, medications, malignancies, systemic inflammatory diseases) etiologies can result in aseptic meningitis syndrome
5. Common symptoms in patients presenting with aseptic meningitis include headache, nausea/vomiting, neck stiffness, photophobia, and respiratory symptoms; presence of fever and nuchal rigidity are variable depending on age
6. Most patients have a normal neurologic examination. Certain physical findings may suggest specific etiologies
7. History and physical examination may suggest aseptic meningitis, but cerebrospinal fluid analysis and other lab tests are necessary to definitively establish diagnosis and exclude other potential causes of meningitis (bacterial meningitis being of significant concern)
8. Screening head CT scan is recommended before lumbar puncture in certain patients with suspected meningitis and risk factors for brain herniation
9. Lumbar puncture with cerebrospinal fluid analysis is the cornerstone of aseptic meningitis diagnosis and evaluation and may identify a specific etiology
10. Additional testing may also help with establishing diagnosis, ruling out competing diagnoses, and identifying a specific etiology of meningitis
11. Distinguishing bacterial meningitis from aseptic meningitis is a significant diagnostic challenge with important management implications. Clinical prediction rules have been developed to help identify patients at low risk for bacterial meningitis
12. In patients with potential bacterial meningitis or encephalitis, intravenous dexamethasone and antibiotics should be initiated while awaiting cerebrospinal fluid studies; empiric intravenous acyclovir is indicated if there is concern for herpes simplex virus or varicella-zoster virus infection
13. Once bacterial meningitis has been excluded with cerebrospinal fluid studies and cultures, or a nonbacterial etiology (eg, viral) has been confirmed, antibacterials can be stopped
14. If a specific infectious etiology is identified, antimicrobial therapy can be tailored accordingly
15. In patients deemed to have aseptic meningitis secondary to a noninfectious cause, management is directed at the underlying etiology
16. Supportive care is the mainstay of treatment for most cases of aseptic meningitis
17. Aseptic meningitis is generally benign, self-limiting, and has a good prognosis

Alarm Signs and Symptoms

• Altered mental status, focal neurological signs, seizures should prompt evaluation and treatment for bacterial meningitis, brain abscess, and/or viral encephalitis
• Chronic meningitis should prompt evaluation for tuberculosis, fungal, brucella, or non-infectious etiologies

Introduction

• Meningitis refers to inflammation of the meningeal membrane layers surrounding the brain and spinal cord while encephalitis refers to inflammation of the brain itself. Meningoencephalitis is a term used to indicate concurrent meningitis and encephalitis¹
• Aseptic meningitis is defined as an acute community-acquired meningitis syndrome with CSF (cerebrospinal fluid) pleocytosis in the absence of a positive CSF Gram stain and CSF or blood culture, without a parameningeal focus or a systemic illness, and (typically) with a good clinical outcome¹
• No specific etiology of aseptic meningitis is identified in up to half or more of reported cases. When a specific etiology is found, viral etiologies are most common, with enteroviruses the leading viral cause¹²
• Viral meningitis is sometimes (inaccurately) used as a synonym for aseptic meningitis, but the term “aseptic meningitis” encompasses all cases of meningitis for which initial evaluation for bacteria is negative; in addition to viruses, various nonviral infectious (eg, bacteria, mycobacteria, fungi, parasites, spirochetes) and noninfectious (eg, medications, malignancies, systemic inflammatory diseases) etiologies can result in aseptic meningitis syndrome²
• The majority of patients with aseptic meningitis are empirically started on intravenous antibiotics while awaiting cultures³

Etiology

Enteroviruses¹

• Enteroviruses are a leading cause of aseptic meningitis worldwide in infants, children, and adults, accounting for up to 55% of viral meningitis cases or more¹
• Enteroviruses also can cause hand-foot-and-mouth disease, myocarditis, encephalitis, and acute flaccid paralysis
• The most common mode of acquisition is fecal–oral route
• Enteroviruses typically present more commonly during the summer and fall in temperate climates but in tropical climates can present any time of the year
• In infants, enteroviral meningitis commonly presents without CSF pleocytosis

Human Parechoviruses¹

• Human parechovirus can cause asymptomatic infection, sepsis, aseptic meningitis, or encephalitis⁴
• It most commonly affects children with severe disease such as sepsis and encephalitis in patients younger than 3 months of age
• Fever is the most common manifestation followed by irritability, skin rash, poor feeding, and seizures
• The presence of white matter abnormalities on MRI is associated with seizures, and the development of adverse neurodevelopmental outcomes

