Infections of the Central Nervous System

Basic Anatomy

• The central nervous system (CNS) is encased within three membranous layers, called meninges. These meninges, from the outermost layer inward, are the Dura mater, the arachnoid, and the pia mater. The dura adheres to the inner surface of the cranium; the arachnoid attaches to the inner surface of the dura; and the pia is attached to the brain, following all of its contours. The space between the arachnoid and pia-the subarachnoid space-is filled with cerebrospinal fluid (CSF).
• The cranial dura extends through the foramen magnum to become the spinal dura mater. The spinal epidural space is located between the periosteum of the vertebrae and the dura and is filled with fatty connective tissue and a vertebral venous plexus.
• The spinal arachnoid closely attaches to the inner surface of the dura, creating the subarachnoid space between itself and the spinal cord that, like the cranial subarachnoid space, is filled with CSF. The spinal cord ends (i.e., becomes the cauda equina) at about the level of the disk between the first and second lumbar vertebrae; however, the spinal dural sheath (and its arachnoid lining) ends at about the second sacral vertebra. The large subarchnoid cistern, between these two points, is the site at which sampling of CSF occurs (i.e., lumbar puncture) with relatively little risk of damage to the spinal cord.

• Meningitis
• Meningitis is inflammation of the membranes of the brain or spinal cord, which may accompany an infectious, neoplastic, toxic, or autoimmune process. Because the precise etiology may not be evident in the emergency department, empiric treatment for bacterial meningitis is of utmost importance.
• Despite early and aggressive use of antibiotics, the overall mortality rate remains at 25% for bacterial and fungal meningitis.
• The causative organism varies with the age, immune status, living conditions, travel history, and overall health of the individual. However, with the decline in frequency of Haemophilus influenzae meningitis as a result of the H. influenzae type b vaccine, S.pneumoniae is now the most common cause in adults and children over one month old. N. meningitidis is the second most common organism isolated in both age groups.
• Antibiotic resistance is a frequently observed trend, with increasing resistance of S. pneumoniae to penicillin and third-generation cephalosporins.
• Long-term sequelae of bacterial meningitis include cognitive deficits, seizure disorders, hearing loss, blindness, gait disturbances, focal motor deficits, and hydrocephalus.
• "Aseptic" meningitis refers to conditions in which there is CSF pleocytosis and a clinical suspicion of meningitis, but with negative bacterial cultures. Typical etiologies include viral meningitis, fungal infections, and drugs (e.g., NSAIDs, TMP-SMX, and INH).
• Encephalitis
• Encephalitis is inflammation of the brain parenchyma. It may coexist with viral meningitis or it may present as a distinct entity, caused most commonly by arboviruses, herpes viruses, and rabies. Listeria and cat-scratch disease are rare etiologies.
• Encephalitides caused by certain arboviruses (Japanese, Eastern equine, and St. Louis encephalitides) are associated with high mortality rates and severe neurologic sequelae.
• The death rate from HSV encephalitis has been reduced by acyclovir; however neurologic emergencies deficits-including epilepsy, focal motor deficits, and altered mentation-are common.
• West Nile Virus
• West Nile virus, an arthropod-borne virus (arbovirus), may cause encephalitis, meningitis, or meningoencephalitis. Patients at highest risk for symptomatic infection include persons over age 50 and the immunosuppressed. Associated symptoms may include fever, headache, nausea, vomiting, weakness, altered mental status, stiff neck, and an erythematous rash. West Nile virus is not cultured from the CSF or brain tissue, but IgM antibodies may be present in the CSF or serum. Alternatively, PCR testing of the CSF for West Nile virus RNA may be positive.
• CNS Abscess
• CNS abscess denotes a circumscribed collection of purulent material, or a localized infection, which may exist within the brain parenchyma (brain abscess); within the meninges (epidural or subdural empyema); or within or surrounding the spinal cord (intramedullary or epidural spinal abscess). Complications of intracranial abscess include epilepsy, focal motor or sensory deficits, and intellectual deficits. Patients with spinal abscesses may have residual motor or sensory deficits, or bowel or bladder dysfunction.

