Bacterial meningitis remains the most dangerous and often rapidly fatal infection. Hence, a timely diagnosis and prompt treatment are key to preventing mortality from this disease. Annual incidence in the United States is 3/100,000 population.
CASE 7-1
A 21-year-old man with no significant past medical history presents with a 1-day history of fever, headache, and rash. Twelve hours earlier he developed a headache and fever. He told his friends from the dormitory where he attends college that he did not feel well and was going to rest. His friends went to check on him a few hours later and found him confused and brought him to the Emergency Department (ED). On physical examination he was obtunded with a fever of 40ºC (104ºF), nuchal rigidity, and a purpuric (non-blanching) rash on his extremities. Fundoscopy showed no papilledema. Which anatomic site of the central nervous system (CNS) is involved?
The brain is surrounded and protected by three connective tissue layers called meninges. These meninges, from superficial to deep, are the dura mater, arachnoid mater, and pia mater (see Figure 7-1).1 The dura mater is made up of outer periosteal layer and the inner meningeal layer. The dural venous sinuses are venous channels located between the periosteal and the meningeal layers of the dura mater. The venous sinuses, in addition to receiving blood from the cerebral, diploic, and emissary veins, receive the cerebrospinal fluid (CSF), drained by the arachnoid granulations. Deeper to the dura is the arachnoid followed by pia mater. Between the arachnoid and the pia mater is the subarachnoid space in which the CSF circulates. CSF is the special ultrafiltrate of plasma that bathes and protects the brain. CSF is produced mainly by the choroid plexus located in the lateral ventricles and the fourth ventricle. The spinal cord is also enveloped in arachnoid, so that CSF covers its surface as well. A specimen of CSF is commonly obtained through a lumbar puncture (LP) performed between the fourth and the fifth lumbar space when meningitis is suspected. The arachnoid granulations around the longitudinal fissure reabsorb CSF into the dural sinuses. Obstruction of CSF flow causes hydrocephalus. The capillaries of the CNS differ from other anatomical areas due to presence of tight junctions linking the endothelial cells. The limited permeability forms a physiologic barrier referred to as the blood–brain barrier (BBB). The BBB protects the brain from toxic substances and pathogens but, on the other hand, also prevents entry of immunoglobulins, complements, and antibiotics.
Meningitis is an inflammation of the arachnoid membrane, the pia mater, and the intervening CSF. The inflammatory process extends throughout the subarachnoid space around the brain and spinal cord.
The organisms most commonly responsible for community-acquired meningitis are Streptococccus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, and Haemophilus influenzae. The etiologic organisms differ based on age, immunity of the host, and predisposing factors (See Table 7-1).
Etiologic Pathogens for Bacterial Meningitis Depending on Risk Factors
| Predisposing Factor | Bacterial Pathogens |
|---|---|
| Age <1 month | S. agalactiae, E. coli, L. monocytogenes |
| Age 1–23 months | S. agalactiae, E. coli, H. influenzae, S. pneumoniae, N. meningitidis |
| 2–50 yrs | S. pneumoniae, N. meningitidis |
| >50 yrs | S. pneumoniae, N. meningitidis, L. monocytogenes |
| Immunocompromised state | S. pneumoniae, N. menigitidis, L. monocytogenes, aerobic Gram-negative bacilli |
| Basilar skull fracture | S. pneumoniae (most common) |
| Nosocomial: associated with neurosurgery, head trauma | Staphylococcus aureus, coagulase-negative staphylococci, aerobic Gram-negative bacilli (including Pseudomonas aeruginosa) |
The bacterial pathogens gain entry into the subarachnoid space via nasopharyngeal colonization, direct extension from a contiguous source, or secondary to bacteremia.2,3 The most common primary sites of infection are the sinuses, middle ear, pulmonary, endocarditis, or gastrointestinal. The bacteria multiply unimpeded in the subarachnoid space due to the BBB that hinders the entry of immunoglobulins and complements, which are key steps for opsonization and resultant phagocytosis of bacteria. The polymorphonuclear (PMN) cells eventually reach the subarachnoid space and release inflammatory cytokines. The lysis of bacterial cells by the PMNs leads to release of bacterial cell wall components, which in turn generates an inflammatory response and leads to the formation of purulent exudate in subarachnoid space. The inflammation damages the BBB allowing entry of serum proteins, increasing the protein levels in the CSF, and alters glucose transport, lowering glucose concentration in the CSF. The inflammation results in obstruction of flow of CSF through the ventricular system and diminishes the resorptive capacity of the arachnoid granulations. Progressive cerebral edema, increased intracranial pressure (ICP), and decreased cerebral blood (CBF) flow lead to irreversible ischemic damage.
Patients with bacterial meningitis classically present with fever, headache, nuchal rigidity, and signs of cerebral dysfunction. However, all the aforementioned signs and symptoms may not be present.4 Clinical presentation may vary based on age, underlying disease state, and etiologic bacterial pathogen. Meningitis can present either as an acute fulminant illness that progresses rapidly in few hours or as a subacute infection that progressively worsens over several days. Nausea, vomiting, and photophobia are also common complaints. Seizures and focal neurologic deficits may be present in 20–30% of cases. Neonates may not present with classic symptoms but with nonspecific signs such as hypo- or hyperthermia, lethargy, fretfulness, refusal to feed, irritability, vomiting, and diarrhea. Bulging of the fontanelle occurs late in the illness, and seizures are observed in 40% of neonates with bacterial meningitis. In neonates and children, classic clinical signs have a limited clinical value.5 In adults, physical examination usually demonstrates fever or hypothermia. Nuchal rigidity should be assessed for by asking the patient to touch his/her chin to their chest. Meningeal inflammation limits flexion of the neck due to pain and stiffness.4 The two classic maneuvers to elicit meningeal inflammation, Brudzinski and Kernig signs, have a very low sensitivity of 5%. Eliciting nuchal rigidity by passively flexing the neck also has a low sensitivity of 30% for diagnosing meningitis.6
Therefore, physicians should have a low threshold for LP in patients with high risk and suspicion for bacterial meningitis. Cranial nerve (CN) palsies and focal neurologic deficits may be present in 10–20% cases. Papilledema is present in less than 5% of cases early in infection. With disease progression, signs of raised ICP develop. Physicians should perform a thorough physical exam to assess for a primary source, including: examination of the ears, nose, and throat for otitis media and sinusitis; assessment for cardiac murmurs for endocarditis; lung examination for signs of pneumonia; and a thorough examination of the skin looking especially for petechiae and purpura commonly encountered in meningococcal meningitis. Similar skin findings may be seen in splenectomized patient with overwhelming sepsis caused by S. pneumoniae, H. influenzae, endocarditis, and Rickettsial infections.