Herpes Viruses¹

• Herpes viruses include HSV (herpes simplex virus) types 1 and 2, VZV (varicella-zoster virus), CMV (cytomegalovirus), EBV (Epstein-Barr virus), and HHV (human herpesvirus) types 6, 7, and 8
• HSV-2 is the most common herpetic cause of aseptic meningitis, and of recurrent benign lymphocytic meningitis (Mollaret meningitis)
• A double-blind, randomized clinical trial of valacyclovir suppression showed no impact on decreasing recurrent rates in patients with HSV-2 meningitis⁵
• HSV-2 meningitis most commonly is seen in young females with only half of them having a history of genital herpes and one-third having a history of previous viral meningitis⁶
• A minority of patients with HSV-2 meningitis have genital mucocutaneous lesions on presentation⁶
• HSV-1 most commonly causes encephalitis which typically presents with unilateral temporal lobe abnormalities
• VZV can also cause acute aseptic meningitis with or without vesicular rash, the latter known as zoster sine herpete
• VZV is most commonly seen in older adults or in individuals with immunosuppression
• VZV meningitis in a young patient should prompt checking for HIV¹
• VZV is most likely underdiagnosed as a CSF VZV PCR (polymerase chain reaction) is rarely ordered in adults with aseptic meningitis³
• CMV can present as meningitis, encephalitis, retinitis, or as disseminated infection in immunosuppressed individuals
• CMV more commonly presents as an encephalitis in patients with AIDS and has worse clinical outcomes⁷
• Primary EBV infection, with or without infectious mononucleosis, or reactivation of latent infection in immunocompromised individuals has been associated with encephalitis, meningitis, acute disseminated encephalomyelitis, cerebellitis, multiple sclerosis, and CNS (central nervous system) lymphomas⁸
• HSV-6 most commonly causes PALE (posttransplant acute limbic encephalitis) in bone marrow transplant recipients or in patients that received chimeric antigen receptor T cell therapy⁹
• It is important to note that a positive CSF HHV-6 may represent a true infection, a reactivation, or chromosomal integration. True infections are typically seen in highly immunosuppressed individuals with no other alternative diagnosis
• HSV-7 and HSV-8 can occasionally cause encephalitis in immunosuppressed individuals such as those with AIDS or a solid-organ transplant¹⁰

Arboviruses¹

• WNV (West Nile virus) is transmitted by mosquitos and is the most common arboviral cause of aseptic meningitis in the United States¹¹
• In 2020, the CDC reported a total of 884 cases of arboviral disease in the United States, including those caused by WNV (731 cases), La Crosse virus (88 cases), Powassan virus (21 cases), St. Louis encephalitis (16 cases), eastern equine encephalitis (13 cases), Jamestown Canyon virus (13 cases), and unspecified California serogroup viruses (2 cases)¹¹
• WNV can also cause encephalitis, retinitis, and acute flaccid paralysis¹²
• WNV most commonly presents between June and October but only one-third of patients with meningitis and encephalitis are being tested for WNV¹³

Respiratory Viruses¹

• Despite the availability of effective vaccines, measles and mumps infections continue to occur, and can cause meningitis and encephalitis
• In 2024, 15 outbreaks of measles in the United States have occurred accounting for more than 200 cases (as of November).¹⁴ Similarly, due to waning immune protection, there have been more than 200 cases of mumps reported in the United States¹⁵
• Influenza viruses, respiratory syncytial virus, and coronavirus disease 2019 (COVID-19) can also occasionally present as meningoencephalitis

Non-viral Causes²

• Bacterial meningitis with previous antibiotic exposure may present with negative CSF Gram stain and cultures
• Borrelia burdogferi (Lyme disease) can present with meningitis in endemic areas after tick bite in the summer and fall. Clues include erythema migrans rash and a facial palsy
• Treponema pallidum can present with meningitis in secondary syphilis in patients with recent unprotected sexual exposure
• Cryptococcus neoformans and Histoplasma capsulatum may present with a subacute meningitis in immunosuppressed individuals (eg, AIDS, solid-organ transplant)
• Coccidioides immitis presents with meningitis in endemic areas (eg, New Mexico, Arizona, California, West Texas) and requires life-long fluconazole suppression
• Mycobacterium tuberculosis causes a basilar meningitis that can also have hydrocephalus and tuberculomas. Patients typically present with cranial nerve palsies
• Parasitic causes typically present with an eosinophilic meningitis (eg, Angiostrongylus cantonensis, Gnathostoma spinigerum, Baylisascaris procyonis)
• Noninfectious causes include malignancy, neurosarcoidosis, autoimmune disorders, medications, systemic lupus erythematosus, vasculitis
• Idiopathic: a large proportion of patients with aseptic meningitis (up to half or more of reported cases) lack an identified etiology

