Acute bacterial meningitis is a menace in developing nations like India. Despite the advances in medical diagnostics and therapeutics, the mortality and morbidity associated with meningitis is high. Understanding the pathophysiology of meningitis is important to ensure that the clinical features are recognise in a timely manner and appropriate treatment is instituted immediately.

The Monro-Kelley doctrine or hypothesis states that the sum of volumes in the brain will always remain constant due to the constricting pressures of the skull. There are three volumes in skull - brain parenchyma, CSF and blood. In meningitis, there is inflammation of the meninges which leads to increased CSF pressure and also parenchymal edema, both of which contribute to neuronal damage. At the same time they also cause compression of the vessels which can lead to ischemia and further neuronal damage.

So here is the take away - edema is major damaging factor in meningitis. How does it happen? Let’s find out.

What is bacterial meningitis?

Bacterial meningitis is infection and inflammation of the meninges covering the brain. The pia and arachnoid mater are commonly involved (aka. leptomeninges). The invasion of the meninges by bacteria seeds into the subarachnoid space and CSF with subsequent dissemination.

What are the phases of bacterial meningitis?

1. Bacterial invasion

2. Inflammation

3. Neuronal damage

How does bacterial invasion take place?

It is accepted that the most common route of infection is through the blood stream. While the exact site of entry is unknown, the choroid plexus is assumed to be site of entry.

Anatomical breaks in the CNS defences can also lead to seeding of the infection into the meninges. Orofacial trauma, especially fracture of the base of the skull can easily cause seeding of the infection into the meninges.

In addition, most of the bacteria implicated in meningitis have specific features which allow them to enter and cross the blood brain barrier. Examples of these features include:

• Streptococci - CbpA protein interact with platelet activating factor and promote endocytosis

• Meningococci - PilC1 adhesin interacts with CD46 and connects to integrins and adheres to the BBB

What is the inflammatory response?

The first structure that is damaged by pathogenic bacteria are the vascular endothelial cells and the endothelial cells lining the meninges. Endothelial damage weakens the CNS defences. A weakened endothelium leads to further transmigration of bacteria and also rapid leukocyte recruitment.

The presence of leukocytes, especially granulocytes, is one of the hallmarks of meningitis.

Once the bacteria enter the subarachnoid space, they replicate in the CSF, undergo autolysis and can promote inflammation even further.

Remember that live bacteria AND the products of dead bacteria can lead to a continued inflammatory response in the CNS. Invasion of bacteria and the inflammatory mediators released by the leukocytes synergistically damage the blood brain barrier creating a vicious cycle.

How are the neurons damaged?

The neuronal damage is caused by live bacteria, products of dead bacteria and body’s inflammatory response.

Some live bacteria have toxins which can directly damage the neurons. For example, Streptococci release hyderogen peroxide and pneumolysin which can both directly damage the neurons.

The products of dead bacteria like lipopolysaccharides and prostaglandins activate the leucocytes. They are recognized by toll like receptors and presented by antigen presenting cells. This can in turn, induce an acute cytotoxic response and also a delayed antibody based response.

Activated leucocytes release inflammatory mediators like matrix metaloproteinases (MMPs) and Nitric oxide (NO) which can lead to local damage and also promote further leucocyte invasion.

• It has been noted that the presence of leucocytes in the CSF does more damage than good. Newer therapies are targeting the leukocyte recruitment systems to try and inhibit or diminish the leukocyte response and the subsequent inflammation.

• The cytokine TRAIL was recently shown to reduce the lifespan of activated granulocytes. Mice with TRAIL deficiency had a more profound neurotoxicity in experimental meningitis. TRAIL supplementation, on the other hand provided neuroprotection.

Recent studies have shown that the most vulnerable area of the brain is the hippocampus. One of the commonly documented sequelae of meningitis is hippocampal atrophy. This is hypothesised to be because of the proximity of the hippocampus to the third ventricle. Depending on the viral load and the strength of the inflammatory response, other areas of the brain can also be affected.