Author: Labeeba Nusrat, Sponsored by Neurowiki2012

Bacterial meningitis is a form of meningoencephalitis that causes inflammation of meninges in the brain, particularly the arachnoid and the pia mater.[1] Apart from meningeal inflammation, it has also shown to affect other regions of the central nervous system (CNS), such as the parenchymal, ventricular parts of the brain including regions of the spinal cord. It is the most severe form and is particularly notorious for producing detrimental long-term clinical manifestations and life-threatening consequences in comparison to aseptic (i.e. viral or fungal) forms of meningitis.[1][2] Therefore, it is important to be able to differentiate bacterial meningitis from other milder forms through the employment of appropriate diagnostic tools to ensure that correct clinical treatments and antimicrobial therapy can be provided for individuals within an appropriate time frame. This will help to reduce the major neurological damages or even the risk of death. Forms of treatments can vary depending on the age and physiological condition of the affected individual.[2]





1. Pathophysiology


1.1. Common Pathogens


Pathogens implicated in causing bacterial meningitis are Strep­tococcus pneumonia (S. pneumonia), Haemophilus influenzae (H. Influenzae), Neis­seria meningitidis (meningococcus), Group B streptococci Listeria monocytogenes.[2][3] From these the most common pathogens are S.pneumonia and meningococcus, contributing to 61% of cases and 16% of cases in the United States respectively.[1][2] The general mechanism of invasion and promoting inflammation is similar for these bacteria however slight differences might exist making one more potent and aggressive than the other.[4] For example, mechanisms involved in nasopharyngeal invasion are different for meningococci and H. Influenzae type b. Meningococci undergoes endocytosis following mucosal colonization which leads to meningococcal meningitis; whereas, H. influenzae type b promotes cytotoxicity in epithelial cells with which it associates and promotes tight junctions to break down causing cell death and rapid movement of the bacteria. Different age groups might differ in terms which pathogens they are most susceptible; however, infants below the two years of age are the most in-danger population as they are susceptible to a broad range of pathogens causing bacterial meningitis.[2]

1.2 Nasopharyngeal Invasion

Defects in areas in and around the central nervous system can promote infections responsible for bacterial meningitis. Initial infections, prior to meningeal inflammation, originates usually in the nasopharynx. Healthy forms of pathogens that are usually present in the nasopharynx can become virulent which then colonize and invade nasopharyngeal host cells leading to infection. Several molecules or processes are involved in facilitating the initial colonization and systemic invasion of potent pathogens. For example, single or bundle of filaments called fimbrae, is one of the special organelles that is characteristic of these pathogens which allows them adhere well to epithelial cells and colonize the nasopharyngeal mucous properly.[4]

Immunoglobulin A (IgA) antibody which is responsible for preventing association of pathogens with the mucosal surface, is affected in two general ways by different pathogens: 1) IgA production is stimulated resulting in increased binding of pathogens with IgA and this reduces the capacity of other antibodies to attack these pathogens; and 2) IgA is cleaved and modified by pathogen-produced proteases which allows the pathogens to easily adhere to the mucosal layer of the nasopharynx.[4] Because most of these pathogens are unencapsulated, they survival rate is higher and can easily undergo phagocytosis and enter the blood stream.[1][4] Upon entering the blood stream, pathogens are able to cross the blood-brain barrier and cause inflammation of the meninges. Colonization of bacteria involved in causing meningitis usually colonize near regions that are richly vascularized for easy transporation via the bloodstream to parts of the central nervous system.[1]

These pathogens need to survive in the subarachnoid space following access into the brain through blood brain barrier and employs different mechanisms to reduce the ability of host defense mechanisms to promote pathogenic mortality. Bacterial meningitis-causing pathogens, inhibit, stimulate production of, or recruit molecules responsible for mediating defense responses to enhance their ability to infect host cells following access to the blood brain barrier, which makes it difficult to control the rate of infection.[4] Both the levels of complements and immunoglobulins reduce in concentration making leaving very little defense mechanisms on site to promote host-defence mechanisms to take control of the infection site. Complements, generally, can opsonize the infection site by tagging it leaving it as a potential site for destruction and phagocytosis, however, this ability is reduced following the entrance of pathogens into the blood brain barrier, leading to an increased number of pathogens in the cerebrospinal fluid (CSF).[4]