Risk Factors¹²

• Fecal oral contamination (eg, enterovirus, human parechovirus, Angiostrongylus cantonensis, Gnathostoma spinigerum, Baylisascaris procyonis)
• Otitis media and sinusitis (eg, Streptococcus pneumoniae)
• Unprotected sexual exposure (eg, syphilis, HSV-2)
• Mosquito bites (eg, WNV)
• Tick bites (eg, Lyme disease, Powassan virus, tick-born encephalitis)
• Immunosuppression (eg, CMV, Cryptococcus neoformans, Histoplasma capsulatum, VZV, Listeria monocytogenes)
• Endemic areas; southwest (Coccidioides), northeast (Lyme disease, Powassan virus), Mississippi and Ohio river valleys (Histoplasma capsulatum, Blastomyces)

Diagnosis

Approach to Diagnosis

• Common symptoms in patients presenting with aseptic meningitis include headache, nausea/vomiting, neck stiffness, photophobia, and respiratory symptoms
• Fever is usually present in children and is less common in adults. Presence of frank nuchal rigidity is variable but increases with age; more subtle signs of meningeal/CNS irritability may be more common. Certain physical findings can suggest specific viral etiologies
• Most patients with aseptic meningitis will have a normal Glasgow Coma Score and a normal neurologic examination.³ Although viral meningitis is generally a more benign, less severe, and self-limited illness (and thus more mild presentations favor diagnosis of viral meningitis over bacterial meningitis), bacterial meningitis and viral meningitis cannot be reliably distinguished based on clinical findings alone due to overlapping presentations²
• Clinical history, epidemiologic features, and physical examination may suggest aseptic meningitis and form the basis of a presumptive diagnosis (eg, when lumbar puncture is deferred, declined, or contraindicated), but laboratory studies and lumbar puncture with CSF studies are necessary to definitively establish diagnosis and exclude other potential causes of meningitis (bacterial meningitis being of significant concern)
• Screening head CT scan is recommended before LP (lumbar puncture) in certain patients with suspected meningitis and risk factors for brain herniation
• LP with CSF analysis is the cornerstone of aseptic meningitis diagnosis and evaluation and may identify a specific meningitis etiology
• Additional testing may also help with ruling out competing diagnoses, establishing diagnosis, and identifying a specific etiology of meningitis

Diagnostic Criteria

• An international working group has defined aseptic meningitis as patients with¹⁶:
  • Meningitis symptoms
  • CSF white cell count of greater than 5 cells/mm³
  • Negative CSF Gram stain
• The diagnostic certainty of this syndrome was further stratified into 3 levels, in order of decreasing certainty:
  • Level 1 if the patient had negative CSF cultures without previous antibiotic exposure
  • Level 2 with negative CSF cultures with previous antibiotic therapy
  • Level 3 with concomitant encephalitis
• Positive testing for viral infection or other causative etiology (eg, positive CSF PCR or serology) helps confirm diagnosis in many cases

Workup

History

• Obtaining a thorough history including recent mosquito or tick bites, unprotected sex, travel to endemic areas, medications including antibiotic therapy, medical history of immunosuppression such as AIDS or recent ill contacts are important to elucidate possible etiologies. For example:
  • Mosquito/tick bites raise concern for arboviral disease
  • High-risk sexual exposures raise concern for syphilis, HSV-2, and the like
  • Travel raises concern for endemic organisms such as Coccidioides, Lyme disease, Histoplasma capsulatum, Blastomyces, and the like
  • Recent antibiotic therapy raises concern for partially treated bacterial meningitis and decreases diagnostic certainty of aseptic meningitis diagnosis based on CSF WBC count and negative CSF Gram stain
  • History of immunosuppression raises concern for CMV, Cryptococcus neoformans, Histoplasma capsulatum, VZV, Listeria monocytogenes, and the like
  • Recent sick contacts raise concern for respiratory viruses
• In adults, the most common symptoms of aseptic meningitis are headache (99%), nausea or vomiting (75%), neck stiffness (50%), photophobia (46%), malaise (35%), and respiratory symptoms (11%)³
• In children, the most common symptoms are fever (87%), nausea or vomiting (63%), headaches (60%), respiratory symptoms (31%), photophobia (27%), stiff neck (24%), and malaise (7%)³

