Residency · Residency · Infectiousdisease

CNS Infections - Meningitis and Encephalitis

Bacterial Meningitis

Epidemiology

Bacterial meningitis has an incidence of approximately 1.2 per 100,000 in the United States, a figure that has been dramatically reduced by widespread vaccination. Despite these advances, mortality remains substantial at 10 to 30 percent depending on the causative organism, with S. pneumoniae and Listeria monocytogenes carrying the highest mortality rates at 20 to 30 percent each. Among survivors, long-term neurologic sequelae occur in 20 to 50 percent and include sensorineural hearing loss, cognitive deficits, seizure disorders, and focal neurologic deficits, underscoring the devastation this disease inflicts even when patients survive the acute illness.

Microbiology by Age and Risk Factor

The microbiology of bacterial meningitis is highly predictable based on the patient's age and underlying risk factors. In neonates under one month of age, the predominant organisms are Group B Streptococcus (S. agalactiae), E. coli with the K1 capsular antigen, and Listeria monocytogenes. In infants and young children between one and twenty-three months, S. pneumoniae and N. meningitidis are the leading causes, with Haemophilus influenzae type b now rare in the post-vaccine era and GBS persisting as a cause. In adults aged two to fifty years, S. pneumoniae is the most common pathogen followed by N. meningitidis. Adults over fifty years are additionally at risk for Listeria and aerobic gram-negative bacilli. Neurosurgical patients, those with ventricular shunts, and victims of penetrating trauma are at risk for staphylococci including both S. aureus and coagulase-negative staphylococci, gram-negatives including Pseudomonas, and Cutibacterium acnes. Immunocompromised patients must be evaluated for Listeria, Cryptococcus neoformans, gram-negatives, Nocardia, and Mycobacterium tuberculosis.

Clinical Presentation

The classic triad of headache, fever, and nuchal rigidity is present in only approximately 45 percent of adults with bacterial meningitis, making reliance on this triad alone a dangerous clinical practice. However, at least two of the four cardinal features, which include headache, fever, neck stiffness, and altered mental status, are present in approximately 95 percent of cases. The Kernig sign, elicited by pain with knee extension when the hip is flexed, and the Brudzinski sign, manifested by involuntary hip flexion with passive neck flexion, have low sensitivity of approximately 5 percent but high specificity. A petechial or purpuric rash is highly suggestive of N. meningitidis, though it can occasionally occur with S. pneumoniae. In neonates, the presentation is nonspecific, with irritability, poor feeding, a bulging fontanelle, and temperature instability being the predominant findings.

Diagnosis

Lumbar puncture is mandatory for the diagnosis of bacterial meningitis unless specific contraindications exist. CT imaging before lumbar puncture is indicated in patients who are immunocompromised, have a history of CNS disease, present with new-onset seizures, demonstrate papilledema, have altered consciousness, or display focal neurologic deficits. The cardinal principle is that antibiotics must never be delayed for CT imaging: empiric antibiotics should be administered, then imaging obtained, then lumbar puncture performed.

CSF Analysis

The cerebrospinal fluid profile in bacterial meningitis characteristically shows a white blood cell count of 1,000 to 5,000 per cubic millimeter with neutrophil predominance exceeding 80 percent, protein above 200 milligrams per deciliter, glucose below 40 milligrams per deciliter with a CSF-to-serum ratio below 0.4, and elevated opening pressure above 30 centimeters of water. In contrast, viral meningitis produces a white blood cell count of 10 to 500 with lymphocyte predominance, protein of 50 to 100, normal glucose, and normal or mildly elevated opening pressure. Tuberculous meningitis shows a white blood cell count of 100 to 500 with lymphocyte predominance that may be neutrophilic early in the course, protein of 100 to 500, very low glucose below 45, and variable opening pressure. Cryptococcal meningitis demonstrates a white blood cell count of 20 to 200 with lymphocyte predominance, protein of 50 to 200, low glucose, and often markedly elevated opening pressure above 25 centimeters of water.