1.3. Factors in Inflammatory Responses

Most of the clinical symptoms or consequences that cause permanent damages to patients contracting bacterial meningitis are secondary to the inflammatory responses stimulated by potent pathogens. The initial processes of inflammation and pathogenic invasion through the BBB into the CNS occur almost simultaneously.[1] During BBB invasion, which follows nasopharyngeal invasion, these pathogens actively recruit molecules that are characteristic of the immune system to cause inflammation. Inflammation is not limited to the region of meninges but can affect other parts of the CNS (i.e. brain parenchyma and ventricles, and regions of the spinal cord). Increase in CSF neutrophillic pleocytosis, in particular granulocytes, is a hallmark of the onset of bacterial meningitis.[1][4] In general, neutrophils (leukocytes) are involved in the primary phases of infection.[5] Consequently, they are observed in large numbers in the initial stages of meningeal inflammation following infection in bacterial meningitis.[4] Following inflammation of the endothelial cells, adhesion molecules like I-CAM-1 are recruited which help in processes required to facilitate leukocyte invasion from the blood stream into the CSF.[6] Cytokine-mediated signaling gets the molecules coordinated which promotes leukocyte adhesion with endothelial cells of blood vessels prior to invasion.[4][5]
Lysis of cell wall of these pathogens, such as H.influenzae and S. pneumonia, is also known to be involved in initiating CSF inflammation through mediators such as IL-1, TNF, etc in inflammatory responses.[4][7] Structural patterns of these patterns are similar to many molecules crucial for the functioning of the body which make them look no different compared to other living bacteria (i.e. the structural motifs of lipoprotein, peptidoglacan, and etc).[8] Hoffman (2009) and Tunkel (1993) suggest that these structural motifs or in other words PAMP (pathogen-associated molecular patterns), such as, lipoteichoic acid, peptidoglycan, lipopolysachcharid, peptpdoglycans, on pathogens that cause bacterial meningitis are shown to promote inflammatory response in the CSF-containing subarachnoid space. CD14 and LBP are dectection molecules of the immune system that recognize these structural motifs of the meningitis-causing pathogens and in turn send signals to other molecules such as TLR which promote downstream signaling cascades via MAP Kinase pathway and other signaling pathways to rapidly facilitate inflammatory responses.[1]

1.4. Molecules in Neuronal Damage

In bacterial meningitis, release of multiple molecules involved in brain during pathogenic invasion in the subarachnoid space is common are responsible for causing inflammation, intracranial pressure, and neuronal damage. Neuronal damage is evident in patients with bacterial meningitis which nearly half of the survivors contracting neurophysiological and neuropsychological impairments.[1] Neuronal damage in hippocampus seems to be the most affected due to its proximity to the ventricles, facilitating most CSF contact and molecular diffusion to and from CSF to hippocampus and vice versa.Although it is suggested that patients with bacterial meningitis can have severe learning and memory deficits due to damages in the hippocampal neurons, it is unknown why neurogenesis is unable to regenerate in areas where neurons are damaged. Hofer et al, (2011), with the employment of neurosphere assay which allows for counting of new progenitor cells, was able to find out that stem cells or progenitor cells were more at risk of being damaged than neurons that were mature and differentiated in bacterial meningitis. To mimic the condition of bacterial meningitis, they used antibody mediated lysis of pathogens which released pathogen-associated factors in CSF - allowing the CSF of resemble CSF environment of the affected animals in vitro – and promoted rapid caspase-independent apoptosis of cells. In addition, sensory motor deafening due to loss of damage of spinal ganglion cells, vision loss, or other impairment in cognition were observed in patients with bacterial meningitis.[9] [10]
Inflammation might be one of the first components involved in neuronal damage. Leukocytes that enter CSF to initiate host defense responses, starting first with inducing inflammatory responses. The dual role of neutrophils in causing inflammation and sustaining pathogenesis is an established idea from previous publications.[4][5] Neutrophils following their temporary involvement in initiating defense mechanisms might switch their role from attaching pathogens to aiding pathogens by preventing mechanisms that might traverse pathogens from CSF back into the blood stream, making it more susceptible to be attacked by the immune system. Moreover, in a study, treatment of monoclonal antibodies reduced leukocyte-mediated neuronal damage by preventing pleocytosis in CSF.[11] This is because leukocytes, in addition to killing these pathogens, also release toxic factors which promote CNS damage.[12]
Two most aggressive forms of pathogens involved in causing bacterial meningitis produce cytotoxins that are pore-forming cytolysins: Streptococcus Group B producing b-hemolysin and meningococcus producing pneumolysin. Reiss et al. (2011) proposes that the specific roles of these cytotxins were related to neuronal damage. Their activity is caspase-independent which prevented inhibition by caspase-inhibitors, and these molecules adversely affected clinical outcome and promoted drastic weight loss in patients. Stimulated growth of toxins from these pathogens cause damages to the mitochondria which, in essence, facilitates programmed cell apoptosis.