Based on the etiologic pathogen, how do the epidemiology and clinical presentation of acute bacterial meningitis vary?
It is the most common cause of community-acquired bacterial meningitis and accounts for 58% of cases with a mortality ranging from 18 to 26%.7 Primary sites of infection are ear, sinuses, and lungs leading to subsequent bacteremia and seeding of meninges. S. pneumoniae is also the most common cause of recurrent meningitis in patients with CSF leakage following head trauma. Serious infection may be observed in patients with functional asplenia, splenectomy, hypogammaglobulinemia, alcoholism, malnutrition, liver or renal disease, diabetes mellitus, and malignancy. Children with cochlear implants are at a high risk of meningitis, especially pneumococcal meningitis.8
N. meningitidis most commonly causes sporadic disease in children and young adults and is associated with a mortality of 3–13%.7 Meningococcal serogroups B, C, and Y account for most of endemic disease in the United States; disease caused by serogroup A and W135 is rare.3 Nasopharyngeal carriage of N. meningitidis is an important factor that leads to invasive disease. Patients with terminal complement deficiencies are at an increased risk. Crowded environments such as dormitories and military bases facilitate the spread of this organism. A screening test for complement function should be considered for patients with invasive meningococcal disease, especially recurrent disease. Annual epidemics of meningococcal meningitis occur in sub-Saharan Africa in the meningitis belt during dry season (December to June).
H. influenzae was previously the most common cause of bacterial meningitis with a mortality of 3–7%. Fortunately, due to widespread use of conjugate vaccine against H. influenza type b, there has been a 90% decrease in the number of meningitis cases due to this organism.7
L. monocytogenes causes 2–8% of cases of bacterial meningitis in the United States and carries a mortality risk of 15–29%.7 Listeria infection is more commonly seen in infants, adults more than 60 years of age, alcoholics, patients with malignancy, individuals with depressed cell-mediated immunity, and chronic lymphocytic leukemia. Other predisposing conditions include diabetes mellitus, liver disease, collagen vascular disease, iron overload, and chronic kidney disease. Listeria can contaminate unpasteurized cheese, dairy products, and processed meat.9 Primary site of infection is the gastrointestinal tract, which leads to bacteremia and meningeal seeding.9
Group B streptococcus (GBS) is a common cause of meningitis in neonates. Maternal vaginal colonization with GBS predisposes to the acquisition during birth.10 Aerobic Gram-negative bacilli such as Klebsiella spp, Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter spp, and Salmonella spp have become increasingly important etiologic agents of bacterial meningitis especially after head trauma and neurosurgical procedures.3 Hyperinfection syndrome from disseminated strongyloidiasis may result in bacteremia and meningitis with enteric organisms, including Enterococcus spp and Gram-negative bacteria, due to the migration of larva. Meningitis due to Staphylococcus aureus is found in the setting of neurosurgical procedures, CNS shunts, head trauma, and endocarditis.
CASE 7-1 (continued)
There were no focal neurologic findings on physical examination and no papilledema was noted. LP was performed and empirical antibiotics were initiated immediately. What antibiotics should be started at this time?
The cornerstone of diagnosis is CSF examination by LP. Brain imaging should precede LP in patients who have new-onset seizures, an immunocompromised state, signs that are suspicious for space-occupying lesions or ICP, focal neurological findings, history of CNS disease, or moderate-to-severe impairment of consciousness (see Figure 7-2).11
Figure 7-2
Management algorithm for adults with suspected bacterial meningitis. AIDS, acquired immunodeficiency syndrome; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus; STAT, statim (immediately). Reproduced with permission from Bennett JE, Dolin R, Blaser MJ: Mandell, Douglas, and Bennett’s: Principles and Practice of Infectious Disease. 8th ed. Philadelphia, PA: Elsevier; 2015.
*HIV infection or AIDS, receiving immunosuppressive therapy, or after transplantation.
†Mass lesion, stroke, or focal infection.
‡See text for specific recommendations for use of adjunctive dexamethasone in adults with bacterial meningitis.
§See Table 7-2.
||See Table 7-3.
In almost all cases the opening pressure is high (200–500 mm of H2O) with high white blood cell count (WBC) in CSF usually in range of 1000–5000 cells/mm3 with a neutrophilic predominance on cell differential (see Table 7-5). In Listeria meningitis there may be lymphocytic or monocytic predominant pleocytosis. CSF glucose concentration is usually low in bacterial meningitis with CSF glucose concentrations less than 60% of serum glucose concentration. CSF protein content is elevated in virtually all the patients. The combination of neutrophilic predominant pleocytosis, low CSF glucose, and high protein concentrations should warrant treatment for bacterial meningitis.12 Because of the prodromal symptoms of headache and fever, some patients take or are prescribed antibiotics and as a result their CSF profiles reflect partial treatment. The CSF in partially treated meningitis will have all the hallmarks of untreated bacterial meningitis but to a lesser degree. The opening pressure will be moderately elevated with a CSF WBC that may have a more mixed differential even though PMNs still predominate. The CSF glucose concentration will be low to low normal but not profoundly depressed and the CSF protein concentration will be high to high normal but not markedly elevated.
The sensitivity of Gram stain is 60–90% and specificity is >97%.13 CSF Gram stain is positive in less than 50% of patients with L. monocytogenes meningitis. CSF culture is the gold standard for diagnosis and is positive in 80–90% cases of community-acquired bacterial meningitis.12 Prior antimicrobial therapy reduces the sensitivity of Gram stain and cultures. Urine and CSF latex agglutination assays that detect the antigens of H. influenzae type b, S. pneumoniae, and N. meningitidis are available and helpful if positive.3 However, the sensitivity is variable, and hence their use is not routinely recommended. Polymerase chain reaction (PCR)-based assays have shown high sensitivity and specificity in detecting viable and nonviable organisms in CSF. These tests may be diagnostically most useful in the setting of pretreatment with antibiotics prior to lumbar puncture and in whom the CSF Gram stain and/or culture are negative.
