Aseptic meningitis is a term used to define inflammation of the brain meninges due to various etiologies with negative cerebrospinal fluid (CSF) bacterial cultures. It is one of the most common, usually benign, inflammatory disorders of the meninges. Viruses are a common etiology, however, there are many other infective and non-infective causes. Therefore, the terms aseptic meningitis and viral meningitis are not interchangeable. Presentations may differ based on the etiology and the immune status of the host. Patients with deficient humoral immunity are at a higher risk of negative outcomes, including neonates and patients with agammaglobulinemia.
Etiology of aseptic meningitis can be categorized into infectious causes and non-infectious causes. Infectious causes include viruses, bacteria, fungi, and parasites. Non-infectious causes include post-infection/vaccination inflammation, drugs, systemic diseases, and neoplastic disorders, to name a few. The cause can ultimately only be identified in 30% to 65% of the cases. The most common cause is viral, most often the enteroviruses, followed by herpes simplex virus-2 and varicella-zoster. Other associated viruses include respiratory viruses (adenovirus, influenza virus, rhinovirus), mumps virus, arbovirus, HIV, and lymphocytic choriomeningitis.
Bacterial causes may include partially treated meningitis, parameningeal infection, Mycoplasma pneumoniae, endocarditis, Mycobacterium tuberculosis, Borrelia burgdorfi, ehrlichiosis, Brucella, Treponema pallidum, Bartonella henselae, and leptospirosis. Rocky Mountain spotted fever and typhus are common rickettsiae on the differential. 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.
Non-infectious sources include post-infection or post-vaccination of rubeola, rubella, varicella, variola, yellow fever vaccine, rabies vaccine, pertussis vaccine, and the influenza vaccine. Drugs including non-steroidal anti-inflammatory drugs (NSAIDs), isoniazid, azathioprine, intrathecal medications (methotrexate, cytosine arabinoside), antibiotics (trimethoprim-sulfamethoxazole, amoxicillin), allopurinol, carbamazepine, sulfasalazine have all been associated with aseptic meningitis.
Systemic diseases that can cause aseptic meningitis include Behcet disease, Vogt-Koyanagi syndrome, sarcoidosis, leptomeningeal cancer, collagen vascular disorders, and post-transplantation lymphoproliferative disorder.
Patients may present with a myriad of symptoms including fever, headache, photophobia, and stiff neck, but non-specific symptoms like irritability, myalgia, sore throat, and abdominal pain, have also been described. No single aspect of clinical history has high enough sensitivity or specificity for definitive diagnosis. A comprehensive history should include sick contacts, recent travels, substance abuse, sexual history, preceding or concomitant infections, and recent use of medications. Drug-induced aseptic meningitis has been associated with 4 groups of drugs: nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, intravenous immunoglobulins (IVIGs), and OKT3 monoclonal antibodies. For neonates, birth history including premature at birth, maternal illnesses, 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.
Physical exam findings may differ slightly with the age group. Neonates and infants of less than three months of age may have a bulging anterior fontanelle and irritability. 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 cause. Most of the adults will either have a fever, headache, nuchal rigidity, or altered mental status, thus an absence of all of these symptoms should prompt a clinician to consider an alternative diagnosis.
Primary evaluation should include labs and tests to look for alternative causes of the presenting symptoms. If there is clinical suspicion for meningitis, a lumbar puncture (LP) should be performed for definitive diagnosis. There has been a rare association with performing a lumbar puncture and cerebral herniation. If there is suspicion for elevated intracranial pressure due to a space-occupying lesion and/or inflammation, consider obtaining a computed tomography (CT) scan of the head prior to the LP. This may provide an alternative diagnosis and make the LP unnecessary. CT scan is not usually necessary in neonates and infants with open fontanelles. 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 CNS disease, immunocompromised state, altered mental state, seizure within 1 week of presentation, and neurological deficits.