1.5. Epidemiology

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Susceptibility of Bacterial Meningitis Contraction Based on Age Groups. (Picture reproduced from:http://microbiology2009.wikispaces.com/Bacterial+Meningitis)

Epidemiology is a good measure of understanding the significance of bacterial meningitis. Bacterial meningitis varies in terms of how it affects people on a global spectrum. Some age groups are more susceptible to contracting this form of meningitis in comparison to other age groups which makes it difficult to design different age-specific treatments. The most susceptible groups are children under the age of 5 years old and adolescents.[13] It is more prevalent in developing countries with poor resources than developed countries that are more industrialized. Apart from actual epidemics, 1 million cases are observed every year out of which 170000 are life-threatening.[14]

Meningococcal meningitis is the most prevalent form of bacterial meningitis around the world and is responsible for the majority of cases in children under 2 months of age. Fatal cases account for 3% to 19% in the developed countries, an incidence which is much lower than poor countries (37% to 60%) possibly due to delayed access to medical care. Preventative vaccinations against H. influenzae have declined rates of contraction in children by 50%, who were most susceptible.[13] World Health Organization (WHO) states that around 5% to 10% of people contracting meningococcal meningitis die within 24 to 48 hours after the initial onset of symptoms even if they receive appropriate and immediate treatments. Current continental incidence rates of bacterial meningitis are as follows: North America: 1.1 to 2 cases per year in United States and 3.66 to 3.37 out of 100000 people[15] ; Europe: up to 12 cases per year; Africa: up to 100000 cases per year.[1]



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Demographics of Bacterial Meningitis on a Global Spectrum. (Picture reproduced from: http://apex.oracle.com/pls/otn/f?p=2400:1001:2965398679913610::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,81511)




Meningitis Belt In Africa: Running from Senegel to Western Ethiopia

Regional Locations Most Prone to Epidemics

Regional Locations with Intermittent Cases Only












2. Clinical Symptoms


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Testing for Kernig's sign in patients with Bacterial Meningitis. (Picture reproduced from http://www.turner-white.com/pdf/hp_jul99_signs.pdf)

Onset of bacterial meningitis may produce several secondary physiological responses. Headache, fever, stiffness of the neck (meningismus)[1], impaired cognition are a set of cardinal characteristics of bacterial meningitis and at least of these features may follow 99 to 100 % of the time with the onset of meningitis-causing bacterial infection and inflammation in patients.[2] There are other very specific signs of bacterial meningitis, such as the Kernig and Brudzinsky symptoms, however it is quite difficult to detect them.[16] In patients with positive Kernig’s sign, they perceive pain when their hip is flexed 90 degrees and their legs are extended. In patients with positive Brudzinsky symptoms, the upon neck flexion, their hips and knees also flex. A featured rash may also present upon the onset of meningitis caused by N. meningitidis (meningococcus), H. influenzae, Streptococcus pnueomonia. Seizures, cognitive deficits and specific neurologically relevant symptoms are more specific to meningococcal meningitis.[2]
Symptoms may vary based on when the disease occurs, or in other words, the age of the patient. Patients over 65 years of age or below 5 years of age are less likely to exhibit the common symptoms that are associated with bacterial meningitis.[2] They may complain of being be tired, lethargic, and irritated; whereas, young adults may vomit, have headaches, rigidities , nausea and are more proned to seizures and hemiparesis. Other symptoms include phobia to light,sound, irritation of the meninges, and hearing loss.[1][10]


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Testing for Budzinski's Signs in patients with Bacterial Meningitis. (Picture reproduced from http://www.turner-white.com/pdf/hp_jul99_signs.pdf)

3. Diagnosis


Multiple processes are available for diagnoses and research is conducted constantly to improve diagnostic methods and enhance differentiation between different forms of meningitis, and more specifically, different forms of bacterial meningitis. It is very important that appropriate methods of diagnostics are employed to ensure detection of infection early enough to tackle the disease and prevent detrimental consequences, or even death.