Gram stain sensitivity varies by organism, being highest for S. pneumoniae at 90 percent, 75 percent for N. meningitidis, 50 percent for H. influenzae, 25 to 50 percent for Listeria, and 50 percent for GBS. Rapid diagnostic platforms including latex agglutination and CSF PCR panels such as the FilmArray meningitis and encephalitis panel have transformed the diagnostic landscape, with multiplex PCR sensitivity exceeding 95 percent.

<image>A comprehensive CSF analysis comparison table showing five columns for different types of meningitis: Bacterial, Viral, Tuberculous, Fungal (Cryptococcal), and Normal CSF. Rows should include: Opening pressure (with numerical ranges), WBC count (with ranges), Cell predominance (with pie charts showing PMN vs. lymphocyte percentages), Protein level, Glucose level, CSF:serum glucose ratio, Gram stain findings, and special tests (latex agglutination, India ink, cryptococcal antigen, AFB smear, PCR). Each cell should contain specific numerical values. Use color coding: red for bacterial, blue for viral, yellow for TB, green for fungal. Include a small illustration of a lumbar puncture needle in the header. Professional medical table format.</image>

Empiric Antibiotic Therapy

Antibiotics must be administered immediately upon clinical suspicion of bacterial meningitis, with a door-to-antibiotic time of less than one hour and ideally less than thirty minutes. Every hour of delay in effective antibiotic therapy increases mortality. For patients aged two to fifty years, empiric therapy consists of vancomycin plus ceftriaxone 2 grams intravenously every 12 hours. For patients over fifty years or those who are immunocompromised, ampicillin 2 grams intravenously every 4 hours is added to provide coverage for Listeria, which is intrinsically resistant to cephalosporins. In the neurosurgical, post-traumatic, or shunt-related setting, vancomycin plus cefepime 2 grams every 8 hours or meropenem is used to provide Pseudomonas coverage. Vancomycin is dosed at 15 to 20 milligrams per kilogram every 8 to 12 hours with a loading dose of 25 to 30 milligrams per kilogram, targeting an AUC/MIC of 400 to 600.

Dexamethasone at 0.15 milligrams per kilogram intravenously every 6 hours for four days should be started before or simultaneously with the first dose of antibiotics, based on the de Gans trial of 2002, which demonstrated that adjunctive dexamethasone reduces mortality and hearing loss in pneumococcal meningitis in high-income countries. Administering dexamethasone after antibiotic initiation reduces its benefit, making the timing of steroid administration a critical quality metric.

Definitive Therapy by Organism

Susceptible S. pneumoniae with an MIC below 0.06 is treated with penicillin G 4 million units intravenously every 4 hours for 10 to 14 days. Intermediate or resistant S. pneumoniae with an MIC of 0.12 or above requires ceftriaxone 2 grams every 12 hours with or without vancomycin for 10 to 14 days, with vancomycin discontinued if the MIC to ceftriaxone is 1 or below. N. meningitidis is treated with penicillin G or ceftriaxone for 7 days, with droplet precautions maintained until 24 hours of effective antibiotic therapy and close contact chemoprophylaxis provided. Listeria is treated with ampicillin 2 grams every 4 hours for 21 days, with or without gentamicin for synergy during the first 7 days; trimethoprim-sulfamethoxazole is the alternative for penicillin-allergic patients. Neonatal GBS meningitis is treated with ampicillin plus gentamicin for 14 to 21 days. Nosocomial gram-negative meningitis requires cefepime or meropenem for 21 days, with consideration of intrathecal aminoglycosides for ventriculitis.

Chemoprophylaxis

Close contacts of patients with N. meningitidis should receive chemoprophylaxis with rifampin 600 milligrams orally every 12 hours for 2 days, ciprofloxacin 500 milligrams orally as a single dose, or ceftriaxone 250 milligrams intramuscularly as a single dose, with ceftriaxone preferred in pregnancy. For H. influenzae type b contacts, rifampin at 20 milligrams per kilogram (maximum 600 milligrams) daily for 4 days is indicated when the household includes an unvaccinated child under four years of age.