On CSF analysis, obtain cell count, glucose, gram stain, protein, culture, bacterial PCR (usually includes N. meningitides, S. pneumonia, H. influenza), and selected viral PCR studies (based on clinical presentation). Other tests to consider include syphilis serology, tuberculosis testing, serum human immunodeficiency virus (HIV) testing. Viral CSF PCR can detect enterovirus, HSV-1, HSV-2, varicella-zoster, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and arbovirus.
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%).
Initially, it may be difficult to differentiate between bacterial and other types of meningitis. Begin antimicrobial therapy immediately if bacterial meningitis is suspected. If a patient is critically ill or imaging and lumbar puncture will be delayed, start antimicrobials immediately and initiate respiratory droplet isolation precautions until the etiology is identified. If HSV and/or varicella-zoster is suspected, start therapy with acyclovir. Steroid therapy prior to antibiotics should be considered.
Once the diagnosis of aseptic meningitis has been established, the patient can often be discharged home with the exception of the elderly, immunocompromised, and children with pleocytosis. If discharging the patient, home care 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.
All patients will need pain management and fever control. Antipyretics such as acetaminophen and ibuprofen can be used.
The signs and symptoms of aseptic meningitis are often vague and nonspecific, so the differential is broad. The headache and fever, being some of the most common symptoms, drive the differential.
Bacterial meningitis is the most concerning and common alternative cause and should be the default diagnosis until it is ruled out. Intracranial hemorrhage, especially subarachnoid hemorrhage should be considered in the appropriate patient. Neoplastic disorders (leukemia, tumors of the brain), other types of headaches (migraine), inflammation of brain structures (brain abscess, epidural abscess) should also be considered.
Fever from almost any source can give headache and neck stiffness. Urinary tract infections and pneumonia can present with headache, body aches, and fever. Thus, an exhaustive search for infectious sources is part of every workup.
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 headache, muscle aches, weakness, and fever.
The broader differential includes anemia, which classically causes headaches and weakness. The list includes carbon monoxide exposure, child abuse, tick-borne illness, and TB, which demonstrates the breadth of possibilities.
Prognosis varies with the cause. Viruses are the most common cause of aseptic meningitis and have low rates of morbidity and mortality. Most patients will recover fully within 5 to 14 days, with fatigue and lightheadedness in some patients. Others, including the herpes viruses, may not be as benign. Tuberculosis meningitis can cause significant morbidity and mortality if not diagnoses and treated.
Aseptic meningitis can cause seizures, even status epilepticus. Treat if seizures occur, do not treat prophylactically.
A variable component of encephalitis may occur 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.
The focus should be on preventing the spread of virulent infectious causes. Viral meningitis and many other infectious causes’ spread can be prevented with strict isolation. Appropriate hand hygiene must be practiced, 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. For populations living or visiting endemic areas, arboviral vaccines are also available.
Fever, headache, nuchal rigidity, and/or altered mental status raise concerns for meningitis. However, these symptoms may be associated with other diagnoses. A thorough history and physical exam may indicate that the patient has meningitis. Because meningitis represents a dangerous infectious disease, communication with all levels of the staff is essential. Ensuring the proper isolation and PPE to prevent spread to the medical team or other patients is of paramount importance and should be of primary concern. Once the diagnosis of aseptic meningitis is established, and more concerning diagnoses are excluded, then these precautions can be discontinued.
A lumbar puncture is necessary to confirm the diagnosis. A lumbar puncture may be performed by an emergency medicine clinician, by an internist on an inpatient floor, or by an interventional radiologist in an IR suite. Laboratory expertise is necessary to analyze the specimen. The most common etiology of aseptic meningitis is a virus that can be diagnosed with various available PCR studies, which, unfortunately, are underutilized. [Level 3]
Depending on the cause of meningitis, other consultation services need to be involved. For instance, if a patient has tuberculosis meningitis, an infectious disease specialist might be needed 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 may be of assistance. The nurses play an important role by administering the needed medications, checking vital signs, and maintaining isolation of the patient.
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