Physical Examination

• Fever is more commonly seen in children (87%) than adults (23%)³
• Nuchal rigidity is seen more frequently in adults (31%) than in children (12%)
• More subtle signs of CNS/meningeal irritability may be more common than frank nuchal rigidity. These may be particularly important to note in infants and younger children who are unable to verbalize symptoms
  • Infants may be irritable and fussy
  • Pain worse with movement: infants may cry more when picked up or moved, children may be reluctant to move, patients may resist neck flexion
  • Bulging fontanel may be present in infants
  • In infants and children, photophobia may manifest as crying or turning away from light. Photophobia may be indicative of increased intracranial pressure
  • Brudzinski sign (knees and hips bending with neck flexion) and Kernig sign (resistance/pain when knee is flexed to a 90° angle and slowly straightened) have very low sensitivity (~5%) for meningitis and may not be present¹⁷
  • Jolt accentuation (headache exacerbated by rotating head horizontally 2 or 3 times per second) has fair sensitivity (65.3%) and specificity (70.4%) for meningitis¹⁸
• The majority of patients with aseptic meningitis present with a normal Glasgow Coma Scale score and a normal neurologic exam³
  • The presence of altered mental status, focal neurologic deficits, or seizures raises concern for bacterial meningitis, brain abscess, and/or viral encephalitis, and should prompt appropriate urgent evaluation and treatment²
  • Although mild and more subtle presentations favor diagnosis of viral meningitis over bacterial meningitis, bacterial meningitis and viral meningitis cannot be reliably distinguished based on clinical findings alone and LP for CSF analysis is generally recommended when meningitis is suspected²
• Findings suggestive of specific meningitis etiologies
  • Peripheral facial palsy and/or erythema migrans rash should raise the possibility of Lyme meningitis in the appropriate endemic region and season
  • A maculopapular rash can be seen in several viral etiologies (eg, enterovirus, parechoviruses, WNF)
  • A dermatomal vesicular rash should raise the possibility of VZV meningitis
  • A petechial rash may be seen in bacterial meningitis (eg, Neisseria meningitides) or in rickettsial diseases
  • Oral thrush or cervical adenopathy should suggest concomitant AIDS infection
  • Genital ulcers may be seen in patients with HSV meningitis
  • Parotitis should raise suspicion of mumps meningitis

Laboratory Tests

CSF Testing

• Obtain the following studies¹²¹⁹:
  • Opening pressure
  • Cell count and differential
  • Glucose concentration
  • Protein concentration
  • Gram stain and bacterial culture
  • PCR testing
    • PCR (singleplex or multiplex) for the most common viral etiologies (eg, enterovirus, human parechovirus, HSV-1, HSV-2, VZV) should be obtained when viral meningitis infection is suspected. Use of multiplex PCR for viral testing is increasingly common
    • Viral PCR assays are generally highly sensitive and specific. Example findings of diagnostic accuracy reported in studies include:
      • Enterovirus singleplex²⁰: 99% specificity, 96% sensitivity
      • Human parechovirus singleplex²¹: 100% specificity, 100% sensitivity
      • HSV-1/HSV-2²²: 97.1% specificity, 98.9% sensitivity
    • PCR for the most common bacterial meningitis etiologies can be performed to complement Gram stain and bacterial culture in excluding bacterial meningitis. Use of multiplex PCR for bacterial testing is increasingly common
    • Although PCR for bacterial organisms has excellent test performance (greater than 90% sensitivity and specificity for tested organisms), Gram stain and culture remains the gold standard for bacterial meningitis diagnosis, as even multiplex PCR assays are not comprehensive for all potential bacterial meningitis pathogens, and culture is necessary for antibiotic sensitivity testing²³
    • Multiplex PCR has the advantage of being rapid, requires as little as 0.2 cc of CSF, and can simultaneously evaluate for multiple common viral and bacterial causes of meningitis
    • The most commonly used multiplex PCR array for meningitis/encephalitis evaluates for the presence of 7 viruses (CMV, enterovirus, HSV-1, HSV-2, HSV-6, human parechovirus, VZV), 6 bacteria (Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae), and 1 yeast (Cryptococcus); meta-analyses have reported overall sensitivity of approximately 90% and specificity of approximately 97% for the panel²⁴²⁵
  • WNV immunoglobulin M during the endemic months (June to October)
  • Consider testing for other endemic viruses with the appropriate travel history (eg, Toscana virus, Dengue, Zika, Tick-borne encephalitis)¹
  • Borrelia burgdorferi antibodies in endemic areas during the summer or fall
  • CSF VDRL (Venereal Disease Research Laboratory) test for syphilis in patients with recent high risk sexual exposure
  • Acid-fast bacilli and fungal cultures in subacute or chronic meningitis if risk factors or immunosuppression is present. CSF Mycobacterium tuberculosis PCR and CSF fungal antigen tests (eg, Cryptococcus, Coccidioides) are available and can be considered depending on clinical suspicion
  • Metagenomic sequencing is a novel tool that has been used successfully in identifying etiologies of meningitis and encephalitis¹
• CSF analysis and interpretation²:
  • CSF analysis can help differentiate between different infectious causes of meningitis and help narrow the differential diagnosis while awaiting CSF cultures and molecular studies
  • Typical CSF findings for different kinds of meningitis are summarized in Table 1

Table 1. CSF analysis in meningitis.

