Neurologic infections can be classified by clinical syndrome/localization (e.g., meningitis vs encephalitis vs myelitis vs radiculitis) and by the type of infection (e.g., viral, bacterial, tuberculous, fungal, parasitic). This chapter is organized by clinical syndrome, with each section organized into subsections by the type of infection. At the end of the chapter, the neurologic manifestations of HIV/AIDS are discussed. Table 20–1 provides a summary of the most common types of clinical syndromes caused by each pathogen or group of pathogens.

Meningitis (inflammation of the meninges) can be caused by:

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  Infection: most commonly bacterial, viral, fungal, or tuberculous

  
  
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  Systemic inflammatory disease: e.g., sarcoidosis, inflammatory bowel disease, rheumatoid arthritis, granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis), IgG4-related disease

  
  
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  Medications (chemical meningitis): nonsteroidal anti-inflammatory drugs (NSAIDs), intravenous immunoglobulin (IVIg), trimethoprim-sulfamethoxazole

  
  
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  Malignancy: leptomeningeal metastases (also called carcinomatous meningitis)

Most infectious meningeal processes predominantly affect the leptomeninges (arachnoid and pia), whereas most inflammatory processes predominantly affect the pachymeninges (dura mater), although there can be simultaneous involvement of both the pachymeninges and leptomeninges in both types of processes (see Figure 2–10 and accompanying discussion “Contrast-enhanced Neuroimaging” in Chapter 2). Carcinomatous meningitis typically refers to leptomeningeal metastases (see “Leptomeningeal Metastases” in Chapter 24). Dural metastases also occur (most commonly with prostate and breast cancer).

Bacterial meningitis and viral meningitis tend to be acute in onset and evolution, whereas fungal meningitis, tuberculous meningitis, inflammatory meningitis, and carcinomatous meningitis are more commonly subacute or chronic in onset and evolution.

Viral meningitis and chemical meningitis are sometimes referred to as aseptic meningitis.

Bacterial Meningitis

Bacteria can infect the meninges by spreading from sinus infections or inner ear infections, spreading hematogenously from remote sites of infection, or infecting the meninges directly in the setting of open head trauma or neurosurgery.

The most common causes of bacterial meningitis vary with age and immunocompetence. In infants less than 1 month of age, Listeria, E. coli, and Streptococcus agalactiae (group B) are most common (mnemonic: less than 1 month of age: Listeria, E. coli, Strep. agalactiae). In children and adults, Streptococcus pneumoniae and Neisseria meningitidis are most common. Listeria should be considered in patients who are older than age 50 or immunocompromised (e.g., HIV, immunosuppressive therapy). In addition to meningitis, Listeria may cause involvement of the brainstem (rhombencephalitis), producing cranial nerve and cerebellar deficits. Haemophilus influenzae should be considered in children, although this is now rare due to widespread vaccination in childhood. In the setting of open head trauma or neurosurgery, Staphylococcus aureus and gram-negative bacteria should be considered.

Head trauma does not need to be open to create a passage for entry of bacteria from outside: Basilar skull fracture can create a communication between the meninges and the outside world. A skull defect should be considered as a cause of bacterial meningitis if a patient with prior neurosurgery or head trauma presents with cerebrospinal fluid (CSF) leak (clear fluid from the nose or ears) and/or recurrent meningitis. CSF can be distinguished from nasal secretions by testing fluid for beta-2-transferrin (present in CSF but not mucus) or for glucose (present in CSF but not mucus, although CSF glucose may be extremely low in bacterial meningitis, limiting utility of this test).

Clinical Features of Bacterial Meningitis

Bacterial meningitis can be rapidly fatal, so prompt diagnosis and treatment are crucial. The classic features are fever, neck stiffness, headache, and altered mental status, although a systematic review found that fewer than half of patients have all of these symptoms at presentation (Attia et al., 1999). Additional symptoms can include photophobia and nausea/vomiting. Purpuric rash may be seen with Neisseria meningitis.

Meningitis should be considered as a possibility in any patient with fever and headache, although many systemic illnesses that cause fever may also cause some degree of headache. A particularly high index of suspicion for meningitis must be maintained in the elderly, who may have minimal or no fever, and whose neck stiffness may be attributed to osteoarthritis (erroneously or appropriately, but misleadingly in either case if the patient has meningitis). Additionally, careful consideration of meningitis is important in febrile infants, in whom mental status may be difficult to assess.