Endocarditis, bacteremia, brain abscess, drug-induced meningitis, systemic lupus erythematosus (SLE), nonbacterial meningitis, subdural empyema, and Rocky Mountain spotted fever are diagnoses to be considered in this clinical setting.
CASE 7-1 (continued)
Opening pressure was 300 mm H2O. CSF analysis revealed a cell count with 1,500 white blood cells/mm3 with a differential of 92% neutrophils and 8% lymphocytes, a CSF protein concentration of 538 mg/dL, and a CSF glucose concentration of 12 mg/dL with simultaneous serum glucose concentration of 78 mg/dL. The Gram stain showed numerous Gram-negative diplococci, some within the neutrophils. Culture yielded N. meningitidis. What specific antimicrobial therapies are indicated based on culture results?
Antimicrobial therapy should be initiated promptly and should not be delayed in suspected cases of bacterial meningitis if the LP is delayed for neuroimaging or the patient is severely ill. Empiric antimicrobial therapy depends on the age, immune status of the patient, and whether the infection is community acquired or nosocomial (see Table 7-2 and Table 7-4).3 Choice of antibiotics depends on the drug’s ability to cross the BBB. For ages 3 months to 50 years, therapy is targeted toward N. meningitidis and S. pneumoniae and less commonly H. influenzae, and hence maximal intravenous doses of a third-generation cephalosporin (ceftriaxone or cefotaxime) are recommended. As more than 50% of S pneumoniae isolates are resistant to penicillin, addition of intravenous (IV) vancomycin is recommended. For immunocompromised individuals, adding ampicillin to vancomycin and ceftriaxone is recommended for coverage of Listeria. Use of corticosteroids has been shown to reduce inflammation and neurologic sequelae,14 especially hearing loss, and hence it is recommended in infants and children with H. influenza type b meningitis.11,15 In adults, use of adjunctive dexamethasone (0.15 mg/kg q6h for 2–4 days) is recommended for suspected or proven pneumococcal meningitis.11 Dexamethasone should be given 10–20 minutes before or concomitantly with the first dose of antibiotics, as inflammatory mediators are released when lysis of bacteria occurs after antibiotic administration. Once a specific pathogen is identified, therapy should be narrowed to the specific appropriate agent based on susceptibilities (see Table 7-3 and Table 7-4).3 Duration of therapy is at least 7 days for N. meningitidis and H. influenzae and 14–21 days for all other pathogens. Listeria meningitis requires 21 or more days of antimicrobial therapy.11
Empiric Antimicrobials for Purulent Meningitis
| Predisposing Factor | Empiric Antimicrobial Therapy |
|---|---|
| <1 month | Ampicillin plus cefotaxime; or ampicillin plus an aminoglycoside |
| 1–23 months | Vancomycin plus a third-generation cephalosporina,b |
| 2–50 years | Vancomycin plus a third-generation cephalosporina,b,c |
| >50 years | Vancomycin plus ampicillin plus a third-generation cephalosporina |
| Immunocompromised state | Vancomycin plus ampicillin plus either cefepime or meropenem |
| Basilar skull fracture | Vancomycin plus a third-generation cephalosporina |
| Head trauma; after neurosurgery | Vancomycin plus either cefepime or ceftazidime, or meropenem |
Recommendation for Specific Antimicrobial Therapy in Bacterial Meningitis Based on Isolated Pathogen and Susceptibility
| Microorganism, Susceptibility | Standard Therapy | Alternative Therapy |
|---|---|---|
| Streptococcus pneumoniae | ||
| Penicillin MIC | ||
| <0.1µg/mL | Penicillin G or ampicillin | Third-generation cephalosporina |
| 0.1–1.0µg/mLb | Third-generation cephalosporina | Cefepime, meropenem |
| ≥2.0µg/mL | Vancomycin plus a third-generation cephalosporina,c | Fluoroquinoloned |
| Cefotaxime or ceftriaxone MIC ≥1.0µ g/mL | Vancomycin plus a third-generation cephalosporina,c | Fluoroquinoloned |
| Neisseria meningitidis | ||
| Penicillin MIC | ||
| <0.1µg/mL | Penicillin G or ampicillin | Third-generation cephalosporina |
| 0.1–1µg/mL | Third-generation cephalosporina | Fluoroquinolone, meropenem |
| Listeria monocytogenes | Ampicillin or penicillin Ge | TMP-SMX, meropenem |
| Streptococcus agalactiae | Ampicillin or penicillin Ge | Third-generation cephalosporina |
| Escherichia. coli and other Enterobacteriaceae g | Third-generation cephalosporin | Aztreonam, fluoroquinolone, meropenem, TMP-SMX, ampicillin |
| Pseudomonas aeruginosa g | Cefepimee or ceftazidimee | Aztreoname, ciprofloxacine, meropeneme |
| Haemophilus influenzae | ||
| β-lactamase negative | Ampicillin | Third-generation cephalosporina, cefepime, fluoroquinolone |
| β-lactamase positive | Third-generation cephalosporin | Cefepime, fluoroquinolone |
| Staphylococcus aureus | ||
| Methicillin susceptible | Nafcillin or oxacillin | Vancomycin, meropenem |
| Methicillin resistant | Vancomycinf | TMP-SMX, linezolid |
| Staphylococcus epidermidis | Vancomycinf | Linezolid |
| Enterococcus species | ||
| Ampicillin susceptible | Ampicillin plus gentamicin | |
| Ampicillin resistant | Vancomycin plus gentamicin | |
| Ampicillin and vancomycin resistant | Linezolid |
Recommended Dosages of Antimicrobial Therapy in Patients with Bacterial Meningitis
| Antimicrobial Agent | Total Daily Adult Dose (Dosing Interval in Hours) |
|---|---|
| Ampicillin | 12 g (4) |
| Aztreonam | 6–8 g (6–8) |
| Cefepime | 6 g (8) |
| Cefotaxime | 8–12 g (4–6) |
| Ceftazidime | 6 g (8) |
| Ceftriaxone | 4 g (12–24) |
| Meropenem | 6 g (8) |
| Nafcillin or oxacillin | 9–12 g (4) |
| Penicillin G | 24 mU (4) |
| Rifampin | 600 mg (24) |
| Vancomycin | 30–45 mg/kg (8–12); maintain serum trough concentrations of 15–20µ g/mL |
What chemoprophylaxis is indicated for the patient’s close contacts including friends and healthcare personnel involved in his care?
