Case 4: Bacterial Meningitis

Case 4: Bacterial Meningitis -

Alice was a normal, full-term baby who was breast-fed and gained weight appropriately in the first 6 weeks of life. At 7 weeks she became acutely miserable, stopped feeding and her mother felt that she was very warm; when she took her temperature, it was 40°C. Her mother took her to the surgery where the doctor found that she had neck stiffness and Alice then vomited all over the couch. There was no rash or bruising but the left ear drum was inflamed. The doctor gave Alice an intramuscular injection of penicillin and instructed her mother to take her straight to the hospital where the on-call pediatrician was waiting.

Blood and cerebrospinal fluid (CSF) samples were taken immediately and intravenous antibiotics started. The CSF showed: increased numbers of neutrophil leucocytes (131 x 106/l) and a few Gram-negative coccobacilli despite the initial dose of penicillin. Culture, 3 days later, showed these to be Haemophilus influenzae and serotyping showed them to be Haemophilus influenzae type b. The full blood count showed: Circulating neutrophilia (29 x 109/l) and C-reactive protein level was 230mg/l.

Summary:  Meningitis

Meningitis is an infection that causes an inflammation of the meninges, or the membranes that protect the brain and spinal cord. If left untreated, meningitis can be life-threatening since the inflammation compromises the body’s central nervous system (CNS). In most cases, the disease results from bacterial invasion, but viral and, less commonly, fungal forms are also seen (Siegel A. and Sapru, H. N., 2011). 

The major complications resulting from meningitis are not so much directly attributed to the contamination itself, but rather the inflammatory response directed by the body’s immune system. Common symptoms include headache, neck stiffness, fever, and vomiting. Prolonged inflammatory responses may also evolve into edema-derived increases in cranial pressure, ultimately resulting in uncal herniation, or protrusion of the brain through its compartment in the skull. In addition, excessive inflammation can cause non-communicating hydrocephalus, or accumulation of cerebrospinal fluid (CSF) in the cavities of the brain, resulting from obstruction of the aqueduct of Sylvius (Tunkel A.R. et al, 2004).

 

Blood-Brain Barrier

The blood-brain barrier (BBB) is in charge of maintaining the homeostasis of the CNS environment by separating the brain tissue from systemic blood circulation. It is comprised of tight junctions between capillary endothelial cells, a basal lamina, and astrocytes with foot processes that surround the capillaries and conserve the barrier function. In addition, pericytes control the growth of endothelial cells and limit the transport of phagocytized compounds that have crossed the endothelial barrier (Vries H. et al, 1997). To further reinforce the barrier, endothelial cells have no pinocytotic vesicular activity to ingest substances and have enzymes that degrade blood-borne compounds. Normally, the BBB only allows the entry of compounds that possess certain physiochemical properties, like lipid soluble compounds, and strictly limits the passage of immune cells.

 

Blood-Brain Barrier Infiltration

The cerebral capillaries effectively protect the entry of circulating substances, including microorganisms, into the brain. However, meningeal infection occurs when normal immunologic processes are disrupted and bacterial microbes are able to infiltrate the BBB (Vries H. et al, 1997). Microglial cells are the major constituents of innate immunity within the CNS and are activated by bacterial products to protect the brain against infections. The LPS of gram negative bacteria triggers TLR-4 activation, causing the release of inflammatory mediators that participate in antibacterial immunity (2010, S. Liu and T. Kielian). During this response, the permeability of the BBB is increased by the opening of tight junctions and improved pinocytotic activity. The production of cytokines IL-1β and TNF-α by BBB cells contributes to the inflammatory response of the CNS after infection and makes the BBB more penetrable. Additionally, bacterial LPS and other bacterial toxins can break down the barrier (Vries H. et al, 1997).

 

Clinical Applications

Bacterial Meningitis Diagnosis

Evidence of invasion by a particular microorganism can be determined through laboratory analysis of the CSF. Bacterial meningitis is differentiated from viral and fungal types by performing a spinal tap to extract CSF from the CNS. In adults, a CSF sample is taken from lumbar regions 3-4 and in children, from the cerebellomedullary cistern. It is then analyzed for protein, glucose, WBC and PMN content. The fluid’s opening pressure is also measured and its color is observed. Bacterial meningitis is characterized by increased protein, decreased glucose, and increased PMNs and WBCs. Other symptoms include painful stiff neck with limited mobility, irritability, fever, and vomiting. In Case 4, the child presented with these physical symptoms plus elevated protein and PMN values, all indicative of a diagnosis of bacterial meningitis (Adarsh B., 2012).

Knowing how to deal with a case of bacterial meningitis in a clinical scenario is a very important aspect of our career as future physicians. We need to follow certain clinical procedures such as determining the white blood cell (WBC) count present in the cerebrospinal fluid (CSF) collected. This is done by collecting CSF through a lumbar puncture (see figure 4) procedure and measuring afterwards its CSF white blood cell count. If the WBC count is > 1.0 x 109/L (dominantly of neutrophils) we can make our diagnosis. We also hope to see elevated protein and a ratio of CSF glucose-to-blood glucose lower than 0.4 (Domino F. J., 2013).

