Continuing Education Activity

Aseptic meningitis is an umbrella term for all of the causes of inflammation of the brain meninges that have negative cerebrospinal fluid (CSF) bacterial cultures. It is one of the most common inflammatory disorders of the meninges. This activity reviews the etiology, clinical features, evaluation, treatment, and prognosis of aseptic meningitis, and highlights the role of an interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of aseptic meningitis.
• Outline the history and physical findings of patients with aseptic meningitis.
• Describe the management options available for aseptic meningitis.
• Review interprofessional team strategies for improving care coordination and communication to advance the treatment of aseptic meningitis and improve outcomes.

Introduction

Aseptic meningitis is a term used to define inflammation of the brain linings, called meninges, due to various etiologies with negative cerebrospinal fluid (CSF) bacterial cultures. Many studies and books determine it by showing CSF pleocytosis of more than five cells/mm3.[1]  It is one of the most common, usually benign, inflammatory disorders of the meninges.[2]

Viruses are the most common etiology for aseptic meningitis, but other causes can be divided into two main categories: infectious and non-infectious.[1][2] This fact leads us to state that aseptic meningitis and viral meningitis are not interchangeable terms. Manifestations may differ based on the underlying cause and the host's immune status, placing patients with deficient humoral immunity at a higher risk of negative outcomes, including neonates and patients with agammaglobulinemia.[1][2][3]

Etiology

The etiology of aseptic meningitis can be categorized into infectious and non-infectious. Ultimately, the exact etiology can only be identified in 30-65% of the cases, despite all the diagnostic advancements made to date.[4] The rest of the cases of unknown etiology are labeled "idiopathic."[1]

In terms of infectious causes, these include viruses, bacteria, fungi, and parasites, the most common agent being viral.[2] More than half the cases encompassed enteroviruses (Coxsackie and ECHO viruses), followed by herpes simplex virus-2, West Nile virus, and varicella-zoster.[2][4] Other associated viruses include respiratory viruses (adenovirus, influenza virus, rhinovirus), mumps virus, arbovirus, HIV, and lymphocytic choriomeningitis.[2][4][5]

Bacterial, fungal, and parasitic infectious are less common than viral. Bacterial causes of aseptic meningitis may include partially treated meningitis, parameningeal infection (such as epidural abscess and mastoiditis), Mycoplasma pneumoniae, endocarditis, Mycobacterium tuberculosis, Treponema pallidum, and leptospirosis. Fungal causes may include Candida, Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitides. Parasites causing aseptic meningitis include Toxoplasma gondii, naegleria, neurocysticercosis, trichinosis, and Hartmannella.[6][7]

For the non-infectious causes of aseptic meningitis, etiologies can be classified into three main groups:[1] 

1. Systemic diseases with meningeal involvement (e.i sarcoidosis, Behçet's disease, Sjögren's syndrome, systemic lupus erythematosus and granulomatosis with polyangiitis)
2. Drug-induced aseptic meningitis (most commonly reported with non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics (sulfamides, penicillins), intravenous immunoglobulin, and monoclonal antibodies)
3. Neoplastic meningitis (that could be related to either solid cancer metastasis or lymphoma/leukemia.

Aseptic meningitis secondary to certain vaccines has also been described, such as measles, mumps, rubella vaccine primarily,[8] but also varicella vaccine, yellow fever vaccine, rabies vaccine, pertussis vaccine, and the influenza vaccine.[9][10] Some even describe it after vaccination with the meningococcal vaccine.[11] 

Epidemiology

In general, the annual incidence is unknown due to underreporting.[7] It occurs at all ages but is more common in children than adults. [2] It is thought that the overall incidence is 11 per 100,000 people per year in the US, 7.5 per 100,000 adults, three times more likely to occur in males than females, without any particular preference for age or racial difference.[2] The condition is responsible for 26,000 to 42,000 hospitalizations per year in the US.[2] Also, European studies have shown 70 per 100,000 children younger than one year, 5.2/100,000 children one to fourteen years of age, and 7.6 per 100,000 in adults.[7]