The classic signs of Kernig and Brudzinski are highly specific when present, but unfortunately quite insensitive (Attia et al., 1999). Both signs demonstrate meningismus by causing traction on the inflamed meninges. The Kernig sign is performed by flexing the hip and then extending the knee with the patient in the supine position. If pain prohibits extension of the knee, this is a positive sign (mnemonic: to look for Kernig’s sign: extend the knee). The Brudzinski sign is performed by flexing the patient’s head: If the patient flexes at the hips and knees, this is a positive sign.

Treatment of Bacterial Meningitis

In most medical texts (including this one), diagnosis of a disease is generally discussed before treatment. In contrast, when discussing bacterial meningitis, treatment is discussed first because if bacterial meningitis is being considered, treatment should be rapidly initiated before/while pursuing diagnostic evaluation since delayed initiation of antibiotic treatment—even by hours—leads to poorer outcomes. Therefore, antibiotics should not be delayed while awaiting lumbar puncture. CSF cultures remain positive up to hours after initiation of antibiotics, and protein, glucose, and cell count abnormalities persist up to several days following initiation of antibiotics. The theoretical concern that antibiotics should be delayed so as not to alter the CSF results is unfounded, and so antibiotic treatment should be given as soon as possible if bacterial meningitis is in the differential diagnosis. Blood cultures are positive in a large proportion of patients with acute bacterial meningitis and can be drawn at the time of antibiotic administration.

Empiric treatment while awaiting CSF culture for adults with presumed community-acquired bacterial meningitis is ceftriaxone (covers N. meningitidis and Streptococcus) and vancomycin (to cover potentially resistant strains of Streptococcus). Ampicillin should be added to cover for Listeria if the patient is younger than 1 month old, older than 50 years old, or immuncompromised. Some practitioners recommend initiating ampicillin in all patients since a patient’s immune status may not be known at the time of presentation. If there has been prior neurosurgery or penetrating trauma, or in immunocompromised patients, cefepime or ceftazidime should be used in place of ceftriaxone to expand gram-negative coverage to include Pseudomonas. In patients with penicillin/beta-lactam allergy, regimens may include fluoroquinolones, chloramphenicol, and/or trimethoprim-sulfamethoxazole. Antibiotic treatment can be modified once the culture and sensitivity data from the CSF become available. If there is concern for encephalitis in addition to meningitis based on the clinical picture, acyclovir should be added empirically to treat possible herpes simplex virus (HSV) encephalitis (see “Herpes Simplex Virus Encephalitis” below) while awaiting CSF results and neuroimaging.

Steroids (dexamethasone) are generally also administered in parallel with antibiotics for bacterial meningitis, beginning before or with the first dose of antibiotics (de Gans et al., 2002). This intervention appears to have the most effect on outcomes in patients with meningitis due to S. pneumoniae, and some practitioners discontinue steroids if CSF culture reveals an alternative pathogen. In resource-limited/low-income settings with high HIV prevalence, steroids may not necessarily be as beneficial as they are in high-resource/high-income settings (Nguyen et al., 2007; Scarborough et al., 2007). This may be because patients included in studies in low-income settings may not all ultimately have had bacterial meningitis (limited diagnostics), may not have presented early enough in the disease (limited access to health facilities), and may not have had access to adequate resources for supportive care of critical illness.

Lumbar Puncture in Bacterial Meningitis

As discussed above, antibiotics should be administered immediately if there is concern for bacterial meningitis, and lumbar puncture (LP) should not delay initiation of empiric therapy.

Head CT should be considered before LP if the diagnosis of meningitis/encephalitis itself is in question or if the patient is felt clinically to be at risk for a mass lesion (abscess) or diffuse cerebral edema that could raise the risk of herniation with LP. Symptoms/signs that indicate that CT should be considered before LP include focal deficit, seizure, papilledema, depressed mental status, immunocompromise, known intracranial mass lesion, or age greater than 60 (Hasbun et al., 2001).

The classic CSF findings in bacterial meningitis are elevated opening pressure, extremely elevated protein (generally >100 cells/mm³), extremely elevated white blood cell (WBC) count (>100 cells/mm³, but often in the 1000s) with neutrophil predominance, and decreased glucose (less than 40% of serum glucose, but often much lower) (Table 20–2). CSF culture is used to diagnose the particular bacterial organism and determine antibiotic sensitivity.