Viral Meningitis and Encephalitis

Viral Meningitis

Enteroviruses, including echoviruses and coxsackieviruses, are the most common cause of viral meningitis, accounting for 85 to 95 percent of cases, and the illness is self-limited with resolution in 7 to 10 days with supportive care. Other causes include HSV-2, which produces Mollaret meningitis, a syndrome of recurrent lymphocytic meningitis, HIV during the acute retroviral syndrome, mumps, and arboviruses.

Herpes Simplex Encephalitis (HSE)

HSV-1 encephalitis is the most common sporadic fatal encephalitis, with a bimodal age distribution and a characteristic predilection for the temporal lobes. Untreated mortality reaches 70 percent, while treatment with acyclovir reduces mortality to 15 to 20 percent, though significant morbidity persists among survivors. The clinical presentation includes fever, altered mental status, personality changes, seizures, and focal deficits including aphasia and hemiparesis. MRI demonstrates T2/FLAIR hyperintensity in the temporal lobes, insular cortex, and cingulate gyrus, with possible hemorrhagic changes. CSF shows lymphocytic pleocytosis with 50 to 500 white blood cells, elevated protein, normal glucose, and occasionally red blood cells reflecting hemorrhagic encephalitis, with HSV PCR achieving sensitivity exceeding 95 percent and specificity exceeding 99 percent.

Treatment consists of acyclovir 10 milligrams per kilogram intravenously every 8 hours for 14 to 21 days, initiated empirically whenever HSE is suspected without waiting for PCR results. A repeat lumbar puncture at 14 days should be performed, and if HSV PCR remains positive, acyclovir should be continued for an additional 7 days. Unlike bacterial meningitis, adjunctive dexamethasone has no proven benefit in HSE.

Other Viral Encephalitides

West Nile virus encephalitis characteristically produces asymmetric flaccid paralysis reflecting anterior horn cell involvement, with MRI sometimes showing basal ganglia or thalamic signal abnormalities, and no specific treatment is available. Eastern equine encephalitis is the most lethal arboviral encephalitis in the United States, with mortality of 30 to 70 percent, concentrated in New England and Gulf Coast regions. Japanese encephalitis is the most common vaccine-preventable cause of encephalitis worldwide, with characteristic thalamic involvement on MRI. Rabies is almost universally fatal once symptomatic, making post-exposure prophylaxis the critical intervention, and presents in either furious or paralytic forms.

<image>A brain MRI comparison showing four panels of different encephalitis etiologies. Panel 1: "HSV encephalitis" - axial FLAIR MRI showing hyperintensity in the temporal lobe and insular cortex (unilateral), with mass effect. Panel 2: "West Nile encephalitis" - showing bilateral basal ganglia and thalamic signal abnormalities. Panel 3: "Autoimmune encephalitis (NMDA-R)" - for comparison, showing subtle medial temporal lobe changes or normal MRI. Panel 4: "Normal brain MRI" for reference. Each panel should be labeled with the etiology, key MRI findings (arrows pointing to abnormal areas), and typical CSF findings listed below. Use standard radiology grayscale with pathology highlighted. Include a note that HSV encephalitis is a medical emergency requiring immediate acyclovir.</image>

Special Topics

Cryptococcal Meningitis

Cryptococcal meningitis is most common in HIV-infected patients with CD4 counts below 100 and in solid organ transplant recipients and other immunosuppressed individuals. The presentation is subacute, with headache, fever, and altered mental status evolving over days to weeks. Diagnosis rests on serum and CSF cryptococcal antigen testing, which has sensitivity exceeding 95 percent, India ink preparation with sensitivity of 60 to 80 percent, and fungal culture. Opening pressure is often markedly elevated above 25 centimeters of water, and management of this elevated intracranial pressure is as critical to survival as antifungal therapy.