In a study done on children in South Korea, the age distribution was relatively uniform, with a higher incidence in children less than one year old and aged 4 to 7. The male-to-female ratio was 2 to 1.[12] Although aseptic meningitis is a year-round condition, they have marked peaked times of the year with a higher incidence of aseptic meningitis during the summer months in temperate climates.[2][7][12]

History and Physical

No single aspect of clinical history has high enough sensitivity or specificity to lead us to a definitive diagnosis. A comprehensive and thorough history should always be taken in these patients since the differential is so broad. History taking should include sick contacts, recent travels, substance abuse, sexual history, preceding or concurrent infections, and recent use of medications keeping in mind drug-induced aseptic meningitis.[2][6]

• For neonates, birth history including premature birth, maternal illness, high serum white blood cell count, low hemoglobin (<10.7mg/dL), and the onset of symptoms before one week of age warrant an early and aggressive workup and management.[2][13]
• When tackling the clinical presentation of patients, it is essential to differentiate how children may present compared to adults.
• Adults can present with a myriad of symptoms and are more likely to complain of headaches, nausea, vomiting, malaise, weakness, stiff neck, photophobia, or even altered mental status.[2][6] 
• In children, symptoms at presentation seem less specific, consisting of fever, coexisting respiratory illness, rash and irritability.[2][6] Neonates and infants less than three months of age may have a bulging anterior fontanelle and irritability.[2]

Nuchal rigidity (sensitivity 70%) and fever (sensitivity 85%) are common physical findings in both children and adults. Kernig and Brudzinski's signs have a high specificity of 95%, but the sensitivity of 5% limits their use. There may be other associated findings depending on the underlying cause.[2][3]

Evaluation

Over the years, even though up to two-thirds of the aseptic meningitis cases are of unknown etiology, new diagnostic tools have appeared that have aided in identifying pathogens, such as polymerase chain reaction (PCR) and next-generation sequencing. In the same way, significant advancements have been made in determining and diagnosing autoimmune or paraneoplastic neurological syndromes.[2]

Primary evaluation should include laboratory testing to look for alternative causes of the presenting symptoms. These tests include complete blood counts (CBC) (including platelet count), erythrocyte sedimentation rate (ESR), and IgM and IgG for enterovirus, adenovirus, EBV, and HSV.[2]

A lumbar puncture (LP) should be performed to collect cerebrospinal fluid (CSF) to make a definitive diagnosis.[2][3][6]

On CSF analysis, obtain cell count, glucose, gram stain, protein, culture, bacterial PCR (which usually includes N. meningitides, S. pneumonia, H. influenza), and selected viral PCR studies (which should are based on the clinical presentation of the patient). Other tests to consider include syphilis serology, tuberculosis testing, serum human immunodeficiency virus (HIV) testing. Viral CSF PCR can detect enterovirus, Herpes Zoster Virus 1 (HSV-1), HSV-2, varicella-zoster, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and arbovirus.[2][3][6]

Typical CSF results in patients with aseptic meningitis include: Opening pressure either normal (<180 mmH2O) or slightly elevated, glucose normal to mildly decreased, protein normal to mildly elevated (<200mg/dL), cell count of 10-1000 cells per microliter (initially neutrophils (>50%) may predominate with a gradual shift toward lymphocytes (>80%).[2][3][6]

Numerous differences have been found between adults and children concerning their presentation and their laboratory findings.[6]

Adults complain of headache, nausea/vomiting, neck stiffness, malaise, photophobia, and have nuchal rigidity present on exam more than children. Fever, concurrent respiratory illness, and rash are symptoms more common to children.[6] Also, on initial CSF evaluation, adult patients tend to have a higher CSF WBC count and higher CSF protein than the pediatric population. Children also had more CSF neutrophilic pleocytosis than adults, as well as higher leukocyte counts than adults.[3][6]