• Meningitis
• As mentioned above, the most common pathogens in patients over one month of age are S. pneumoniae and N. meningitidis; risk factors for other organisms are shown in Table 4D.1.
• Encephalitis
• The means of access to the CNS varies according to the virus (Table 4D.2).
• CNS Abscess
• CNS abscesses develop as an extension of a contiguous infection (e.g., otitis media, sinusitis, dental infection), or by hematogenous seeding from a remote site (e.g., pulmonary, endocarditis, osteomyelitis). Other risk factors include intravenous drug abuse, neurosurgical procedures, and penetrating head injury. The causative organisms vary according to the primary source of the infection and the immune status of the patient (Table 4D.3).

History

• The classic triad of fever, nuchal rigidity, and altered mental status is seen in approximately two-thirds of patients with community-acquired bacterial meningitis.
  All patients, however, will likely have at least one of these findings. Other signs and symptoms which should cause one to suspect meningitis include headache, chills, vomiting, myalgias/arthralgias, lethargy, malaise, focal neurologic deficits, photophobia, and seizures. Elderly patients may present with subtle findings, frequently limited to an altered sensorium. Fungal meningitides present with an atypical constellation of symptoms, including headache, low-grade fever, weight loss, and fatigue; similarly, tuberculous meningitis may be associated with fever, weight loss, night sweats, and malaise, with or without headache and meningismus.

  Table Organisms causing meningitis
  

  Population	Additional Potential Pathogens
  Neonate (< 1 mo)	Group B streptococci, E. coli, Listeria monocytogenes
  1 mo to 50 yr	H. influenzae (rarely), L. monocytogenes (unlikely)
  Adults (over 50 yr), alcoholics, other debilitating diseases	L. monocytogenes, Enterobacteriaceae
  Closed head injury with CSF leak	S. aureus, Enterobacteriaceae, P. aeruginosa
  Recent neurosurgical procedure or penetrating head injury	S. aureus, S. epidermidis, other Streptococcus species, Bacteroides fragilis, Enterobacteriaceae CSF shunt infection S. epidermidis, S. aureus, Enterobacteriaceae, diphtheroids, P. acnes
  Splenectomy	H. influenzae
  Chronic otitis media	Streptococcus species, Enterobacteriaceae Bacteroides fragilis
  Malignant otitis externa (diabetes)	Pseudomonas species
  Sickle-cell disease, diabetics	Enterobacteriaceae
  Immunosuppressed host	L. monocytogenes, P. aeruginosa, Enterobac teriaceae, S. aureus, H. influenzae, Streptococci, anaerobes, Mycobacterium tuberculosis, Actinobacter spp., syphilis, Cryptococcus neoformans, toxoplasmosis, Herpes simplex, Cytomegalovirus

  Table Encephalitis, causative organisms
  

  Virus	Route of Entry
  Arbovirus (California, W. Equine, E. Equine, St. Louis, West Nile)	Mosquito bite; hematogenous spread
  Herpes virus Herpes simplex type 1 Varicella zoster E-B virus	Skin lesions; retrograde neuronal spread Skin lesions; retrograde neuronal spread Mononucleosis
  Rabies	Animal bite; retrograde neuronal spread
  Measles, mumps	Post-infectious

  Table Etiology of CNS abscess
  

  Source of Infection	Likely Pathogen
  Local or remote infection
  Sinuses, teeth	Streptococci
  Otitis media, pulmonary infection	Bacteroides
  Endocarditis	S. aureus
  Other sources	Enterobacteriaceae, Nocardia (rarely)
  Neurosurgical procedure,	S. aureus, Enterobacteriaceae
  penetrating head injury

• Other important historical factors include:
• Duration of symptoms: a fulminant course indicates a bacterial meningitis or aggressive viral encephalitis, while a subacute presentation suggests a viral, fungal, or parasitic infection.
• Antecedent infection: recent otitis media, sinusitis, respiratory tract infection, pharyngitis, or intracranial abscess may suggest recent colonization with, or contiguous spread of, a particular organism.
• Recent course of antibiotics: may alter CSF analysis and clinical presentation.
• History of a penetrating or closed head injury, neurosurgical procedure (including VP shunt placement), or congenital dural defect.
• Living conditions or epidemic exposure: college dormitories, military barracks, and jails/prisons are typical areas for epidemics of N. meningitidis; exposure in day-care centers, or to family members with a specific infectious disease (e.g., M. tuberculosis) may suggest an otherwise atypical causative organism.
• Immune suppression: HIV, malignancy, splenectomy, or other immunologic deficits.
• Social history: alcohol or IV drug abuse, low socioeconomic status.
• Underlying medical conditions: sickle cell disease or thalassemia major, bacterial endocarditis, cirrhosis, diabetes.
• Barrier disruption: VP shunt, central IV lines, loss of cutaneous integrity (including prior varicella-zoster infection).
• History of mosquito or tick bite; exposure to animals at risk for rabies infection.

