CNS Infections: Diagnosis and Causes

• Immediate emergency department referral is necessary for all suspected central nervous system (CNS) infections.
• A high index of suspicion should be maintained for patients with fever, headache, stiff neck, and mental status changes.

Definition and Epidemiology

• CNS infections consist primarily of meningitis (inflammation of the meninges) and encephalitis (inflammation of the brain parenchyma).
• These infections are caused by a variety of microorganisms.
• The mortality rate for adults with community-acquired CNS infections averages 9% in the United States and Europe.
• About 18% of survivors experience long-term neurologic sequelae.
• Bacterial meningitis has a high morbidity and mortality rate.
• Bacterial meningitis diagnosis and early treatment is a high priority in primary care due to high mortality.
• Bacterial meningitis was most common in children younger than 5 years old, but with advances in vaccinations, meningitis is now more common in adults over 50 to 60 years of age.
• The annual overall incidence rate in the United States is 1.3 to 2 per 100,000 persons.
• Encephalitis is typically viral in origin, and is primarily caused by herpesviruses, arboviruses, and enteroviruses.
• Herpes simplex virus 1 (HSV-1) is the most common cause of encephalitis in the United States.
• Varicella zoster virus (VZV) is considered an uncommon cause of encephalitis.
• An increase in encephalitis caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus is occurring because of an increase in immunocompromised states.
• Encephalopathy associated with COVID-19 may be an autoimmune reaction to the virus rather than a direct infection.
• Viruses cause CNS infection by direct spread of cranial nerve or olfactory tract infections, reactivation of a latent virus within the CNS as in HSV, or viremia followed by spread across the blood–brain barrier.
• Untreated, HSV encephalitis is fatal in up to 70% of patients.
• Even with appropriate treatment, mortality for HSV encephalitis can still be as high as 20% to 30%.
• Autoimmune encephalitis caused by autoantibodies against neuronal surface or synaptic proteins is an emerging, likely underdiagnosed type of encephalitis.
• Meningitis can be divided into different types based on the organism involved.
• Historically, the terms septic and aseptic meningitis have been applied, pertaining to bacterial and viral infections, respectively, however, with the emergence of fungal, tuberculous, and chemical meningitis, this naming system has become vague.
• Viral meningitis is caused mostly by enteroviruses, for which there is a good prognosis and no specific therapy.
• Bacterial meningitis is usually spread hematogenously from another primary source (predominantly the respiratory tract) or by contiguous spread from sinusitis, mastoiditis, or otitis media.
• Group B streptococci and Escherichia coli are most common in children younger than 1 month.
• Listeria monocytogenes is more common in the very young (younger than 1 month) and adults older than 50 years.
• Streptococcus pneumoniae and Neisseria meningitidis are common causes in children and adults, with the latter seen in epidemics involving young adults.
• Haemophilus influenzae used to be the leading cause of meningitis in young children until universal vaccination.
• There has been a dramatic rise in multidrug-resistant S. pneumonia because of the widespread overuse of oral antibiotics.
• S. pneumonia meningitis has the highest mortality rate.
• L. Monocytogenes has a mortality rate of 30%.
• Mycobacterium tuberculosis is also seen not infrequently in adult CNS infections.
• Staphylococci and Gram-negative bacilli are seen in meningitis associated with neurosurgery and trauma.
• In 2012, 158 cases of iatrogenic fungal meningitis were reported in the United States in patients who received contaminated epidural steroid injections.

Pathophysiology

• Risk factors for bacterial meningitis are previous basilar skull fracture, recent infection or neurosurgery, implanted medical devices, intravenous drug use, diabetes, sickle cell disease, complement deficiency, hypogammaglobulinemia, asplenia, alcohol use disorder, immunodeficiency (HIV infection or organ transplant recipient), recent travel to an endemic area, and exposure to a community outbreak.
• Once the pathogen gains access to the cerebrospinal fluid (CSF), where there is little natural host defense, it replicates and releases bacterial cell wall proteins, which stimulate cytokine release and capillary leak.
• This process leads to the accumulation of protein and leukocytes, cerebral edema secondary to blood–brain barrier breakdown, microvascular thrombosis, and, ultimately, cerebral ischemia and hypoxia.
• Tissue damage in HSV encephalitis is believed to be both directly viral mediated and indirectly immune mediated.