It is critical to use age-adjusted values for leukocyte counts when interpreting CSF results in neonates and young infants. Neutrophils predominate the CSF in up to 57% of children with this condition, which means that cell type alone cannot be used to discriminate between aseptic and bacterial meningitis in children.[3]

Drug-induced aseptic meningitis, in particular, may have few lab abnormalities, so clinicians have to maintain a high level of suspicion and perform a comprehensive history regarding all medications a patient might be taking and how much.[2][3]

Although differentiation between aseptic and bacterial meningitis can be difficult, some tools have been developed to ease the choice. The Bacterial Meningitis Score has a sensitivity of 99% to 100% and a specificity of 52% to 62% and is the most specific tool readily available at the time. Other laboratory findings such as procalcitonin, serum C-reactive protein, and CSF lactate levels can help discern between aseptic and bacterial meningitis.[3]

Of note: when the time comes for an LP, and there is any suspicion for elevated intracranial pressure due to a space-occupying lesion or inflammation, obtaining a computed tomography (CT) scan of the head before the LP is recommended.[3][14] The CT imaging may provide an alternative diagnosis and make the LP unnecessary. CT scan is not usually necessary in neonates and infants with open fontanelles. The imaging of choice in this age group is head ultrasound.[3][15] Studies have shown that imaging might be safely avoided if all of the following are absent: age greater than or equal to 60, history of central nervous system disease, immunocompromised state, altered mental state, seizure within 1 week of presentation, and neurological deficits.[2][3]

Treatment / Management

Early recognition of the most plausible cause of meningitis is crucial to begin treatment as soon as possible. Initial stabilization of the patient is necessary, and intravenous fluids for 48 hours have been proven beneficial.[3] If bacterial meningitis is suspected, prompt initiation of empiric antibiotics is recommended (broad coverage according to the most plausible pathogens with each age group in pediatrics).[3] Obtaining CSF would be ideal before starting antibiotics. Still, if this will delay treatment or if the patient is critically ill, antimicrobials should come first. The patient should also be placed on droplet isolation precautions until the etiology is identified. If HSV or varicella-zoster (VZV) is suspected, intravenous acyclovir should be added to the empiric treatment.[3]

If the CSF results are more consistent with aseptic meningitis, antibiotics should then be discontinued (keeping in mind the initial presentation of the patient and his clinical status). Viral meningitis (excluding HSV and VZV) management is more supportive care.[3] Specific treatments of different bacterial, fungal, and others are beyond this article's scope but should be considered, as mentioned before, depending on the clinical presentation and the host in question.

Steroids are used as adjunctive therapy to reduce the inflammatory response. Evidence supports the use of dexamethasone 10 to 20 minutes prior to antibiotics or concomitant with their administration, even though the etiology is initially unknown while awaiting culture results.[3] They have been shown to decreased the sequelae (short-term neurologic sequelae and hearing loss), although this is more true about bacterial meningitis.[16]

Repeat LP is unnecessary but should be considered in patients whose clinical status does not improve after 48 hours. 

Once the diagnosis of aseptic meningitis has been established, the patient can often be discharged home except for the elderly, immunocompromised, and children with pleocytosis. When discharging the patient, home care needs should be based on etiology. For instance, patients with diagnosed enterovirus should be advised to practice excellent hand hygiene and avoid sharing food as it is primarily transmitted via the fecal-oral route.[2][3]

Supportive treatment is needed in all patients, including pain management and fever control with antipyretics such as acetaminophen/paracetamol and ibuprofen.