Chemoprophylaxis is necessary for close contacts of patients with invasive meningococcal disease. CDC currently recommends oral rifampin for 48 hours or single-dose oral ciprofloxacin, or single-dose intramuscular ceftriaxone, all of which are 90–95% effective.16 Most recently ciprofloxacin-resistant N meningitidis strains have been detected in certain communities in the United States, precluding oral ciprofloxacin use for prophylaxis.17
Routine vaccination against H. influenzae type b has reduced meningitis due to this organism by 90%. Advisory Committee on Immunization Practices (ACIP) now recommends a 13-valent pneumococcal conjugate vaccine in infants and children ages less than 6 years. ACIP recommends use of both 13-valent pneumococcal conjugate vaccine PCV13 and 23-valent pneumococcal polysaccharide vaccine PPSV23 administered in a series to adults ages ≥65 years to prevent invasive pneumococcal disease. Pneumococcal vaccine-naïve persons should receive a dose of PCV13 first followed by a dose of PPSV23 6–12 months after the PCV-13.18
Meningococcal conjugate vaccine containing serogroups A, C, W135, and Y polysaccharides in two dose series is recommended for age 11–18 years and for persons ages 2–54 years with terminal complement deficiency, asplenia, adolescents with HIV, and persons at risk of meningococcal disease such as military recruits and college students living in dormitories. FDA recently licensed the first serogroup B meningococcal vaccine for ages 10–25 years. However, it is not currently listed on the ACIP vaccination schedule.19
Bacterial meningitis carries significant mortality. The strongest risk factors for an unfavorable outcome are those indicative of systemic compromise, impaired consciousness, low WBC in the CSF, and infection with S. pneumoniae. Neurologic sequelae are common among survivors. Children often suffer from intellectual delay, hearing loss, or seizure disorder. Older patients may develop CN palsies, hydrocephalus, paresis, seizure disorder, and hearing loss.4
Viral meningitis refers to viral infection of the meninges covering the brain and spinal cord.1 Uncomplicated viral meningitis does not involve the brain parenchyma (encephalitis) or the spinal cord (myelitis). The clinical course is usually self-limited and resolves without treatment. When infection involves both the meninges and the brain (meningoencephalitis) or the meninges and the spinal cord (meningomyelitis), the clinical course can be more severe. Viral meningitis is also referred to as aseptic meningitis. Aseptic meningitis refers to the setting in which there is clinical and laboratory evidence of meningeal infection or inflammation but with negative bacterial cultures. Aseptic meningitis may be caused by infectious agents other than viruses, such as mycobacteria, fungi, and spirochetes.20 In the setting of a parameningeal focus of infection such as sinusitis, otitis media, mastoiditis, brain abscess, and epidural abscess, the meninges may demonstrate inflammation that is indistinguishable from viral meningitis. The etiology of aseptic meningitis may also be noninfectious due to medications, autoimmune conditions, or malignancy.
When a patient presents with fever and headache, differentiation of viral meningitis from both acute bacterial meningitis and viral encephalitis is critical. Acute bacterial meningitis is a life-threatening infection requiring immediate initiation of antibiotics. The outcome of viral encephalitis may be impacted by early recognition and beginning available treatment. The majority of viral meningitis will be self-limited and not require treatment other than supportive. The patient’s clinical history and symptoms, the setting in which the illness has occurred, and the CSF analysis will allow the clinician to stratify the diagnostic possibilities and proceed with treatment and any additional diagnostic tests that might be indicated.
CASE 7-2
A 42-year-old woman who works at a daycare center presents to the ED in September complaining of a 1-day history of severe headache, fever, nausea, vomiting, and photophobia following a flu-like illness with myalgias and diarrhea 3 days ago. Current symptoms failed to improve with antipyretics and bed rest. On physical examination her temperature was 39.0ºC (102.3ºF). The patient was ill appearing but alert and oriented and preferred to be in a dark room because of her severe headache and intense photophobia. She had pain on neck flexion, a fine blanching reticular rash was noted on her skin, and her neurologic examination was nonfocal. What etiologies should be considered for this patient’s clinical presentation?
The Centers for Disease Control and Prevention report between 25,000 and 50,000 hospitalizations each year in the United States for viral meningitis.21 Although any person at any age can develop viral meningitis, those at highest risk for getting viral meningitis are children less than 5 years of age, and persons with weakened immune systems caused by coexisting medical problems, medications (such as chemotherapy), and recent bone marrow or solid organ transplantations.22 Except in infants and young children, long-term neurologic sequelae from viral meningitis are rare and mortality, excluding the neonatal period, is less than 1%.
Enteroviruses are estimated to cause 85% of all cases of viral meningitis.23 This group of viruses is most prevalent during the late summer and early fall months, accounting for the increased incidence of aseptic meningitis reported during this time period. Enteroviruses are members of the Picornaviridae family and include echoviruses, coxsackieviruses A and B, polioviruses, and the numbered enteroviruses. The nonpolio enteroviruses are extremely common, and the majority of viral meningitis cases are causes by coxsackievirus and echoviruses.22 Enteroviruses are shed in the feces, secretions (from the eyes, nose, mouth), and blister fluid of infected individuals. Exposure to the virus occurs when an individual has close contact with an infected person, such as touching or shaking hands, or changing diapers, and then touches their eyes, nose, or mouth prior to washing their hands. The virus can also be acquired by touching infected surfaces and by drinking water in which the virus is present. Asymptomatic individuals can shed nonpolio enteroviruses in their stool and respiratory secretions for up to 3 weeks after being infected.22
The herpes family viruses account for approximately 4% of cases of viral meningitis primarily associated with herpes simplex type 2 (HSV-2) genital infections, varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). Arthropod-borne viruses are another significant cause of acute viral meningitis. Referred to generally as arboviruses, they account for about 5% of cases.20 Depending upon the time of year and local activity of mosquitoes and ticks, viruses such as West Nile virus (WNV)24 may present with acute meningitis. Other causes tend to be sporadic, such as meningitis associated with the human immunodeficiency virus (HIV) acute retroviral syndrome25 ; in specific circumstances, such as lymphocytic choriomeningitis virus (LCMV), which occurs in the setting of exposure to rodents or their excreta; or, viruses which occur only in unvaccinated individuals such as mumps virus.