Examination

• Meningitis
• Evaluate the patient’s overall appearance and mental status.
• HEENT exam should include a search for evidence of trauma, surgery, infections (otitis, mastoiditis, sinusitis, pharyngitis), or pupillary abnormalities. Note that papilledema takes time to develop, and this finding can be absent in the majority of patients with bacterial meningitis. In infants < 12 mo of age, when meningeal signs are unreliable, the anterior fontanelle should be evaluated for bulging.
• Test the neck for rigidity: Brudzinski’s sign (if the neck is passively flexed, flexion of the hips occurs; or, on passive flexion of one hip, flexion of the other hip occurs); and Kernig’s sign (resistance to passive extension of the knee). Neck stiffness is often absent at the extremes of age, or in patients with altered levels of consciousness, immunosuppressed, or partially treated disease.
• Examination of the chest may reveal a concurrent pneumonia.
• A new heart murmur may indicate endocarditis.
• Examination of the abdomen may suggest an infectious process, and thus a source for bacteremia and meningitis or abscess.
• A complete neurologic exam must be documented, revealing a number of potential abnormalities: isolated cranial nerve deficits (including ophthalmoplegia); focal motor or sensory deficits; cerebellar dysfunction; and increased deep tendon reflexes.
  Localizing signs are generally absent in bacterial meningitis; their presence suggests the possibility of a focal infection, such as an abscess. The level of consciousness may range from confusion or delirium to stupor or coma.
• The skin should be examined for the petechial or hemorrhagic lesions suggestive of meningococcemia, or a rash characteristic of HSV, herpes zoster, or leptospirosis (purpura and petechiae on the oral, vaginal, or conjunctival mucosa).
• Arthritis may be associated with N. meningitidis or, less commonly, other bacterial meningitides.
• Encephalitis
• Clinical suspicion of encephalitis should be raised in the setting of new "psychiatric" symptoms, cognitive deficits (especially memory disturbances and aphasia), acute confusion, and movement disorders (e.g., choreoathetosis and parkinsonism).
• Abscess
• Patients with CNS abscess often experience a delay in diagnosis as a result of nonspecific presenting complaints.
• While headache is almost universally present, fever is seen approximately half of the time.
• One-third of patients may have focal neurologic signs, including hemiparesis and seizures.
• Increased intracranial pressure may cause vomiting, confusion, or altered levels of consciousness in 50% of patients.
• Meningismus is noted on < 50% of exams, while papilledema is present in one-third of patients.

• Delay in the diagnosis of bacterial meningitis in the elderly, especially with nonspecific symptoms, is responsible for the high mortality in this population. While urinalysis or chest X-ray may indicate an infectious process outside the CNS, it is important to remember that the diagnosis of meningitis still needs to be suspected-and aggressively pursued-because of the risk of hematogenous spread of the involved organisms.