3.1. Lumbar Puncture and CSF Gram Staining

Lumbar puncture is a process that involves needle insertion at the lower levels of the spinal cord of patients to draw out CSF for diagnosis. The CSF sample then undergoes both polymerase chain reaction (PCR) and culture analysis. A CSF profile is generated by testing the CSF culture for molecules or factors that are indicative of Bacterial Meningitis.[2] CSF samples can undergo polymerase chain reaction which can detect protein abnormalities better through immunoassays of the protein structures that make bacterial meningitis-causing pathogens distinguishable. However, PCR processes require a lot of time which creates difficulties during the process of diagnosis.[17] CSF cultures, in that sense, are more efficient.Quantifying lactic acid levels in CSF is a trustworthy method of distinguishing whether the patient has viral or bacterial meningitis. Bacterial meningitis that has been treated partially will have a CSF level of 3-6 mmol/liter and untreated patients will have an amount of over 6 mmol/liter.[17] CSF sample is also used to count number of neutrophils.[3] Gram staining of CSF proteins allows distinguishing of abnormal protein structures that are characteristic of the particular pathogens of interest. Patients are usually 60 to 70% positive on Gram stain, confirming their diagnosis of having bacterial meningitis.[2] Following gram staining, PCR, and other forms of CSF sample analysis and a positive diagnosis of patients with bacterial meningitis, specific antimicrobial therapies should be provided immediately before condition worsens.

3.2. Sleepex Meningitis ACE Detection Kit

Shin et al. (2011) has formulated a new technique of detecting 12 different forms of microorganisms that can cause different forms of meningitis. The kit consists of three components which allow for it to detect five types of bacteria that cause bacterial meningitis, 6 types of viruses that cause viral meningitis, and human enterovirus which also causes viral meningitis. They performed PCR to create a genomic library of the pathogens they were interested in which were responsible for causing either viral or bacterial meningitis. The detection kit contains primers for all of these bacteria and viruses of interest and is able to detect CSF samples of patients. This detection ability was initially tested by using vector cells with genes of these bacteria incorporated into it. These genes are reliable reference strains of the pathogens. The kit has performed with high accuracy in terms of the level of sensitivity for detecting these pathogens in CSF samples of patients. Therefore, it is highly encouraged that this kit is employed for quick detection of pathogens from patient CSF samples.[3]



3.3. Other Forms

A computed tomography (CT) is also suggested for patients with bacterial meningitis at the early stage of detection.[1] Whether it should be used prior to CSF analysis remains controversial. The reason why CT is given significant importance to is because it is able to provide information about the brain structure and inform the clinician as to where there are any structural abnormalities like edema, intracranial pressure, hydrocephalus and any infarctions. It is important to know about intracranial pressures before CSF analysis, since it can have major effects on neurological functioning which might be responsible for secondary or more permanent behavioural and neurophysiological deficits. Moreover, clinicians have to use sound judgment to determine how long they should wait before their patient can receive treatment. If clinical symptoms are very suggestive of the pathogenesis, treatment should be initiated prior to obtaining results from diagnostic procedures to avoid lethal secondary consequences, or death.[1]




4. Treatment


Most treatments are designed to treat a variety of pathogens causing bacterial meningitis. They usually attack the pathogens, or reduce primary complications that arise upon the onset of the disease. Specific, secondary symptom-specific treatments are also available, for example, resorting to cochlear implants for sensorymotor deafness. Demel et al. (2011) showed in their study that providing neurotrophic growth factors such as neurotrophin-3 to patients who have been suffering from long-term deafness resulting from pneumococcal meningitis, had improved hearing abilities. Therefore, growth factors may help to grow back and reform some of the damaged neuronal connections and restore neurological functioning.[10]

4.1. Anti-Microbial Therapy (Antibiotics)

Providing treatment as quickly as possible is imperative. If delays during diagnosis occur, it is important that therapies are started before hand. Anti-microbial therapy is the initial form of treatment given to get the pathogens in control and ensure that further harm is not done to the body. Which form of medications are given depend on age, existing body condition, type of bacteria responsible for the onset of meningitis and the resources available around the clinic.[1] To ensure that the antimicrobial treatment works successfully, it is important to identify the type of pathogen and how likely it is that the patient going to be affected by it. Bamberger et al. (2010) provides detailed lists (See Tables1 and 5 from Bamberger et al. (2010)) of the types of antibiotics that are age-appropriate and are geared towards treating specific types of pathogens following variable durations of application depending on the severity of onset and the healing properties of the therapy itself. Treatment durations are generally 10 to 14 days for treating most pathogens, however, shorter durations can also be adhered to if the complications are less severe.[1]
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4.2. Corticosteroids