Patients with acute viral meningitis will have fever and severe headache. These symptoms are often accompanied by meningismus, photophobia, nausea, vomiting, and rash. Less commonly there may be diarrhea, myalgias, and cough. The onset is usually acute, over 18–36 hours, or the development of symptoms may follow a preceding flu-like illness by 1–2 days.9 The distinguishing feature between acute viral meningitis and encephalitis is the presence of normal brain function.26 Patients may be irritable, uncomfortable, lethargic, or distracted by the severe headache, which usually accompanies acute viral meningitis but cerebral function remains normal. Altered mental status, seizures, or focal neurologic findings suggest the possibility of another CNS process.
The most common causes of acute viral meningitis are enteroviruses (coxsackieviruses, echoviruses, and human enteroviruses 68–71), HSV-2, VZV in the presence of either active chickenpox or shingles lesions, EBV, acute HIV infection, and arthropod-borne viruses, especially WNV. HSV-2 genital infections often precede or less often occur simultaneously with HSV-2 viral meningitis. HSV-2 may also be associated with recurrent bouts of viral meningitis, which may occur in the presence or absence of HSV-2 genital lesions, known as Mollaret meningitis.27 HSV-1 skin lesions may also be associated with Mollaret meningitis. The other members of the herpes family viruses principally cause encephalitis (herpes simplex type 1 [HSV-1], cytomegalovirus [CMV], and human herpes virus 6 [HHV-6] in immunocompromised patients, and varicella zoster virus [VZV] chickenpox infection in adults) rather than meningitis.
What CSF findings would one expect in viral meningitis? How does the CSF profile of viral meningitis differ from other etiologies such as bacterial and chronic meningitis?
Obtaining CSF is the most important procedure for diagnosing and differentiating viral meningitis from other causes of CNS infection such as bacterial meningitis. LP can be performed without CT or MRI imaging of the brain first if the patient has no focal neurologic deficits and there is no papilledema on examination in a presentation consistent with viral meningitis (Figure 7-2). In general, the CSF will demonstrate a white blood cell (WBC) lymphocytic pleocytosis in the range of 25–500 cells/mm3, a mildly elevated CSF protein concentration, and a normal CSF glucose concentration (see Table 7-5). Opening pressure should be normal or at most slightly elevated. The CSF Gram stain, acid-fast bacilli (AFB) smear, and fungal smear will be negative for organisms. India ink preparations of CSF are generally no longer done in favor of cryptococcal antigen testing, which has a higher sensitivity and specificity. Viral culture generally has low sensitivity, especially compared with cultures in bacterial meningitis, but may still provide useful diagnostic information. In the first 48 hours the CSF in acute viral meningitis may have a polymorphonuclear (PMN) predominance before shifting to a lymphocytic predominance. The findings of a high percentage of PMNs in the CSF should prompt consideration of alternative diagnoses, such as partially treated bacterial meningitis or parameningeal site of infection. Although the CSF in patients with LCMV and mumps virus can have higher numbers of WBCs and low CSF glucose, these causes of acute viral meningitis are rare. A normal CSF glucose concentration is one of the hallmarks of acute viral meningitis. The findings of lymphocytic predominance with high numbers of CSF WBCs and low CSF glucose concentration suggest the possibility of tuberculous or fungal meningitis or noninfectious etiologies such as autoimmune diseases (neurosarcoidosis, carcinomatous meningitis).
General Guidelines for Use of CSF Profiles for Differentiating the Etiology ofMeningitis
| Etiology | CSF Opening Pressure | CSF WBC Cells/mm3 | CSF WBC Type | CSF Protein (mg/dL) | CSF Glucose (mg/dL) | Other Tests |
|---|---|---|---|---|---|---|
| Normal | 70–180 mm of H2O | 0–5 | – | 15–45 | 50–75 CSF/serum > 60 or 2/3 of serum | |
| Untreated bacterial meningitis | Elevated | 1000–5000 (range <100 to >10,000) | Neutrophils | Elevated 100–500 | ≤40 or ratio < 2/3 of serum | Gram stain, culture, antigen testing |
| Partially treated bacterial meningitis | Elevated | 100–1000 | Mixed, neutrophils predominate | High to higher range of normal | Low to lower range of normal | Gram stain, culture, antigen testing |
| Fungal/TB meningitis | Elevated | 100–1000 | Lymphocytes | Elevated | Low | Fungal: antigen tests, culture; TB: AFB stain and culture, PCR |
| Viral meningitis | Normal | <1000 (range 100–500) | Lymphocytes | Moderately elevated <150 | Normal | PCR for HSV, enterovirus, VZV, arbovirus |
| Parameningealinfection (epidural abscess, paraspinous abscess, otitis media, sinusitis) | Normal | 100–1000 | Mixed | Normal or slightly elevated | Normal | Imaging may help evaluate for abscess |
| Encephalitis | Normal to moderately increased | <1000 (range 100–500) | Lymphocytes | Moderately elevated | Normal | MRI |
PCR amplification of viral specific DNA or RNA has become central to the diagnosis of viral meningitis. The test results are available rapidly, compared to viral culture, and have a much higher sensitivity. Enteroviral CSF PCR is reported to have a sensitivity as high as 98–100% and a specificity of 97%.28,29 Depending upon the availability of the test, the results can be reported within hours. The characteristic enteroviral cytopathic effect in cultured cells can take between 3 and 7 days with reported sensitivity as low as 24% and as high as 75%.30 For HSV in the CSF, PCR is reported to have at least 98% sensitivity and 94% specificity with an HSV viral culture sensitivity as low as less than 10%.31 HSV CSF PCR may be positive as early as 24 hours after symptoms begin but the HSV PCR obtained in the first few days of illness may also be falsely negative.32 Case series have shown that testing usually becomes positive on or after day 4 of illness.32 Viral specific CSF PCR testing is available for almost all other viruses including EBV, CMV, VZV, LCMV, WNV, mumps, and influenza viruses. Serologic testing may be most helpful for patients whose illness is not self-limited or is worsening in the setting of negative PCR testing. Serology is not helpful for the diagnosis of acute viral meningitis in viruses with a high seroprevalence in the population, such as the herpes family of viruses. Serologic testing requires a four-fold rise in antibody titers between acute and convalescent serum to be diagnostic and the information will be available only in retrospect. However, for some viruses, such as WNV, a single serum or CSF IgM is considered diagnostic.33