Also, if the meningitis is drug-induced, the drug should be stopped or, if essential, be replaced with a drug not associated with meningeal irritation.[2][3]

Differential Diagnosis

The signs and symptoms of aseptic meningitis are often vague and nonspecific; therefore, the differential is quite broad. The headache and fever, being some of the most common symptoms, drive the differential.[2][7]

Bacterial meningitis is the most concerning and common alternative cause and should be the default diagnosis until ruled out. Intracranial hemorrhage, especially subarachnoid hemorrhage, should be considered in patients with the appropriate clinical presentation. Neoplastic disorders (leukemia, tumors of the brain), other types of headaches (migraine), inflammation of brain structures (brain abscess, epidural abscess) should also be considered.[2][7]

Fever from almost any source can present with headache and neck stiffness as associated symptoms. Urinary tract infections and pneumonia can present with headaches, body aches, and fever. Thus, an exhaustive search for infectious sources is part of every workup.[2][7]

Many of the causes of aseptic meningitis may give most or all of the symptoms but have no meningeal involvement. Viral syndromes, in particular, often give headaches, muscle aches, weakness, and fever.[2][7]

The broader differential includes anemia, which classically causes headaches and weakness. In addition, the list includes carbon monoxide exposure, child abuse, tick-borne illness, and TB, which demonstrates the breadth of possibilities.[2][7]

Prognosis

Prognosis varies with the age of the patient as well as the etiology of meningitis.[6] Viral meningitis is usually a benign condition, and full recovery generally occurs in 5 to 14 days in most patients with only fatigue and lightheadedness as residual symptoms.[2] Other viruses and non-viral meningitis, including the herpes viruses, may not be as benign.[2] Tuberculosis meningitis being a particularly dangerous disease with high morbidity and mortality if not diagnosed and treated promptly.[2][6]

Complications

Aseptic meningitis can be complicated by seizures and progress to status epilepticus. This complication requires treatment, but prophylaxis is not recommended.[2] If bacterial meningitis is suspected and treatment is delayed, neurologic sequelae such as hearing loss could become permanent.[2][6]

A variable component of encephalitis may occur concomitantly with viral meningitis. Sensorineural deafness and aqueductal stenosis, causing hydrocephalus, can result from mumps meningoencephalitis. Hydrocephalus, infarcts, epilepsy, mental regression, neurological deficits, and cranial nerve palsies can be caused by tuberculosis meningitis.[2][6]

Deterrence and Patient Education

Preventing the spread of virulent infectious should be the main focus. Viral meningitis and many other infectious causes' spread can be prevented with strict isolation (usually droplet isolation) and frequent hand washing, especially after diaper changes in children to prevent the spread of enterovirus infections.[2][6] Appropriate hand hygiene is a necessity, and isolation should be adhered to based on the suspected cause. Vaccines are available for those at risk for polio, mumps, measles, mumps, varicella, and rubella and should be given according to the vaccine schedule. For populations living or visiting endemic areas, arboviral vaccines are also available.[2][7][6]

Enhancing Healthcare Team Outcomes

Fever, headache, nuchal rigidity, or altered mental status are symptoms that raise the concern for meningitis. However, these symptoms may be associated with multiple other diagnoses. A thorough history and physical exam are necessary to aid indicate that a patient has meningitis. Because meningitis represents a dangerous infectious disease, communication with all levels of the staff is essential. Ensuring the proper isolation and personal protective equipment (PPE) to prevent spread to the medical team or other patients is paramount and should be of primary concern. Once the diagnosis of aseptic meningitis is established and more concerning diagnoses are excluded, only then can these precautions be discontinued.[2][6]

An LP is necessary to confirm the diagnosis and may be performed by an emergency medicine clinician, an internist on an inpatient floor, or an interventional radiologist in an IR suite. Laboratory expertise is needed to analyze the specimens sent and PCR studies, which help identify the most common etiology (viruses). Unfortunately, these studies are still underutilized.[2][3][6]

Depending on the cause of meningitis, other services need to be consulted. For instance, if a patient has tuberculosis meningitis, an infectious disease specialist may be required to develop the correct medication regimen for the patient, along with a pharmacist. If a patient has meningitis due to malignancy, the oncology team consult is of assistance. The nurses play an essential role by administering the needed medications, monitoring vital signs, and maintaining patient isolation.

Aseptic meningitis is usually a benign condition, but the prognosis can vary with the cause. For better outcomes for the patient, an interprofessional team including clinicians, specialists, PAs and NPs, nurses, and pharmacists is essential.[2][3][6][7]