	Opening pressure	Cell count (cells/mm3)	Predominant cell type	Glucose	Protein
Viral	Normal	Less than 1000	Lymphocytes	Normal	Normal to high
Bacterial	Elevated	Often greater than 1000	Neutrophils	Low	High
Fungal	Elevated	Variable	Lymphocytes	Normal to low	Normal to high
Tuberculosis	Normal or elevated	100 to 500	Lymphocytes	Low to very low	High to very high

Caption: From Bystritsky RJ et al. Infectious meningitis and encephalitis. Neurol Clin. 2022;40(1):77-91. Figure 2.

Blood Testing¹²¹⁹

• Besides obtaining CSF studies, patients should undergo a CBC that typically shows a normal serum leukocyte count
• Blood cultures (for the exclusion of bacterial infection) should be obtained as soon as possible before the administration of antibiotic therapy
• Procalcitonin and CRP (C-reactive protein) may aid clinicians in differentiating viral from bacterial meningitis²⁶²⁷²⁸
  • Serum procalcitonin and CRP levels are generally higher in bacterial meningitis compared with viral meningitis
  • Various meta-analyses have reported that elevated serum procalcitonin has high diagnostic accuracy in distinguishing between bacterial and viral etiologies of meningitis. Optimal diagnostic threshold is unclear, with widely varying cutoff values used in studies; 0.5 ng/mL is frequently used
  • Similar trends can be seen for CRP, but accuracy is much lower compared with serum procalcitonin assay
• Adults with aseptic meningitis should undergo HIV testing but only approximately 50% get tested in clinical practice²⁹
• Arboviral serologies (eg, WNV) should be sent during endemic seasons¹³
• Lyme disease (ie, Borrelia burgdorferi) serologies should be done in endemic areas during the summer and fall
• Treponema pallidum serologies should be ordered in patients with recent high-risk sexual exposure (in addition to CSF VDRL)
• Additional testing for fungal infection (eg, serologies, [1,3]-beta-D-glucan) depending on clinical suspicion

Imaging Studies

• Screening head CT scan¹⁹³⁰
  • The Infectious Diseases Society of America recommends a screening head CT scan before LP in adults with suspected meningitis who have 1 or more of the following risk factors:
    • Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid-organ or hematopoietic cell transplantation)
    • History of CNS disease (mass lesion, stroke, or focal infection)
    • New onset seizure (within 1 week of presentation)
    • Papilledema
    • Abnormal level of consciousness
    • Focal neurologic deficit
  • If none of these risk factors are present, patients should promptly undergo blood cultures and LP and start empiric treatment for meningitis while awaiting results of CSF studies
  • If any of the risk factors are present, patients should get blood cultures and start empiric treatment for meningitis while awaiting a noncontrast CT scan of the head. If the CT shows no contraindications for LP (eg, mass edema with shift), then CSF should be obtained
  • Of note, even for the patients who do undergo cranial imaging in this setting, imaging is generally normal or only shows meningeal enhancement and does not impact clinical decision-making

Diagnostic Procedures

• LP to obtain CSF for analysis is integral for evaluation. Inability to obtain LP should not delay treatment if there is any concern for bacterial meningitis; delay in antibiotic administration increases morbidity and mortality¹⁹

Differential Diagnosis

• Differentiating between bacterial and aseptic meningitis has major implications for clinical management; important infectious categories of aseptic meningitis include viral meningitis, tuberculous meningitis, Lyme meningitis, syphilitic meningitis, and fungal meningitis

Table 2. Differential Diagnosis: Aseptic meningitis.