Acute viral meningitis can have a similar CSF profile to partially treated bacterial meningitis although the CSF parameters will still tend to be more consistent with bacterial than with viral infection. In partially treated bacterial meningitis, the CSF glucose will be low or in the lower range of normal with CSF protein being high to the upper range of normal. A careful medication history must be obtained as patients may have taken or may have been given antibiotics for early symptoms of bacterial meningitis, which will then alter the appearance and culture results of the CSF. A similar situation exists for CNS parameningeal infections, including epidural abscess, sinusitis, mastoiditis, brain abscess, and otitis media. However, with these infections the CSF glucose concentration should not be depressed and the CSF protein content may be normal or have only a slight elevation. In patients with focal infection, symptoms will reflect the primary site of infection. Bacterial meningitis caused by Listeria monocytogenes and species of Mycoplasma, Coxiella, Brucella, Leptospira, and Rickettsia may have CSF profiles similar to acute viral meningitis. Also, the differential diagnosis comprises neoplastic meningitis and meningitis secondary to noninfectious inflammatory diseases such as SLE and other rheumatologic diseases, hypersensitivity meningitis, nonsteroidal anti-inflammatory drug-induced meningitis, and the uveo-meningeal syndromes (granulomatosis with polyangiitis, sarcoidosis, Behcet disease, Vogt–Koyanagi–Harada syndrome).
CASE 7-2 (continued)
Patient had no focal neurologic findings and LP was performed immediately. The opening pressure was 17 mm of H2O. CSF cell count showed a WBC of 216 cells/mm3 with a differential showing 6% neutrophils, 89% lymphocytes, and 5% mononuclear cells, CSF protein concentration of 95 mg/dL, and CSF glucose concentration of 81 mg/dL with a simultaneous serum glucose concentration of 104 mg/dL. Gram stain is negative for organisms, and subsequently the CSF culture showed no growth. How should viral meningitis be treated?
Primarily supportive treatment for viral meningitis includes symptom control with analgesics, antipyretics, antiemetics, and hydration. Oral or intravenous acyclovir may be helpful in patients with HSV-1, HSV-2, or VZV meningitis. If the patient’s meningitis is found to be caused by an acute HIV retroviral infection, then initiation of highly antiretroviral therapy should be considered. In patients whose CSF has PMN predominance or in whom bacterial meningitis is suspected, antibiotics should be given promptly while awaiting additional testing results.
Adult patients with acute viral meningitis have complete recovery within 7–10 days. In this group, the infection is self-limited and generally without significant morbidity. The outcome of viral meningitis in neonates and young children is less certain, and sequelae may include seizures, hydrocephalus, sensorineural hearing loss, and other cognitive and behavioral abnormalities.
CASE 7-3
A 58-year-old man is brought to the ED in August by his family because of confusion. The patient is a construction site supervisor and has had multiple mosquito bites recently. The patient initially complained of a headache and feeling feverish 10 days ago but continued to work. For the past 5 days his family has since noticed increasing forgetfulness, confusion, and a change in his personality from his usual pleasant demeanor to irritable and agitated. On evaluation in the ED the temperature is 38.7ºC (101.7ºF). There was no nuchal rigidity. Mental status examination demonstrated disorientation and agitation. The patient became irritated easily, did not recognize his wife, and was belligerent to the nurses, stating that he “wasn’t staying here.” What are the main etiologies of encephalitis?
Encephalitis is inflammation of the brain parenchyma, which is most often viral in etiology and is differentiated from acute viral meningitis by the presence of diffuse or focal abnormal cerebral function with an altered level of consciousness. When the meninges are also involved, it is referred to as meningoencephalitis. Encephalitis is distinct from meningitis in which only the meninges are infected or inflamed, but it may present with many of the same symptoms, such as fever, photophobia, and meningismus.34 Encephalitis is also a separate clinical entity from cerebritis, which is an area of unencapsulated inflammation preceding the development of a brain abscess.35 The most common causes of encephalitis and meningoencephalitis are the arboviruses and HSV-1, but the infectious and noninfectious causes are myriad and include infections caused by Bartonella spp, Rickettsial spp, Mycoplasma pneumoniae, Borrelia burgdorferi, as well as mycobacteria, fungi, helminthes, and protozoa.26 Because of the wide range of potential etiologies the diagnostic evaluation of a patient who presents with encephalitis needs to be individualized and guided by the epidemiologic and clinical history as well as laboratory data. While many of the arboviral causes of encephalitis tend to have no definitive treatment, it is important to begin all patients with suspected or documented encephalitis on high-dose intravenous acyclovir given the prevalence of HSV-1 infection in this setting.26 Thereafter therapy can be modified if needed as additional diagnostic information becomes available.