Laboratory

• Cerebrospinal Fluid
• Lumbar puncture (LP) should be performed whenever meningitis is suspected. If there will be a delay in performing the LP, blood cultures should be drawn and antibiotics administered empirically. Immediate LP may be contraindicated in the following situations:
• Suspected HIV disease
• Focal neurologic exam
• Evidence of increased intracranial pressure
• Hemodynamic instability
• Overlying infection at the LP site
• Suspected coagulopathy
• Suspect subarachnoid hemorrhage
• An opening pressure, if measured, should be performed with the patient fully extended.
• Normal adult pressures are 5-19 cm H2O, when the patient is in the lateral recumbent position. Opening pressure may be elevated in bacterial and fungal meningitis.
• The cerebrospinal fluid is normally clear and colorless. Infection, inflammation, or bleeding may cause the fluid to be turbid. Note that fluid can be clear even when several hundred cells are present.
• True CNS bleeding (e.g., a subarachnoid hemorrhage) may be distinguished from a traumatic tap by the presence of xanthochromia. In addition, RBC count will generally decrease in sequential tubes with a traumatic tap.
• CSF analysis should include cell count and differential, glucose and protein, stat gram’s stain and culture, and a fourth tube for special tests as indicated by the clinical scenario.
• Normal adult CSF contains < 6 WBCs/mm3, with no more than one PMN. Early in the course of bacterial meningitis, lymphocytes may predominate.
• CSF analysis in viral meningitis and encephalitis typically reveals < 500 WBCs/ mm3, with almost 100% mononuclear cells (but early presentations may have PMN pleocytosis).
• Brain abscess and parameningeal infections (e.g., subdural empyema, epidural abscess) have cell counts and differentials similar to those of viral meningitis.
• The normal ratio of CSF:serum glucose is 0.6 (0-0.4 in the setting of severe hyperglycemia). CSF glucose may be decreased in bacterial, fungal and tuberculous meningitis; carcinomatous meningitis, and (normal or decreased) in subarachnoid hemorrhage. Mild decreases in CSF glucose may be seen in viral and parameningeal processes.
• CSF protein levels are normally < 45 mg/dl in adults. An elevated protein, usually >150 mg/dl, is suggestive of bacterial meningitis. Other causes of elevated CSF protein include any infectious meningitis, viral or parasitic encephalitis, carcinomatous meningitis, subarachnoid hemorrhage, CNS vasculitis, neurosyphilis, hepatic encephalopathy, and demyelination syndromes.
• Other tests to consider include viral cultures, acid-fast stain and culture for M. tuberculosis, India ink and cryptococcal antigen, VDRL, cytology, bacterial antigens for S. pneumoniae, H. influenzae, and N. meningitidis (especially in patients recently treated with antibiotics), and Borrelia antibodies in cases of suspected Lyme disease. Other more specialized tests are rarely ordered in the ED.
• Blood Tests
• Although a CBC with differential may add to the clinical picture in a patient with suspected meningitis, a normal result does not exclude the diagnosis.
• PT and PTT may be useful to exclude a suspected coagulopathy, or DIC.
• Serum electrolytes, BUN/Cr, and glucose are routinely ordered.
• Blood cultures (two specimens, collected 15 min apart) may identify the organism in up to 80% of cases depending upon the etiology.
• Imaging
• A CT scan of the head should be performed prior to LP in the following situations:
• Altered mental status
• Focal neurologic exam (excluding ophthalmoplegia)
• Evidence of increased intracranial pressure
• Minimal or absent fever
• Recent-onset seizure
• Suspected subarachnoid hemorrhage or intracranial mass lesions
• Contrast-enhanced CT is the study of choice for evaluation of possible CNS abscess. Although not readily available, MRI is equally sensitive.
• MRI is the imaging study of choice when cranial epidural abscess or subdural empyema is suspected.
• A chest X-ray may reveal a concomitant pneumonia, especially in cases of pneumococcal meningitis.
• EEG
• In the setting of suspected herpes encephalitis, focal or lateralized EEG abnormalities may help pinpoint the diagnosis.

Treatment

• Meningitis
• Administration of IV antibiotics should begin as soon as the suspicion of bacterial meningitis is entertained. Empiric therapy should be based on the suspected pathogen, taking into consideration the patient’s age and risk factors for specific organisms. An infectious disease consultant may be helpful for information regarding local drug resistance patterns (Table 4D.4).
• Encephalitis
• Herpes simplex and varicella encephalitis are the only treatable forms of encephalitis. Acyclovir is dosed at 10mg/kg IV q8 h.
• CNS Abscess
• The mainstay of treatment of CNS abscess is antibiotics. Neurosurgical consultation is recommended for possible aspiration or excision (Table 4D.5).
  Table 4D.4. Empiric antimicrobial therapy for meningitis

  Population	Empiric Therapy
  Neonate (0-7 days)	Ampicillin + Cefotaxime or Ampicillin + Gentamicin or Ampicillin + Amikacin
  Neonate (8-28 days)	Ampicillin + Cefotaxime
  1 mo to 50 yr	Vancomycin + Ceftriaxone or Vancomycin + Cefotaxime
  Adults (over 50 yr)	Ampicillin + Ceftriaxone + Vancomycin or Ampicillin + Cefotaxime + Vancomycin
  Recent neurosurgical procedure, penetrating head injury, CSF leak	Vancomycin + Ceftazidime
  CSF shunt infection	Peds: Vancomycin + Cefotaxime or Vancomycin + Ceftriaxone Adults: Vancomycin + Rifampin
  Immunosuppressed host	Ampicillin + Ceftazidime +Vancomycin
  Suspected HSV 2 meningitis	Acyclovir