Condition	Description	Differentiated by
Bacterial meningitis	Most common organisms include: Streptococcus pneumoniae Neisseria meningitidis Listeria monocytogenes Haemophilus influenzae Staphylococcus aureus (with concomitant endocarditis) Gram-negative bacilli (in disseminated Strongyloidiasis)	Very acute presentation (usually less than 24 hours after symptoms develop); presentation may be fulminant Fever typically present on admission Altered mental status, focal neurologic deficits, and seizures more common in bacterial meningitis compared with aseptic meningitis Petechial rash may be seen (eg Neisseria meningitides) Lab findings231Elevated serum WBC count, often greater than 10.0 × 109/LElevated CSF cell count, especially if leukocyte counts are greater than 2000 cells/mm3 or granulocyte counts are greater than 1180 cells/mm3Elevated CSF protein, especially if greater than 2.2 g/LLow CSF glucose, especially less than 1.9 mmol/L+ CSF Gram stain+ CSF culture or PCR for bacteria+ Blood cultures
Viral meningitis	Most common viruses include enterovirus, herpes viruses, and arboviruses	Clinical presentation, epidemiologic features, and physical exam may suggest specific viral etiology Potential historical clues include mosquito/tick bites (arboviruses), seasonality (WNV), recent travel (endemic viruses), sexual exposures (HSV), sick contacts (respiratory viruses) Neurologic exam generally normal and mentation intact. Milder, non-toxic, and less fulminant presentations generally favor viral meningitis over bacterial meningitis, though there is presentation overlap. Presence of altered mental status, focal neurologic deficits, seizures, papilledema/frank signs of increased intracranial pressure increase likelihood for more malignant entities such as bacterial meningitis, brain abscess, and viral encephalitis Sensitivity of “classic” meningitis findings such as nuchal rigidity, Brudzinski sign, and Kernig sign is low. Other more subtle findings of CNS/meningeal irritation may include general irritability and fussiness, pain worse with movement (infants/children may cry when moved, patients may resist passive movement), and jolt accentuation Exam findings may suggest specific viral etiologies (eg, dermatomal vesicular rash in VZV, genital ulcers in HSV, maculopapular rash in several viral etiologies) CSF with negative Gram stain, culture, and bacterial studies + viral testing (CSF PCR, CSF serology, or blood serology)
Tuberculous meningitis	Mycobacterium tuberculosis is causative organism	Lancet consensus scoring system3233 can help differentiate tuberculous meningitis from meningitis caused by other etiologies (bacterial, fungal, viral, and unknown). Scoring system uses combination of clinical criteria, CSF criteria, imaging criteria, and evidence of tuberculosis elsewhere to establish case definition for tuberculous meningitis Symptom duration greater than 5 days and evidence of tuberculosis elsewhere (eg, chest radiograph consistent with active TB, positive AFB culture, positive TB PCR) strongly support diagnosis + CSF for AFB staining/culture + CSF PCR for Mycobacterium tuberculosis
Lyme meningitis	Borrelia burgdorferi is causative organism	Presentation in endemic areas and season, history of tick bite, erythema migrans, and/or facial palsies Aseptic meningitis with + CSF or serum antibodies for Borrelia burgdorferi The “Rule of 7s” classifies patients at low risk for Lyme meningitis when all the following 3 criteria are met34:  1) Less than 7 days of headache  2) Less than 70% CSF mononuclear cells  3) Absence of seventh or other cranial nerve palsy
Syphilitic meningitis	Treponema pallidum is causative organism	Acute meningitis with macular rash involving palms and soles, recent high-risk sexual exposure Lab findings:+ Treponema pallidum antibodies+ Serum RPR+ CSF VDRL
Fungal meningitis	Common organisms include Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis	Subacute to chronic meningitis, immunosuppressed patient (eg, AIDS, solid organ transplant, cirrhosis) Lab findings23135:High opening pressureCSF glucose less than 45 mg/dLCSF protein greater than 100 mg/dL+CSF fungal smear/culture+CSF cryptococcal antigen in cryptococcal disease+CSF and serum fungal antigen/antibody testing for other fungal etiologies+Serum 1,3-beta-D-glucan in invasive fungal disease
Parasitic meningitis36	Meningitis due to parasites is rare in the United States but more common in endemic regions. Causative organisms include Angiostrongylus cantonensis, Gnathostoma spinigerum, and Baylisascaris procyonis (racoon roundworm)	History of travel to endemic regions (angiostrongyliasis, gnathostomiasis, other helminthic infections) or raccoon exposure (baylisascariasis) Lab findings:Eosinophilic meningitis (10 or more eosinophils/mm3 or eosinophilia of at least 10% of total CSF leukocyte count) typically present+CSF antibodies, larvae in CSF (rare) in angiostrongyliasis and gnathostomiasis+Larvae on brain biopsy (baylisascariasis and other helminthic infections)
Aseptic meningitis due to malignancy (neoplastic meningitis)3637	May result from metastatic spread of solid tumors (most frequently adenocarcinoma and most commonly breast, lung, and melanoma), leptomeningeal involvement of leukemia or lymphoma, or primary brain tumor	Typically established diagnosis of malignancy with known potential for leptomeningeal involvement; widely disseminated and progressive systemic disease is common at time of meningitis presentation Typically multifocal neurologic disease affecting cerebral function, cranial nerves, and/or spinal cord and roots CSF profile variable; increased opening pressure (greater than 200 mm of H2O), elevated protein (greater than 50 mg/dL), and decreased glucose (less than 60 mg/dL) are suggestive Imaging (usually MRI with contrast for the brain) may demonstrate focal brain lesions, focal enhancing regions, and/or evidence of malignancy elsewhere in the body Positive CSF cytology or flow cytometry is diagnostic Tissue biopsy of meninges may be diagnostic
Drug-induced aseptic meningitis363839	Rare adverse drug reaction reported in case reports; may result from direct meningeal irritation (ie, intrathecal drugs) or as an immunologic hypersensitivity reaction to systemic administration Main culprit drugs reported in case reports include IVIG, NSAIDs, intrathecal/intraventricular drugs, vaccines, and antibiotics	Diagnosis of exclusion when aseptic meningitis is present, infectious workup is negative, and history is suggestive CSF profile can be variable Rapid occurrence upon initiation of suspect drug, rapid improvement upon cessation of suspect drug, and recurrence upon rechallenge with suspect drug are all suggestive
Aseptic meningitis secondary to SID40	Rare manifestation of SID such as SLE, Sjögren syndrome, Behçet disease, or sarcoidosis	Largely a diagnosis of exclusion when aseptic meningitis is present, infectious workup is negative, and SID is present May have known diagnosis of potentially causative SID at time of presentation with aseptic meningitis; aseptic meningitis may also be initial presentation of SID Patient fulfills standardized diagnostic criteria for diagnosis of SID (eg, SLE, Sjögren syndrome, Behçet disease, or sarcoidosis), if not pre-existing diagnosis at presentation Neurologic signs (focal deficits, delirium, seizure) and extraneurologic signs (uveitis, arthralgia, aphthous ulcers, skin lesions) more common in SID compared with idiopathic aseptic meningitis CSF profile can be variable; high protein and low glucose more frequently associated with SID compared with idiopathic aseptic meningitis Abnormal brain MRI findings (T2-weighted high signal lesions, pseudotumors, arachnoiditis, myelitis, vasculitis) more common with SID compared with idiopathic aseptic meningitis
Idiopathic aseptic meningitis	No specific etiology identified	Diagnosis of exclusion; meets criteria for aseptic meningitis with no specific cause identified