Encephalitis may develop as a complication of a previous infection or following an immunization. Acute disseminated encephalomyelitis (ADEM) is an immunologically mediated demyelinating process of the CNS triggered by an infecting microorganism or a vaccination. For this reason, ADEM is sometimes referred to as postinfectious or postimmunization ADEM.36 Noninfectious CNS conditions such as vasculitis, collagen vascular diseases, and paraneoplastic syndromes can present as encephalitis and can have similar clinical presentations to infectious encephalitis. Differentiating between infectious encephalitis, ADEM, and noninfectious encephalitis is crucial because they are treated differently.37
Encephalitis also must be distinguished from encephalopathy associated with metabolic disarray, medications, hypoxia, and ischemia. Fever, headache, focal neurologic findings, seizures, and MRI abnormalities are all uncommon in encephalopathy. However, systemic infections not involving the CNS directly may have associated encephalopathy related to fever, tachycardia, hypotension, acute kidney injury, acid–base imbalance, and electrolyte derangement, especially in elderly patients.37
Both HSV-1 and HSV-2 can cause encephalitis (HSE) but about 90% of the cases are caused by HSV-1.37 In adults, most cases are sporadic, and because the exact pathogenesis is unclear, risk factors that precipitate HSE or are epidemiologically associated with HSE are unknown. The other main infectious causes of encephalitis are the arboviruses, a group of viruses that are transmitted by the bites of mosquitoes and ticks. The activity of these insects varies by geographic region and time of year. The CDC reports that more than 90% of cases of arboviral infection in the United States occurred during the period of April to September.24 A detailed history of potential exposure including insect contact, travel, outdoor activities, occupation, and animal contact should be obtained. ArboNET is a national arboviral surveillance system managed by CDC and state health departments. Detailed information about local insect and viral activity is available through this weekly updated website. The patient’s immune status is also crucial as is the patient’s age. Immunosuppression may make the presentation of encephalitis atypical in patients with HIV infection, solid organ transplantation, or patients on steroids or other immune-modulating agents. The incidence of arboviral neuroinvasive disease increases with age. A history of recent illness or vaccination may increase the likelihood of ADEM.36 Approximately 50–75% of ADEM cases are preceded by viral or bacterial infection, such as the herpes viruses, influenza A, hepatitis A, and enteroviruses, usually within 1 week or less. A seasonal distribution has been observed with more ADEM cases occurring in the winter and spring as has a predilection for ADEM to occur more often in children and adolescents than in adults.
The hallmark of encephalitis is an altered level of consciousness. It may be focal or diffuse, predominantly neuropsychiatric or neurological in presentation, but some degree of cerebral dysfunction will be present. The prodromal or associated symptoms include fever and headache, with varying degrees of nausea and vomiting, myalgia, and lethargy present. Photophobia and meningismus are less consistently present than in meningitis.9 The presentation may include global symptomatology such as behavioral and personality changes (very common), acute confusion or amnesia, generalized seizures, decreased level of consciousness, or coma.34 Focal findings can include movement disorders, ataxia, CN palsies, focal seizures, and hemiparesis. Dysphagia may be present in rabies virus encephalitis and flaccid paralysis with WNV encephalitis. There are no dependable pathognomic findings that will differentiate infectious encephalitis from ADEM as both will have fever, headache, vomiting, and rapid progressing to altered level of consciousness.37 Patients with noninfectious encephalitis, such as paraneoplastic syndromes and collagen vascular disease, may also have fever.
The causes of encephalitis are extensive and are listed and discussed in detail in the Infectious Disease Society of America Practice Guidelines for management of encephalitis.26 Although many cases of encephalitis go without an identified etiology, attempts to identify a specific etiologic agent or cause such as ADEM are important for treatment, prognosis, and public health considerations. Common causes of infectious encephalitis will be discussed. It is important to use individualized information obtained from the epidemiologic history and clinical presentation to help narrow the differential diagnosis as the general clinical presentation of encephalitis is most often nonspecific.
The prodromal presentation does not distinguish HSE from other causes of encephalitis. It includes fever, headache, malaise, and nausea, and is followed by lethargy, behavioral changes, confusion, and delirium. A cutaneous herpetic eruption is not present.
VZV, EBV, and CMV may additionally present with nonspecific rash, lymphadenopathy, and hepatosplenomegaly. VZV encephalitis may occur in the setting of active acute chickenpox lesions, especially in adults, or a shingles rash but often no cutaneous eruption is present. CMV encephalitis primarily occurs with immunocompromised individuals, such as patients with HIV infection, solid organ transplant recipients, and on steroids or other immunosuppressive medications. Herpes simian B virus is acquired from macaque monkeys.
They include acute HIV infection; rabies virus; measles and mumps viruses, less prevalent due to available immunizations; Nipah virus in individuals who have a history of recent travel to Malaysia and Australia; Toscana virus in individuals who have a history of recent travel to southern Europe; Murray Valley encephalitis in patients who have travelled to Australia and Indonesia; and hiking in the Rocky Mountains associated with Colorado tick fever encephalitis.
It often occurs as an outbreak of viral encephalitis in a specific region but cases may also be sporadic. In 2013, cases of viral encephalitis were reported from every state except Hawaii and Alaska.24 The arbovirus groups include Alphaviruses (eastern equine encephalitis virus [EEEV], western equine encephalitis virus), Flaviviruses (West Nile virus [WNV], St. Louis encephalitis virus, Japanese encephalitis virus [JEV], and Powassan virus [POWV]), and Bunyaviruses (California encephalitis virus serogroup, LaCrosse virus[LACV]). WNV was introduced into the northeastern United States in 1999. Until 2002, St. Louis encephalitis virus was the predominant cause of arboviral encephalitis. Since then WNV has rapidly become and continues to be the predominant cause of arbovirus encephalitis in this country.38 In 2013, CDC received reports of 2605 cases of nationally notifiable arboviral diseases, including those caused by WNV (2469 cases), LACV (85), JCV (22), POWV (15), EEEV (8), unspecified California serogroup virus (5), and St. Louis encephalitis virus (SLEV) (1).24 Most arboviral infections will have no symptoms (70–80%) or will develop into a self-limited febrile illness with headache, myalgia, arthralgia, vomiting, diarrhea, and/or rash (20%). Fatigue and subjective weakness rarely will persist for weeks to months. Less than 1% of cases will be associated with severe neuroinvasive disease including headache, high fever, neck stiffness, disorientation, tremors, coma, seizures, and, in the case of WNV, flaccid paralysis. Although only 8 cases of EEEV encephalitis were reported in 2013, all had severe neuroinvasive disease and 4 died.