• Specific Treatment
• Meningitis
• Glucocorticoids, based on studies in children with predominantly H. influenzae type b meningitis, have been shown to reduce the morbidity associated with an inflammatory reaction to bacteriolysis. Dexamethasone, 0.15 mg/kg IV, may be considered in children as well as adults, especially in cases with positive Gram’s stain (indicating a high bacterial load), altered level of consciousness, or increased intracranial pressure. If dexamethasone is given, benefit is greatest when started prior to or concurrent with initial antibiotic therapy.
• In areas with high prevalence of drug-resistant S. pneumoniae, vancomycin is added empirically.
• In penicillin-allergic patients, trimethoprim-sulfamethoxazole and vancomycin are recommended.
• Amphotericin B and flucytosine are the drugs of choice for cryptococcal meningitis.
• Initial therapy for tuberculous meningitis should include isoniazid (INH), rifampin, ethambutol, and pyrazinamide (PZA).
  Table Antibiotic therapy of CNS abscess

  Source	Empiric Therapy
  Otogenic	Ceftriaxone + metronidazole or Cefotaxime + metronidazole
  Sinogenic, odontogenic	Penicillin G + metronidazole
  Remote infection	Penicillin G + metronidazole
  Post-surgical, head trauma	(Cefotaxime or Ceftriaxone) + nafcillin or (Cefotaxime or Cefotaxime) + oxacillin or (Cefotaxime or Ceftriaxone) + vancomycin (MRSA)
  Unknown source	Ceftriaxone + metronidazole or Cefotaxime + metronidazole

  
  Table Meningitis prophylaxis

  Organism	Treatment
  H. influenzae type b:	Rifampin, 20 mg/kg PO (up to 600 mg) q 12 h for 4 doses
  N. meningitidis:	Peds: Rifampin 10 mg/kg PO q 12 h for 4 doses or Ceftriaxone 125 mg IM, single dose Adults: Rifampin 600 mg PO q 12 h for 4 doses or Azithromycin 500 mg PO, single dose Ciprofloxacin 500 mg PO, single dose or Ceftriaxone 250 mg IM, single dose

• If the CSF pressure is >40 cm H2O, consider giving mannitol. Only the CSF in the manometer should be collected, to reduce the risk of tentorial herniation.Patients with clinical and CT evidence of increased intracranial pressure also require appropriate therapy.
• Complications of meningitis should be anticipated and managed including dehydration, hypotensive shock, hyponatremia, coagulopathies, seizures, cerebral edema, loss of protective airway reflexes, respiratory failure, and stroke.
• Close contacts of patients diagnosed with H. influenzae type b or N. meningitidis should receive prophylactic treatment. Health care personnel coming into contact with respiratory droplets are also candidates for prophylaxis (Table 4D.6).
• Encephalitis
• Post-infectious encephalomyelitis-an acute inflammatory, demyelinating process preceded by infection or immunization with influenza, measles, and varicella-is treated with high-dose intravenous methylprednisolone. Bacterial causes of encephalitis include Listeria, Lyme disease, Rocky Mountain Spotted Fever (RMSF), Leptospirosis, and the Ehrlichioses.
• Immunocompromised patients are at increased risk for amebic encephalitis, toxoplasmosis, and CMV, in addition to the herpes viruses. Empiric therapy of encephalitis-in addition to acyclovir-is shown in Table 4D.7.
• CNS abscess
• Although not a true abscess, focal lesions in the brain parenchyma attributable to toxoplasmosis in the immunocompromised patient are treated with pyrimethamine plus sulfadiazine. Patients with sulfa allergies are treated with pyrimethamine plus clindamycin. If a fungal abscess is suspected, amphotericin B should be added to the empiric regimen.
• Treatment of epidural abscess and subdural empyema includes surgical drainage and intravenous antibiotics, as described above for empiric therapy of CNS abscess.

  Table 4D.7. Encephalitis, empiric therapy
  

  Organism	Treatment
  Lyme disease	Ceftriaxone
  RMSF Peds <8 yo:	Chloramphenicol
  Adults:	Doxycycline
  Leptospirosis	Penicillin G
  Ehrlichiosis	Doxycycline
  Amebae	Amphotericin
  CMV	Gancylcovir or foscarnet (more toxicity)

Disposition

• All patients with suspected bacterial meningitis, encephalitis, or CNS abscess are admitted.
• Patients definitively diagnosed with viral meningitis, if the social situation permits, may be discharged if associated symptoms (e.g., pain, vomiting) are controlled.