Clinical Presentation and Physical Examination

• The onset of symptoms of CNS infection can be acute, subacute, or chronic.
• The classic adult presentation of bacterial meningitis is acute onset of fever, headache, and stiff neck (meningismus).
• Altered levels of consciousness, seizures, and hypotension predict a poor outcome.
• Nausea, vomiting, and photophobia are more common but can also be seen with migraine.
• Ear, sinus, or lung infections may precede pneumococcal meningitis.
• Older-adult patients may lack fever or meningismus but may be confused or even obtunded, often after an antecedent infection such as bronchitis, pneumonia, sinusitis, or urinary tract infection.
• Encephalitis manifests with signs and symptoms similar to those of meningitis but with more prevalent alterations in consciousness, focal neurologic signs, seizures, and autonomic and hypothalamic disturbances.
• Autoimmune encephalitis typically presents over a more subacute to chronic timeline and has prominent psychiatric symptoms.
• A physical examination reveals a fever in most patients.
• Nuchal rigidity, Kernig sign, and Brudzinski sign, all indicative of meningeal irritation, have low sensitivity but a moderate positive predictive value for meningitis in adults.
• In older adults, nuchal rigidity has an even lower sensitivity and specificity.
• Kernig sign is present if a patient in the supine position resists passive knee extension when the hip is flexed to 90 degrees.
• Brudzinski sign is present if a patient in the supine position actively flexes the hips when the neck is passively flexed.
• Jolt sensitivity (observing a worsening of headache when a patient moves their head 2 to 3 times per second horizontally) is another test for meningitis with low sensitivity but may be used as an adjunctive test.
• Purpura and petechiae are often associated with rapidly progressing meningococcemia but can be seen with other infections or can be a sign of disseminated intravascular coagulopathy.
• In patients with CNS infection, focal deficits may suggest brain abscess, cranial nerve inflammation, thrombosis, ischemia, or cerebral edema.
• Meningitis and encephalitis can lead to increased intracranial pressure (ICP), which manifests as depressed consciousness, sluggishly reactive or dilated pupils, ophthalmoplegia, respiratory depression, bradycardia, hypertension, posturing, hyperreflexia, and spasticity.
• It is difficult to distinguish aseptic meningitis from bacterial meningitis or encephalitis with clinical presentation alone.

Diagnostics

• Essential Diagnostics
  • Blood cultures entail two sets (positive in 19% to 70% of patients with bacterial meningitis).
  • Complete blood count (CBC) with differential, electrolytes, coagulation studies, and serum glucose concentration should be obtained immediately.
  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be useful for following the course of the illness.
  • Lumbar puncture (LP) must be performed in all patients with suspected meningitis or encephalitis.
  • The Infectious Diseases Society of America (IDSA) recommends obtaining a head computed tomography (CT) scan before LP if there are signs of altered consciousness, papilledema (surrogate for increased ICP), immunocompromised state (i.e., HIV), new seizures, history of CNS disease, or focal neurologic deficits.
  • Increased ICP would be a relative contraindication to LP because it can cause cerebral herniation.
  • Thrombocytopenia, other bleeding disorders, and epidural abscesses are also relative contraindications to LP.
  • A Swedish-based study demonstrated that eliminating altered mentation as a criterion for CT before LP resulted in earlier treatment initiation and improved outcomes.
  • A sample of the CSF should be sent for protein level, glucose concentration, Gram stain, culture, and cell count with differential.
  • A positive Gram stain examination of CSF has nearly 100% specificity, but a negative Gram stain does not rule out bacterial disease.
  • Further testing of the CSF with viral cultures, polymerase chain reaction, specialized stains, and cultures may be indicated.
  • Some studies have suggested that a CSF lactate level is useful in distinguishing between bacterial and viral meningitis however more study is required to determine the utility of this test.
• Additional Diagnostics
  • Opening CSF pressures should be measured in lateral decubitus position (normal values 180 WNL or mildly increased
  • Cell count (cells/mm3) 80% neutrophils) 10–10,000 (mostly lymphocytes)
  • Protein (mg/dL) 15–50 100–500 50–100
  • Glucose (mg/dL) 45–80 0.5

This module discusses initial steps for suspected CNS infections, including key symptoms that should raise alarm. It reviews common viral causes of encephalitis, mechanisms of infection, mortality rates, and factors contributing to shifts in affected demographics.