Caption: AFB, acid-fast bacilli; CNS, central nervous system; CSF, cerebrospinal fluid; HSV, herpes simplex virus; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal antiinflammatory drugs; PCR, polymerase chain reaction; RPR, rapid plasma reagin; SID, systemic inflammatory disorders; SLE, systemic lupus erythematosus; TB, tuberculosis; VDRL, Venereal Disease Research Laboratory; VZV, varicella-zoster virus; WBC, white blood cell; WNV, West Nile virus.

Treatment

Approach to Treatment

• Distinguishing bacterial meningitis from aseptic meningitis is a significant diagnostic challenge with important management implications⁴¹
  • Aseptic meningitis and bacterial meningitis cannot be reliably distinguished from history and physical alone
  • Additionally, reported sensitivity of CSF Gram stain varies widely, with the vast majority of patients presenting with meningitis having a negative Gram stain result. Many patients with aseptic meningitis are started on empiric antibiotics while awaiting CSF cultures to exclude bacterial meningitis
  • Various clinical prediction rules have been developed to help stratify risk of bacterial meningitis in patients presenting to the emergency department.³¹³⁵ Such tools generally use a combination of clinical and CSF findings to identify patients at low risk for bacterial meningitis
    • Adults³¹:
      • In 1 prediction rule recently developed and validated for use in adults, the presence of any of the following findings on admission is considered high risk:
        • Serum WBC count greater than 10.0 × 10⁹/L
        • CSF WBC count greater than 2000/mm³
        • CSF granulocyte counts greater than 1180/mm³
        • CSF protein levels greater than 2.2 g/L
        • CSF glucose levels less than 1.9 mmol/L
        • Fever on presentation
      • The absence of any of these findings is considered low risk
      • Validation studies have demonstrated 99.6 to 100% sensitivity of this risk tool (for “low risk” patients) in excluding bacterial meningitis
    • Children: the BMS (Bacterial Meningitis Score) is most commonly used⁴²
      • BMS uses the following variables:
        • Positive CSF Gram stain
        • CSF absolute neutrophil count of 1000/mm³ or greater
        • CSF protein levels of 0.8 g/L or greater
        • Peripheral blood absolute neutrophil count greater than 10.0 × 10⁹/L
        • Seizure at presentation
      • The absence of any of these findings is considered very low risk for bacterial meningitis; likelihood of bacterial meningitis increases with higher number of positive findings
      • Sensitivity is 99.2% and negative predictive value is 99.7% for “very low risk” designation⁴³
      • Score should not be used in high-risk patients (eg, aged under 3 months, toxic-appearing, critically ill, immunosuppressed, history of ventriculoperitoneal shunt or recent neurosurgery, antibiotics within 72 hours of LP, high suspicion of bacterial infection); empiric treatment is generally warranted in such cases
• For patients deemed to be low risk (very low risk if BMS used) for bacterial meningitis after initial clinical assessment, expectant management and deferral of empiric antibiotics may be reasonable. Such patients should be managed supportively with close follow-up (eg, 24 hours) and strict return precautions if there is clinical worsening
• In patients with ongoing concern for bacterial meningitis or encephalitis, intravenous dexamethasone and antibiotics should be initiated while awaiting CSF cultures; empiric IV acyclovir is indicated if there is concern for HSV or VZV infection²⁴¹
• Once bacterial meningitis has been excluded with CSF studies and cultures, or a nonbacterial etiology (eg, viral) has been confirmed, antibacterials can be stopped²⁴¹
• If a specific infectious etiology is identified, antimicrobial therapy can be tailored accordingly. Antivirals are used for HSV, VZV, and CMV infections, but antiviral therapies are not available for most other types of viral infections. The management of entities such as tuberculous meningitis and fungal meningitis are complex and best managed in consultation with an infectious disease specialist²
• In patients deemed to have aseptic meningitis secondary to a noninfectious cause, management is directed at the underlying etiology (eg, discontinuation of culprit medication for drug-induced cases, cancer or SID (systemic inflammatory disorders)-focused treatment for cases secondary to these conditions)
• Supportive care is the mainstay of treatment for most cases of aseptic meningitis (especially if no antimicrobial therapies are indicated or available) and include IV fluids, analgesics, antipyretics, antiemetics, and other such supportive care medications