Other procedures, such as doing a meningeal biopsy for detection of TB meningitis or a surgical drainage for intracranial hypertension can also be done. Another important aspect to consider is the process of analysis that needs to be done when encountering a bacterial meningitis case in the clinic. This is explained in figure number 5 (Domino F. J., 2013).

 

Questions

 

1. How is the normal dynamics for immunosurveillance of the central nervous system?

Immune surveillance of the central nervous system (CNS) is carried out by immune cells, e.g. lymphocytes, constantly recirculating from blood into CNS or in other organs and back to the blood or to secondary lymph organs using a multistep process of migration; it involves rolling, tethering of lymphocytes along vessel wall, activation, firm adhesion, and transmigration. Current scientific belief is that there is no routine immunological ‘‘survey’’ of the CNS, since barriers normally restrict the entry of lymphocyte populations into the brain, thus granting the CNS a state of relative immunologic isolation. Only lymphocytes in the activated state are able to enter the CNS, regardless of antigen specificity, T-cell phenotype, or recognition of major histocompatibility complex (MHC); they exist in the CNS and don’t leave the CNS unless they encounter a specific antigen.

 

2. What is the normal role of the blood-brain barrier? How is it affected during CNS infections?

The blood-brain barrier is the interface between the walls of the capillaries and the central nervous system tissue, i.e. the walls of the vessels that carry blood to the brain form the barrier. This barrier consists of tight junctions between neighboring capillary endothelial cells and astrocytic “end feet” processes that surround the outside of the capillary. It functions as an isolator and protector of the CNS neurons from many substances in the blood. The astrocytes help in the formation and maintenance of the BBB. Some regions of the CNS that monitor or secrete agents in the blood lack a BBB. These regions are located near the ventricles and are called circumventricular organs, which are highly vascularized. There are areas of the brain that lack BBB, and are points where the brain can monitor and sample what is happening in the body. Some examples of areas that are missing BBB are: Area Postrema, OVLT, pineal body, neurohypophisis, etc.

 

Bacterial infection of the CNS can result in abscesses and empyemas (accumulations of pus). CNS infections are classified according to the location where they occur. For example, a spinal epidural abscess is located above the dura mater, and a cranial subdural empyema occurs between the dura mater and the arachnoid. As pus and other material from an infection accumulate, pressure is exerted on the brain or spinal cord. This pressure can damage the nervous system tissue, possibly permanently. Without treatment, a CNS infection can be fatal.

 

3. What is the clinical significance of neck stiffness? What is the explanation?

Neck stiffness occurs in Bacterial Meningitis due to the inflammation of the arachnoid and pia matter (Haines 6th Ed). As a result of this inflammation, nerves are pinched as they traverse the meninges resulting in involuntary muscle spasms and in some cases tetany that culminate in a stiff neck (CMC 2014). Clinically, a stiff neck alone is not a complete sign for suspicion of Bacterial Meningitis. Nuchal rigidity should also be accompanied by positive Kernig and Brudzinzki signs. Alternatively, a stiff neck accompanied by two of the following symptoms are grounds to heavily suspect Meningitis: fever, headache, altered mental status, nausea, and vomiting (Mosby 6th Ed).

 

4. What other clinical signs can be associated with meningeal infection?

Bacterial meningitis usually begins with a headache and fever, which at this stage is difficult to differentiate from other diseases. Symptoms more specific to this kind of condition are the previously mentioned, including stiff neck and sensitivity to light. Later symptoms can include confusion, lethargy or seizures. In infants, you should be aware of the following symptoms: fever, irritability, lethargy, crying when moved, high-pitched cry, and seizures. For children older than 1 year: fever, stiff neck, headache, confusion, sensitivity to light, refusing to eat, seizures, nausea and vomiting are seen.

 

References

Adarsh B. Acute community-acquired bacterial meningitis in adults: An evidence-based review. Cleveland Journal of Medicine. 2012; 79(6): 393-400.

Domino F. J., Baldor R. A., Golding J., Grimes J. A., Taylor J. S. The 5-Minute Clinical Consult, 21st ed, 2013

Liu S. and Kielian T. Microglial Activation by Citrobacter koseri is mediated by TLR4 and MyD88 Dependent pathways. J Immuno. 2010; 183(9): 5537.

Siegel A., Sapru, H. N., Essential Neuroscience, 2^nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011: 41-42.

Tunkel A.R., Hartman B.J., Kaplan S.L., et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis., 2004; 39(9): 1267-84.

 

Vries H., Kuiper J., De Boer A., Van Berkel T., Breimer D., The Blood-Brain Barrier in neuroinflammatory diseases. American Society for Parmacology and Experimental Therapeutics, 1997.