Steroids can also be used as supplemental forms of treatment along with anti-microbial therapy. Corticosteroids are known to reduce inflammation, consequently reducing brain swelling, and intracranial pressure. If neuronal damage is arising due to increased inflammation in patients, treating them with corticosteroids should help to reduce neuronal damage by reducing inflammation in those areas. For example, reduce chances of losing hearing.[1] Dosage of steroid should precede antibiotic treatment, by 10 to 12 minutes, since delaying steroid application will not be beneficial due to the possibilities of irreversible neuronal damage due to inflammation.[1]4.3. Induced Hypothermia
Although rare, hypothermia has remained a treatment for conditions pertaining to neurological and other physiological deficits. Lepur et al. (2011) specifically use induced hypothermia as a form of treatment towards infections in the CNS. Hypothermia can protect neuronal function by helping regulate other mechanisms, such as reducing reactive species (i.e. oxygen and nitrogen), hyper activation of neuronal signaling, cytokine-mediated inflammatory responses, intracranial hypertension, and programmed neuronal death. Mechanisms that are employed by pathogens during the onset of the disease are very temperature dependent. Therefore, allowing patients to get a cold treatment of around 34 degrees Celsius, interfered with processing of mechanisms by pathogens, and in essence, resulting in the improvement of their health. Although newly tested, this form of treatment looks promising, especially for patients with bacterial meningitis.

4.4. Preventative Care

Vaccinations are always being improved to reduce susceptibility to existing or any modified strains of the pathogens causing bacterial meningitis. However, the role of vaccinations is only preventative and might not be available to populations all over the world, leaving them at risk of contracting bacterial meningitis. The most successful vaccine developed so far is the one against H. influenza virus which has greatly reduced the risk for children from getting bacterial meningitis.[13] Adolescents are provided with vaccinations in their school to ensure they receive their vaccines on time to protect themselves from contracting meningitis. Preventative measures have also involved focusing on raising awareness for staying away from smoking cigarettes, or travelling to areas of outbreaks.[13]

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  2. ^ Bamberger, D. M. Diagnosis, initial management, and prevention of meningitis. Am Fam Physician 82, 1491–1498 (2010).
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    Shin, S. Y. et al. Evaluation of the Seeplex® Meningitis ACE Detection Kit for the Detection of 12 Common Bacterial and Viral Pathogens of Acute Meningitis. Ann Lab Med 32, 44–49 (2012).
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    Tunkel, A. R. & Scheld, W. M. Pathogenesis and pathophysiology of bacterial meningitis. Clin Microbiol Rev 6, 118–136 (1993).
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  6. ^ Freyer, D. et al. Cerebral endothelial cells release TNF-alpha after stimulation with cell walls of Streptococcus pneumoniae and regulate inducible nitric oxide synthase and ICAM-1 expression via autocrine loops. J. Immunol. 163, 4308–4314 (1999).
  7. ^ Winkelstein, J. A. & Tomasz, A. Activation of the Alternative Complement Pathway by Pneumococcal Cell Wall Teichoic Acid. J Immunol 120, 174–178 (1978).
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  9. ^ KENNEDY, W. A. et al. Incidence of bacterial meningitis in Asia using enhanced CSF testing: polymerase chain reaction, latex agglutination and culture. Epidemiol Infect 135, 1217–1226 (2007).
  10. ^ Demel, C. et al. Reduced spiral ganglion neuronal loss by adjunctive neurotrophin-3 in experimental pneumococcal meningitis. Journal of Neuroinflammation 8, 7 (2011).
  11. ^ Tuomanen, E.I., Saukkonen, K., Sande, S., Cioffe, C., Wright, S.D. (1989) Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes. J Exp Med 170, 959–969 (1989).
  12. ^ Reiss, A. et al. Bacterial pore-forming cytolysins induce neuronal damage in a rat model of neonatal meningitis. J. Infect. Dis. 203, 393–400 (2011).
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    Gold, R. Epidemiology of bacterial meningitis. Infect. Dis. Clin. North Am. 13, 515–525, v (1999).
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    Government of Canada, P. H. A. of C. Bacterial Meningitis In Canada: Hospitalizations (1994-2001) - CCDR Vol. 31-23 - Public Health Agency of Canada. (2005).at <http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/05vol31/dr3123a-eng.php>
  16. ^ Thomas, K. E., Hasbun, R., Jekel, J. & Quagliarello, V. J. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis. Clin. Infect. Dis. 35, 46–52 (2002).
  17. ^ Cunha, B. A. Cerebrospinal Fluid (CSF) Lactic Acid Levels: A Rapid and Reliable Way To Differentiate Viral from Bacterial Meningitis or Concurrent Viral/Bacterial Meningitis. J. Clin. Microbiol. 50, 211–211 (2012).