Drug Therapy

Empiric Antibiotic Therapy

• Empiric therapy for potential bacterial meningitis should be selected based on likely infectious agents based on age, risk factors, and CSF Gram stain results (Table 3)
• If there is concern for HSV or VZV infection, acyclovir 10 mg/kg IV every 8 hours can be initiated, pending results from CSF studies²⁴⁴
• Pain management, intravenous fluids, antipyretics, and antiemetics should be used as needed for symptomatic therapy

Table 3. Empiric antibiotics for bacterial meningitis by age group and comorbidities.

Patient category	Common bacterial pathogens	Antimicrobial therapy
Younger than 1 month	Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes	Ampicillin plus Cefotaxime or an aminoglycoside
1 to 23 months	Streptococcus pneumoniae, Neisseria meningitidis, Streptococcus agalactiae, Escherichia coli	Vancomycin plus A third-generation cephalosporin (ceftriaxone or cefotaxime)
2 to 50 years	Neisseria meningitidis, Streptococcus pneumoniae	Vancomycin plus A third-generation cephalosporin
Older than 50 years	Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, Gram-negative bacilli	Vancomycin plus Ampicillin plus A third-generation cephalosporin
Immunocompromised	Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, Staphylococcus aureus, Salmonella species, Gram-negative bacilli	Vancomycin plus Ampicillin plus A third-generation cephalosporin, cefepime, or meropenem

Caption: Data from Tunkel AR et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-1284; van de Beek D et al. Community-acquired bacterial meningitis. Lancet. 2021;398(10306):1171-1183; and Hasbun R. Progress and challenges in bacterial meningitis: a review. JAMA. 2022;328(21):2147-2154.

Adjunctive Dexamethasone

• Reduces inflammation in CSF and can improve clinical outcomes in bacterial meningitis⁴¹
• Mortality benefit in Strep pneumoniae meningitis in adults and reduces hearing loss in Haemophilus influenzae meningitis in children²⁴¹
• Should be administered before or around the time of antibiotic initiation in adults and considered for pediatric patients aged 6 weeks or older presenting with potential bacterial meningitis²
• Usual dosing¹⁹:
  • Adults: 10 mg IV every 6 hours
  • Infants, children, and adolescents: 0.15 mg/kg IV every 6 hours
• Can be discontinued once bacterial meningitis is ruled out or evaluation reveals causative pathogen (eg, viruses) for which there is no evidence of benefit²

Specific Therapies

• Once a specific etiology of aseptic meningitis is identified, antimicrobial therapy can be tailored accordingly. Antivirals are used for HSV, VZV, and CMV infections, but antiviral therapies are not available for most other types of viral infections

Follow-Up

Monitoring

• Therapeutic drug monitoring is essential for patients treated with antibiotics
• Depending on the empiric antibiotic regimen, routine lab monitoring may be necessary to monitor for treatment-related complications (eg, monitor renal function due to risk of acute kidney injury with acyclovir)
• Aseptic meningitis is generally benign, self-limiting, and has a good prognosis.¹³ Though many patients with meningitis syndrome are hospitalized for intravenous antibiotics, patients with clinical improvement and exclusion of treatable (eg, bacterial) infection are generally stable for discharge and outpatient management

References