Complications of Bacterial Meningitis

The differential diagnosis for an acute neurologic change in a patient with bacterial meningitis includes:

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  Seizures, including nonconvulsive seizures, for which continuous EEG may be necessary to make a diagnosis (see “Nonconvulsive status epilepticus” Ch. 18)

  
  
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  Acute ischemic stroke due to infectious vasculitis (see “Infectious CNS Vasculitis” below)

  
  
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  Venous sinus thrombosis (see “Cerebral Venous Sinus Thrombosis and Cortical Vein Thrombosis” in Chapter 19)

  
  
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  Cerebral edema (management of elevated intracranial pressure is discussed in Chapter 25)

  
  
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  Abscess formation (intracerebral or subdural empyema), which may require surgical drainage (see “Bacterial Focal Brain Lesions” below)

Chronic complications in patients with bacterial meningitis can include:

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  Hearing loss

  
  
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  Epilepsy

  
  
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  Cognitive impairment

  
  
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  Hydrocephalus

Isolation of Patients With Bacterial Meningitis and Prophylaxis of Contacts

While awaiting microbiologic diagnosis, patients should be placed on droplet precautions (mask and face protection for providers), but only patients with N. meningitidis meningitis require isolation and droplet precautions and prophylaxis of close contacts. If N. meningitidis is found to be the etiology, close contacts should receive a single dose of intramuscular ceftriaxone or 2 days of rifampin.

Viral Meningitis

A large number of viruses can cause viral meningitis including herpes simplex viruses (HSV) 1 and 2, enteroviruses, arboviruses, HIV, varicella zoster virus (VZV), and lymphocytic choriomeningitis virus (LCMV). Viral meningitis presents similarly to bacterial meningitis with headache, fever, neck stiffness, and photophobia, but is typically less severe than bacterial meningitis and does not usually cause alterations in consciousness (unless there is an associated encephalitis). Viral meningitis is one type of aseptic meningitis, a term used to describe meningitis with no growth on CSF bacterial culture.

In viral meningitis, CSF protein and WBC count are generally elevated (but not to the degree seen in bacterial meningitis), and glucose is usually normal (see Table 20–2). The CSF WBCs are classically predominantly lymphocytes, although neutrophils may be present early in viral meningitis. Precise diagnosis of the viral pathogen is made by CSF polymerase chain reaction (PCR). Care is supportive with the exception of HSV and VZV encephalitis, which are treated with IV acyclovir.

Aseptic meningitis may occur at the time of HIV seroconversion, so patients with viral meningitis should be screened for HIV risk factors (see “HIV Seroconversion Syndromes Involving the Nervous System” below).

Mollaret’s meningitis refers to recurrent viral meningitis, most commonly caused by HSV-2 (the HSV strain that causes genital herpes).

Fungal Meningitis

Fungal meningitis most commonly affects patients who are immunocompromised (e.g., due to HIV infection or immunosuppressive medications), although immunocompetent patients can be affected. The presentation is typically more subacute than with viral or bacterial meningitis, emerging over days to weeks. Headache is almost always present, but the inflammatory aspects of meningitis such as fever and neck stiffness may be minimal or even absent if the patient develops fungal meningitis in the setting of immunocompromise. Therefore, a high index of suspicion for potential fungal meningitis must be maintained in patients who develop headaches while on chronic immunosuppressive therapy or in the setting of diseases causing immunocompromise (e.g., HIV). Cranial nerve palsies and seizures may also be seen, especially in advanced cryptococcal meningitis. Strokes in the basal ganglia may occur due to infectious involvement of penetrating lenticulostriate arteries at the base of the brain.

Cryptococcal Meningitis

Cryptococcal meningitis is the most common fungal meningitis in immunocompromised patients. Due to meningeal inflammation, communicating hydrocephalus can develop, leading to rapid changes in mental status. This often improves with large-volume LP to relieve intracranial pressure. In severe cases, LP may be required daily, and patients may ultimately require ventriculoperitoneal shunting.

CSF in fungal meningitis demonstrates increased protein and WBC count with decreased glucose, but not typically to the extreme values seen in bacterial meningitis (Table 20–2). The most sensitive diagnostic tests for Cryptococcus are CSF cryptococcal antigen and CSF cryptococcal culture. Cryptococcal antigen is sensitive and rapid, but not available in many areas of the world most affected by AIDS and accompanying central nervous system (CNS) opportunistic infections. Cryptococcal culture is sensitive and more widely available, but results return much less rapidly. India ink stain is not as sensitive as either test.