Treatment in the HIV-associated setting follows a three-phase approach: induction with amphotericin B deoxycholate at 0.7 to 1 milligram per kilogram per day plus flucytosine at 100 milligrams per kilogram per day for 2 weeks, consolidation with fluconazole 400 milligrams daily for 8 weeks, and maintenance with fluconazole 200 milligrams daily until the CD4 count exceeds 100 for six months on ART. The ACTT trial in 2022 demonstrated that a single high-dose of liposomal amphotericin B at 10 milligrams per kilogram plus flucytosine plus fluconazole is non-inferior to the standard two-week amphotericin course in resource-limited settings, representing a significant advance in feasibility. Serial therapeutic lumbar punctures to maintain opening pressure below 20 centimeters of water are essential, with lumbar drain placement for refractory cases.

Tuberculous Meningitis

Tuberculous meningitis presents as a subacute meningitis evolving over weeks, with cranial nerve palsies, most commonly the sixth nerve, and basilar meningeal enhancement on MRI. CSF analysis shows lymphocytic pleocytosis, very low glucose, high protein, with AFB smear sensitivity of only 10 to 30 percent and culture sensitivity of 50 to 80 percent requiring weeks for growth. Xpert MTB/RIF testing on CSF achieves sensitivity of 50 to 70 percent with specificity exceeding 95 percent. Treatment consists of RIPE therapy for 2 months followed by isoniazid and rifampin for 7 to 10 months, totaling 9 to 12 months. Dexamethasone at 0.3 to 0.4 milligrams per kilogram per day for 4 weeks followed by a 4-week taper has a proven mortality benefit, as demonstrated in the Thwaites 2004 trial, making TB meningitis the only form of meningitis besides pneumococcal disease where adjunctive dexamethasone has established benefit.

Brain Abscess

Brain abscess arises from contiguous spread from sinusitis, otitis, or dental infection, from hematogenous seeding in endocarditis, lung arteriovenous malformations, or cyanotic heart disease, or from post-neurosurgical complications. The microbiology includes streptococci in 40 to 60 percent of cases with the Streptococcus anginosus group being particularly common, staphylococci, anaerobes including Bacteroides, Fusobacterium, and Peptostreptococcus, and Enterobacterales, while Toxoplasma and Nocardia are important considerations in immunocompromised patients. Empiric therapy consists of ceftriaxone plus metronidazole with or without vancomycin in post-surgical cases, and aspiration or drainage is indicated for abscesses exceeding 2.5 centimeters. Treatment duration is typically 6 to 8 weeks of intravenous therapy followed by oral therapy, with serial imaging to monitor response.

Key Clinical Pearls

• Never delay antibiotics for imaging or LP in suspected bacterial meningitis -- mortality increases with every hour of delay
• Dexamethasone must be given BEFORE or WITH the first dose of antibiotics for pneumococcal meningitis -- giving it after reduces benefit
• HSV encephalitis is the one encephalitis where treatment (acyclovir) dramatically changes outcomes -- start acyclovir empirically for any limbic/temporal encephalitis until HSV PCR returns
• In cryptococcal meningitis, elevated intracranial pressure management (serial LPs) is as important as antifungal therapy for survival
• The classic triad of bacterial meningitis (headache, fever, nuchal rigidity) is present in fewer than half of adults -- have a low threshold for LP
• Listeria meningitis is not covered by cephalosporins -- always add ampicillin for patients >50 years or immunocompromised
• TB meningitis is the only meningitis where adjunctive dexamethasone has a proven mortality benefit outside of pneumococcal disease

References

1. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-1284.
2. de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347(20):1549-1556.
3. Tyler KL. Acute viral encephalitis. N Engl J Med. 2018;379(6):557-566.
4. Molloy SF, Kanyama C, Heyderman RS, et al. Antifungal combinations for treatment of cryptococcal meningitis in Africa (ACTT). N Engl J Med. 2018;378(11):1004-1017.
5. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004;351(17):1741-1751.

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