Central Nervous System infections – What happens when pathogens reach the brain?

CNS infection – A devastating and deadly illness

Infections of the central nervous system (CNS, which consists of the brain and the spinal cord) are severe and devastating diseases caused by pathogens, e.g., bacteria, fungi, viruses, or parasites capable of invading the CNS through different routes.

These infections can affect the meningeal or parenchymal compartments and mainly involve meningitis, encephalitis, and brain abscesses

While meningitis is an inflammatory process of the meninges (i.e., three membranes surrounding the brain and spinal cord), encephalitis is inflammation in the brain parenchyma caused by infectious microbes. In addition, brain abscesses are also an infectious inflammatory process in the brain known for the formation of pus-filled swelling in focal lesions. They usually start as localized cerebritis and then evolve to these encapsulated collections of pus, inflammatory cells, and dead brain tissue cells.

According to a systematic review from 2019 regarding the global burden of CNS infections that require neurosurgical intervention, bacterial meningitis has an incidence of 9,7% of cases worldwide, with Africa presenting the highest rates. In contrast, intracranial abscesses reach 3,6% of the population and are primarily reported in Southeast Asia. Table 1 shows the global burden of CSN infections by evaluating seven different regions.  

Table 1. Relation between the global incidence of CNS infections in seven different regions and the number of individuals affected4

 

 

Pathogens mechanisms and pathways into the CNS

Although there are specialized physical barriers to protect our CNS from these pathogenic agents and their neurotoxins, 

CNS infections still present a significant morbidity and mortality rate due to the inherent complexity involved in their treatment

Three biological barriers that protect our CNS from pathogens are the blood-brain barrier (BBB), the blood-cerebrospinal fluid barrier (BCSFB), and the arachnoid barrier (Fig. 1).

The BBB is a highly selective structure formed by endothelial cells connected by junctional complexes that promote cell-cell adhesion (e.g., adherens and tight junctions), which compose the wall of the brain microvessels. These junctions limit the paracellular crossing and diffusion of molecules, circulating immune cells, potential toxic plasma components, and pathogens into the brain parenchyma.

 

Figure 1. Representation of the three biological barriers responsible for the protection of the CNS.  A) The Blood-Brain barrier, B) The Blood-Cerebrospinal fluid barrier, and 3) The Arachnoid barrier

 

            However, even though the BBB is one of the tightest barriers in the body, some pathogenic microorganisms manage to bypass it, consequently causing diseases. Some of their mechanisms for neuroinvasion through the BBB include (Fig. 2):

  1. Damage of the brain endothelium; 
  2. Transcytosis (i.e., vesicle-mediated transport of macromolecules); 
  3. Paracellular entry (via disruption of the junctional complexes or damaging of endothelial cells); 
  4. Trojan-horse-mediated entry (via infected leukocytes);  
  5. Via transendothelial entry within the CSF compartment by crossing the BCSFB.

Figure 2. Pathogens pathways through the BBB for neuroinvasion. Different pathogens are represented in the image, such as viruses, fungus, parasites, and bacteria. Their mechanisms to enter the CNS are also depicted.

 

Which pathogens are the most common agents in CNS infections? 

The list of agents that usually causes bacterial meningitis includes Listeria monocytogenes, Escherichia coli, Mycobacterium tuberculosis, Bacillus anthracis, Haemophilus influenzae, Neisseria meningitides, and Streptococcus pneumoniae. The latter three are responsible for the most common causes of bacterial meningitis in infants and adults worldwide. They initially colonize within the human nasopharynx until gaining access to the bloodstream and the cerebrospinal fluid (CSF), finally invading the CNS

On the other hand, more than 85% of viral meningitis cases, often referred to as aseptic meningitis (i.e., when bacterial cultures are not isolated from the CSF), are associated with enteroviruses (e.g., Coxsackie viruses and echovirus). However, other viruses, such as Herpes simplex virus (HSV, types 1, 2, and 6), Varicella-Zoster virus (VZV), human cytomegalovirus (CMV), mumps virus, and HIV, may also cause this disease.  