Mass lesions of cryptococci (cryptococcomas) can occur, appearing as T2/FLAIR hyperintense spherical lesions on MRI, most commonly in the basal ganglia. Treatment of cryptococcal meningitis begins with amphotericin and flucytosine induction therapy, followed by fluconazole until the CD4 count is greater than 200 cells/mm³ for 6 months.

Other Fungal Causes of Meningitis

Other fungi can also cause meningitis, including Aspergillus, Coccidioides (Southwest United States), Histoplasma (Mississippi and Ohio River regions as well as Latin America), Blastomyces (Southeast United States), and Candida. These fungi can affect immunocompetent or immunocompromised individuals, except Aspergillus, which generally only affects immunocompromised patients. Treatment of fungal meningitis caused by these pathogens is with amphotericin or azoles.

Tuberculous Meningitis

Like fungal meningitis, tuberculous meningitis presents more insidiously than viral and bacterial meningitis, typically over weeks. The clinical presentation can include any of the classic features of meningitis (headache, fever, meningeal signs, altered mental status), and may also include cranial nerve palsies. As in cryptococcal meningitis, hydrocephalus and subcortical infarcts in the basal ganglia may develop. Many patients who develop tuberculous meningitis have no prior history of pulmonary tuberculosis (clinically or by chest x-ray).

Neuroimaging may demonstrate hydrocephalus, basal ganglia infarcts, and/or meningeal enhancement. CSF profile is similar to that in fungal meningitis with moderate elevations in WBC count (lymphocytic predominance) and protein, and diminished glucose with values less extreme than in bacterial meningitis (Table 20–2). Unfortunately, CSF culture is insensitive, and molecular testing is often not widely available in areas of highest incidence. Therefore, in areas of high incidence and limited diagnostic resources, empiric treatment is often initiated in the following scenarios: patients who present with meningitis and a CSF pattern inconsistent with bacterial meningitis, patients who fail to improve with treatment of bacterial meningitis, or in HIV-infected patients who have a CD4 count greater than 200 cells/mm³ (making Cryptococcus unlikely) or who do not respond to treatment for cryptococcal meningitis.

Treatment generally consists of 2 months of a four-drug regimen (including isoniazid, rifampin, and pyrazinamide with ethambutol or a fluoroquinolone as the fourth agent) followed by an additional prolonged course of isoniazid and rifampin. Corticosteroids are often added during the initial 2 months. In patients with coexisting HIV infection who are not already on antiretroviral therapy, it may be necessary to defer initiation of antiretrovirals until after an initial period of treatment of tuberculous meningitis due to the risk of immune reconstitution inflammatory syndrome (IRIS) (see “Immune Reconstitution Inflammatory Syndrome (IRIS)”).

Tuberculosis can also cause focal brain lesions (tuberculoma) and disease of the spine (Pott’s disease), which are discussed below (see “Tuberculous Focal Brain Lesions” and “Tuberculosis of the Spine”).

Lyme Meningitis

Lyme meningitis may be preceded by the target rash typical of the disease, although many patients do not develop a rash, or may not have noticed it. Diagnosis is confirmed by detecting CSF Lyme antibody, although this is insensitive. Other neurologic manifestations of Lyme disease that can occur early in the illness include seventh nerve palsy (or less commonly other cranial nerve palsies) and radiculits. Meningitis, seventh nerve palsy, and radiculitis can occur together, and may occur in the same time period as systemic features of Lyme disease such as arthritis and carditis. Lyme meningitis is generally treated with IV ceftriaxone. If the only neurologic manifestation of Lyme disease is a seventh nerve palsy (i.e., no meningitis), oral doxycycline is generally used for treatment.

Syphilitic Meningitis

Syphilitic meningitis occurs within the first few years after initial infection with syphilis. In patients in whom positive serum treponemal antibody confirms syphilis, syphilitic meningitis is diagnosed by positive CSF VDRL (Venereal Disease Research Laboratory) test. CSF VDRL is highly specific but relatively insensitive. Treatment is with high-dose IV penicillin G. Meningovascular syphilis can also occur months to years following initial infection, leading to strokes.

Late neurologic manifestations of syphilis include tabes dorsalis (see “Other Infectious Conditions of the Spine” below) and dementia (called general paresis or dementia paralytica). Both are also diagnosed by CSF VDRL (in patients found to have syphilis by positive serum treponemal antibody) and treated with IV penicillin G. Response to treatment is generally followed with CSF VDRL at 6 month intervals until the CSF normalizes.