martes, 24 de abril de 2018

Meningitis Research

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By Liji Thomas, MD

Meningitis is a term which refers to the inflammation of the meninges, the membranes that surround and protect the brain and spinal cord.

Credit: Jarun Ontakrai/Shutterstock.com

Meningitis typically occurs due to a bacterial or viral infection, but other conditions are sometimes responsible, including fungal or parasitic infection, certain autoimmune inflammatory conditions, trauma, or drug reactions.

Despite being the subject of research for many years, treatments for meningitis are still unsatisfactory in certain respects, with adult meningitis still having a very high mortality rate, despite the discovery of several potent antibiotics. Hence, research is underway in several areas to increase our understanding of meningitis and ability to control the pathogens causing this disease.

Pathogenesis of meningitis

In most cases of meningitis, the pathogenesis is still unknown, and researchers are still attempting to clarify how the brain and spinal cord react to the presence of an inflammation. It is also important to elucidate the mechanisms that underlie the breaching of the crucial blood-brain barrier in this disease.

Understanding how the pathogens are able to infiltrate the brain could guide the development of novel treatments that prevent or resolve inflammation of the neural system. One such method being researched is neuroprotective molecules that can inhibit the occurrence of damage after infection of the meninges.

Research is also underway to find out how exactly the meningeal inflammation produces neurologic complications including permanent brain damage, intellectual disability, and stroke.

Research into the etiology of meningitis

In most cases, aseptic or viral meningitis is a mysterious condition whose etiology remains unknown in almost 50% of the cases. This is partly due to a lack of effective diagnostic technology available for routine testing.

The relative insensitivity and lack of specificity of the clinical signs make them unreliable in the diagnosis of meningitis. For this reason, CSF studies should always be done if meningitis is suspected. In such a case, however, the CSF study picks up at the most only 80% of the cases of bacterial meningitis (BM), and other etiologies go undiagnosed.

This means that more research is required to help diagnose urgent treatable causes of meningitis early, using techniques such as the assay of several potentially diagnostic cytochemicals in serum and CSF. Such assays are important in the prompt diagnosis, which is key to timely intervention in patients where direct CSF examination (by Gram staining and culture) yields a negative result.

They are also vital in preventing avoidable mortality. This is important, as meningitis caused by unknown agents accounts for 36% deaths in elderly patients, compared to only 3% in younger patients.

Improving the diagnosis of meningitis

Markers such as CSF lactate and procalcitonin promise to partially solve the diagnostic dilemma. In one study, a cut-off value of 3.8 mmol/L for CSF lactate demonstrated a 94% sensitivity with a 97% specificity in diagnosing bacterial meningitis, and this has been confirmed as a valuable test by a French consensus conference on the treatment of bacterial meningitis.

Other markers under investigation include serum C-reactive protein (CRP), and serum procalcitonin. The latter is elevated at just 2 hours from the onset of inflammation, and can distinguish BM from viral meningitis at cut-off levels varying from 0.2 to 2 ng/mL. In one study, a cut-off set at 0.28 ng/mL was claimed to have a sensitivity of 97% and a specificity of 100%.

Newer techniques such as multiplex PCR, proteomics and genomics sequencing, may help to reach the diagnosis more accurately and quickly. PCR, for example, would help distinguish viral from bacterial meningitis, in about half the cases, thus preventing inappropriate antibiotic prescriptions and even reducing the total duration of hospital stay.

The diagnosis of BM used to be made using CSF culture, looking for CSF pleocytosis with a predominance of neutrophils, reduced CSF glucose, and increased CSF protein. The need for laboratory set-ups and time periods (up to 48 hours for CSF culture results) counteracts the increased accuracy of diagnosis especially if pre-admission antibiotics have been administered.

Differentiating between meningitis types

Any delay in initiating antibiotics may increase the risk of mortality and severe neurological sequelae, but using antibiotics too often has led to the emergence of resistance. This has led researchers to look for a quick and easy marker for point-of-care testing and diagnosis of BM.

Many African countries have endemic malaria and thus acute BM needs to be distinguished early from cerebral malaria (CM). In absence of this facility, empirical antibiotic use becomes necessary. Some experiments show that the proteome response in the CSF of the host to acute BM is quite different from that to CM.

Proteomics is a fertile area of analysis of proteins in fluids such as plasma and CSF. It may provide specific patterns of host proteins that distinguish different types of meningitis such as pneumococcal, enteroviral, and meningococcal meningitis, or which help quantify the mortality in pneumococcal meningitis. The two key chemicals found to be different include myeloperoxidase and lactotransferrin, with a sensitivity and specificity of about 97%-100%, respectively.

Other studies have shown that several inflammatory mediators such as TNF-α, and interleukins 1, 6, 8, 10 and 12 are present at higher levels in infantile BM. Researchers are working on combinations of cytokines that have a discriminatory value in the diagnosis of different types of meningitis in infants, as well as for avoiding unnecessary treatment of infants who have bacteria in their bloodstream but not meningitis.

Research into treatments

At present, many researchers are attempting to determine which adjunctive treatments can improve the mortality rate in this disease, as antibiotics alone are often not enough to cure the patient. Such corollary treatments include corticosteroids to fight the inflammatory damage and polyvalent vaccines, which are considered to be the best method to reduce mortality by bringing down the disease incidence.

Glycerol and mannitol have been administered in some cases to reduce intracranial pressure in meningitis. Studies show that glycerol may reduce the incidence of deafness but does not affect other complications such as gastrointestinal bleeding, nausea, vomiting, or the mortality rate.

Susceptibility to meningitis as well as the predicted outcome of the disease are other areas of interest, and studies are going on to identify genetically determined variation in the degree and extent of complement activation that may influence the treatment offered, such as the use of complement inhibitors in BM.

Neurologic sequelae may be reduced by metalloproteinase inhibitors based upon the work done to elucidate the role played by metalloproteinase enzymes in this area. Various combinations and dosage levels of appropriately used antibiotics are also undergoing testing to determine the most effective type of treatment. Best practice in emergency care and neurological treatment is also currently being determined, as well as the search for better options.

Finally, vaccines that act against several different types of disease-causative agents to prevent meningitis have been developed, and efforts are on to increase their availability and application across the world, to reduce the burden of the disease.