Encephalitis in patients with a history of recent infectious illness especially associated with an exanthematous rash within 1 week or less of the onset of CNS symptoms, or vaccination in the previous 1–14 days prior to the onset of CNS symptoms, should be evaluated with an MRI for possible ADEM.36,37
Infections causing encephalitis include but are not limited to: Bartonella henselae in the setting of cat scratch disease; M. pneumoniae; Rickettsia rickettsia in the setting of Rocky Mountain spotted fever; Anaplasma phagocytophilum and Ehrlichia chaffeensis often with liver function abnormalities and thrombocytopenia; Treponema pallidum (syphilis of unknown duration and tertiary syphilis); B. burgdorferi (lyme neuroborreliosis); Mycobacterium tuberculosis; the endemic fungi including Coccidioides species, Histoplasma capsulatum, and Cryptococcus neoformans; helminths (Baylisascaris procyonis and Taenia solium); and protozoa (Toxoplasma gondii, Acanthamoeba, and Naegleriafowleri).26
CASE 7-3 (continued)
The patient underwent an MRI of the brain, which showed hyperintensity on fluid-attenuated inversion recovery (FLAIR) images of the thalamus, basal ganglia, and midbrain. An LP was performed. The opening pressure was 170 mm H2O. While awaiting the CSF fluid analysis the patient was started on high-dose intravenous acyclovir. The CSF showed cell count of 227 white blood cells/mm3 with 45% neutrophils, 47% lymphocytes, and 8% mononuclear cells, CSF protein concentration 86 mg/dL, and CSF glucose concentration 79 mg/dL with simultaneous serum glucose 118 mg/dL. CSF Gram stain and cultures were negative. CSF WNV PCR was negative but WNV CSF IgM was detected. Which diagnostic modalities are commonly used to diagnose and differentiate the varied etiologies of infectious encephalitides?
CSF examination should be performed on all patients with suspected encephalitis unless contraindicated by findings suggestive of increased intracranial pressure, such as papilledema, or focal deficits on neurologic examination (Figure 7-2). In these circumstances, neuroimaging should be obtained prior to proceeding with the LP to evaluate for mass lesions or hydrocephalus. CSF findings in encephalitis are very similar to the CSF profile in viral meningitis (Table 7-5). The WBC will generally be in the 100 s range. There may be a lymphocytic pleocytosis on cell differential, a mild-to-moderate elevation in CSF protein concentration, and normal CSF glucose concentration. Some exceptions exist. In WNV, EEE, and some early enteroviral infections, there may be a predominance of PMNs, up to 40%, in the differential.23 Persistence of PMN predominance in the CSF should prompt consideration of an etiology other than viral. A decreased CSF glucose concentration is not consistent with viral encephalitis but is frequently seen in encephalitis associated with mycobacterial and fungal infections.
PCR testing of the CSF for viral pathogens has become the primary diagnostic test for viral encephalitis. It has essentially replaced viral cultures for HSV and enteroviruses, which are insensitive and often require many days for results to become available. CSF should be sent for herpes virus PCRs (HSV, CMV, EBV, VZV, and HHV-6) as well as PCR for enteroviruses. Sensitivity and specificity are high and well documented for HSV and enteroviral PCRs28,29,31; less well studied are the PCRs for CMV, EBV, VZV, and HHV-6. Positive CSF PCR for VZV should be coupled with testing for specific intrathecal VZV antibody production. A positive result on PCR for CMV or EBV could also represent reactivation of one of these viruses in the setting of an concurrent infection and not the true etiology for the patient’s presentation. PCR for WNV is only 70% sensitive. WNV IgM production in the CSF is the diagnostic test of choice for CNS infection as peripheral IgM antibodies to WNV do not cross the BBB. For WNV, IgM in CSF and serum is recommended for diagnosis. Toxoplasma gondii CSF PCR has a sensitivity of 100% and a specificity of 94.4% in patients with HIV infection.
Serologic testing should be guided by the patient’s epidemiologic history. Blood and CSF for specific IgM and IgG antibodies to the arboviruses are diagnostically useful. Arboviral testing panels, sometimes called encephalitis testing panels, are available to be done on both blood and CSF but may not include testing for all viruses that are being considered in the differential diagnosis on a particular patient. These panels vary between laboratories and institutions. Know what is on the panel. Additional individual serologic testing may need to be ordered to evaluate for specific diagnostic possibilities. Testing for HIV should include both antibody and antigen. Awaiting results of IgM and IgG antibody tests for bacterial infections such as Ehrlichia, Anaplasma, and Rickettsia rickettsii, or Western Blot testing for B burgdorferi,33 should not preclude giving antibiotic therapy in the appropriate clinical and epidemiologic setting. Paired acute and convalescent sera will only provide the diagnosis in retrospect, and treatment should not be delayed pending these results for any of the treatable causes of encephalitis.26 Serology is available commercially for some etiologies of amebic meningoencephalitis but may not be FDA approved. The CDC can be contacted for guidance on obtaining amebic serology, such as Balamuthia mandrillaris antibody titers.
Neuroimaging should be done on all patients presenting with encephalitis.26 MRI is more sensitive and specific for CNS abnormalities and is the preferred diagnostic imaging for suspected encephalitis.26,37 If MRI cannot be done then CT with and without contrast administration should be obtained instead. MRI is helpful in excluding other processes that have a similar presentation to encephalitis. It is also more sensitive and specific for the detection of early changes associated with infectious encephalitis but does not differentiate as to the etiology. However, there are radiographic patterns that can be helpful diagnostically. Neuroimaging in HSE may show edema or hemorrhage of either one or both of the temporal lobes. In flavivirus encephalitis, including WNV, MRI may show a characteristic pattern involving the thalamus, basal ganglia, and midbrain. A similar pattern is also seen for EEE encephalitis. MRI is the neuroimaging test of choice for diagnosing ADEM. It will show characteristic subcortical white matter signal abnormality. MRI may be normal and even remain normal during the course of the illness and that does not preclude the diagnosis of encephalitis. An EEG can be particularly useful in distinguishing encephalitis and metabolic encephalopathy.37
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