 

HSV, VZV, CMV, and HIV are usually responsible for causing either meningitis or encephalitis in immunocompromised patients3,13 

Arthropod-transmitted viruses, for instance, West Nile virus, La Crosse virus, Dengue virus, and Chikungunya virus, may also be associated with cases of meningitis and encephalitis.

Regarding encephalitis, around 70% of cases are caused by viruses, with HSV, West Nile virus, and enteroviruses being the most prevalent ones (Said & Kang, 2019). Some of the less frequent viral agents include VZV, Epstein-Barr virus, CMV, measles virus, mumps virus, and flaviviruses (e.g., Dengue virus, Zika virus, and Japanese encephalitis virus)

CNS fungal infections are rarer than bacterial and viral ones and are mainly restricted to immunocompromised individuals. Therefore, opportunistic fungi are less observed to cause meningitis or meningoencephalitis (i.e., simultaneous inflammation and infection of both meninges and brain parenchyma)15. Among fungal organisms, Cryptococcus neoformans and Coccidioides immitis are the two species commonly associated with fungal meningitis or meningoencephalitis, followed by Histoplasma capsulatum Blastomyces dermatitidis, Zygomycetes, Aspergillus spp, and Candida spp. Except for the latter two, all the species mentioned above generally affect immunocompetent hosts. Depending on the environmental conditions, these agents colonize and infect the CNS either as mold, dimorphic fungi, or yeast

In the case of brain abscesses, Streptococcus spp. and Staphylococcus spp (both Gram-positive bacteria) are associated with the majority of bacterial cases, followed by anaerobic bacteria (e.g., Bacteroides spp., Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., and Prevotella spp.) and subsequently by Gram-negative bacteria (Klebsiella spp, Pseudomonas spp, E. coli, Proteus spp, Haemophilus spp).  As well as in meningitis and encephalitis, fungal abscesses cases are rare and are usually associated with Aspergillus spp, Candida spp, and C. neoformans. Nearly 15.0% of brain abscess cases are polymicrobial infections, which are diseases induced by multiple microorganisms.

 

Clinical aspects of CNS infections and their diagnosis

 Clinically, the main symptoms of meningitis include fever, headache, altered mental status (also known as the classic triad), and nuchal rigidity, with patients generally presenting at least two of the four symptoms17. Similarly, encephalitis also leads to fever, headaches, and mental status changes; however, this mental status may range from delirium to coma, with or without the presence of neurological deficits and seizures. Lastly, because brain abscesses are localized lesions, their clinical presentations may vary according to the specific site compressed or affected by the lesion.

When physicians suspect that a patient has one of the previously discussed CNS infections, they should submit the individual under a series of essential diagnostic studies to evaluate potential brain lesions and the etiologic agent involved in them to apply the best treatment.

 

The diagnostic procedure usually involves magnetic resonance imaging, computed tomography, electroencephalography, and CSF analysis, including molecular and serologic testing2,3,5,18

Since it is crucial to identify the pathogenic agent causing the disease, CSF culture and bacterial stain are frequently used as detection methods. Nevertheless, these techniques present some challenges once they may lack sensitivity or specificity19. A more rapid, sensitive, and specific possible approach for clinical settings is PaRTI-Seq® (Pathogen Real-Time Identification by Sequencing). With Devin® filter which produces pathogen-enriched samples ready for downstream diagnostic applications in just 5 minutes, PaRTI-Seq® allows to get test results within less than 24 hours. This presents a promising method for rapid diagnosis followed by an efficient treatment which can significantly decrease the morbidity and mortality of CNS infections in future. You can learn more about PaRTI-Seq® and Devin® filter in the latest paper Novel Human Cell Depletion Method Enables Rapid Pathogen Identification by NGS.

Micronbrane Medical provides an easy and rapid solution with two products: Devin® and PaRTI-Seq® (Pathogen Real-Time Identification by Sequencing). Devin® membrane produces pathogen-enriched samples ready for downstream diagnostic applications. PaRTI-Seq® technology combines the latest third-generation sequencing (Nanopore Sequencing) and proprietary analytical methods, to provide test results within 22 hours.