Bacterial meningitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

The major advancements in the history of bacterial meningitis started in the 16th century by description of an epidemic of meningitis by Thomas Willis. Later on, Robert Whytt and John Cheyne described the stages of tuberculous meningitis in the 17th century. In the 18th and 19th century, major advancements were made regarding CSF analysis and lumbar puncture technique. In the late nineteenth century, causative organisms for bacterial meningitis was identified which includes Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae. The use of antibiotics such as penicillins was in use since 20th century for the treatment of bacterial meningitis.^[1][2]

The major advancements in the history of bacterial meningitis may be summarized as follows:^[1]

• Meningitis may have been described in the Middle Ages, but it was first accurately identified by the Swiss Vieusseux (a scientific-literary association) during an outbreak in Geneva, Switzerland in 1805.
• In 1661, Thomas Willis first described the inflammation of meninges and an epidemic of meningitis.
• In the 17th century, Robert Whytt provided a detailed explanation of tuberculous meningitis and its stages. This was further elaborated by John Cheyne in the same century.
• Meningococcal meningitis was than described by Gaspard Vieusseux, Andre Matthey in Geneva and Elisa North in Massachussetes
• In 1891, Heinrich Quincke provided an early analysis of CSF by introducing a new technique of lumbar puncture.
• In early 19th century, detailed profile of CSF analysis in meningitis was explained by William Mestrezat, and H. Houston Merritt.
• In the late nineteenth century, causative organisms for bacterial meningitis was identified which includes Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae
• Advancements regarding the treatment of bacterial meningitis was given by Georg Joachmann in Germany and Simon Flexnor in USA in 18th and 19th century respectively
• Francois Schwentker introduced the use of sulfonamides for the treatment of meningitis in the 20th century
• Penicillin use was introduced by Chester Keefer in the 20th century
• In the 20th century, another remarkable achievement was attained by introduction of vaccine agianst N. meningitidis and H. Influenza

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

There is no specific classification system for bacterial meningitis. However, it may be classified according to the age group, causative agent, clinical presentation, severity and duration of illness. Prognosis of bacterial meningitis may depend on the severity of the disease and causative agent.^{[1][2][3][4][5][6][7]}

Bacterial meningitis may be classified according to the age group, causative agent, severity, and duration of disease.^{[1][2][3][4][5][6][7]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

Pathogenensis of bacterial meningitis may include the transmission, colonization, invasion and seeding of meninges. It is a complex process involving interaction between bacterial pathogenic elements and host immune response. There may be genetic predisposition to develop infection. The sequence of events that may ensue after bacterial invasion of meninges include injury to the blood brain or blood CSF barrier, disruption of intercellular tight junctions, vasogenic edema, loss of cerebral autoregulation, increased intra cranial pressure, and development of Signs and symptoms due to raised IC pressure. The inflammatory molecules which may play a role in this pathogenic process includes interleukins IL1, IL6, TNF and matrix metalloproteinases.^{[1][2][3][4][5][6][7][8][9]}

Pathogenesis of bacterial meningitis is a complex process which may occur due to imbalance between the host immune response and virulence factors of pathogen causing infection. Following steps may explain the underlying process in a comprehensive way: ^{[1][2][3][4][5][6][7][8][9][10]}

• H. influenza type b and N. meningitides may be transmitted by close contact or prolong contact with patient suffering from meningitis^[10]
• It may also spread by exchanging throat and respiratory secretions (coughing and kissing)
• Listeria monocytogenes may spread by eating contaminated food.
• Most people are carriers and do not develop the disease.

• Colonization of pathogenic organism involves evasion of host immune response mechanism.
• IgA protease produced by bacterial pathogen cleave mucosal IgA antibodies which prevent the bacteria from attachment to the mucosal surface.^[1][2]
• Once host immune response is evaded, bacteria attach themselves to the mucosa via fimbriae or pilli which facilitate colonization process.

• Once colonized, the invasion of bacteria occurs via special adhesion proteins called adhesins.^[1]
• Adhesins may help bacteria to cross epithelial barrier intracellularly or intercellularly.
• Bacteria seeds transcellularly to enter the intravascular space.
• Surface encapsulation may play important role in entry of bacterial pathogen across epithelium into blood stream
• Blood stream entry of bacterial pathogen may result in activation of complement pathway and inflammatory process^[3]
• Bacterial capsule helps evasion of complement system and ultimate entry into the CNS through blood brain barrier^[3]
• Individual genetic susceptibility and immune response determine the severity of infection

• Meningeal inflammation follows bacterial invasion into the blood.^[11]
• Bacterial entry into brain may occur through highly vascularized areas such as leptomeningeal blood vessels or choroid plexus.
• Intracranial entry of bacterial pathogen through tight junctions of blood CSF or blood CNS barrier may occur through special interaction of adhesins and proteins on the surface of choroid epithelial cells^[12]

Inflammatory molecules and bacterial components which may play a role in the pathogenesis of bacterial meningitis may include following:^[13][14]

• Subcapsular bacterial surface components-teichoic acid and peptidoglycans^[14]
• Bacterial lysins-pneumolysins in strept pneumoniae
• Bacterial lipoligosaccharide or lipopolysaccharide-N.meningitides and S.pneumoniae
• In situ production of inflammatory cytokines such as IL-1, IL-6, TNF, and matrix metalloproteinases^[13][14]

• Once inflammation sets in due to combination of bacterial components and host inflammatory cytokines, the sequence of events that causes signs and symptoms may be as follows:^[7][15]
• Injury to the blood brain or blood CSF barrier
• Disruption of intercellular tight junctions
• Vasogenic edema
• Loss of cerebral autoregulation^[15]
• Increased intracranial pressure
• Signs and symptoms of raised IC pressure

• Inflammatory mediators and molecules such as nitric oxide, reactive oxygen species and amino acids
• Neuronal damage, neuronal apoptosis, and brain ischemia may result in complications such as infarction, hydrocephalus and brain abscess

Following conditions may increase the susceptibility to develop bacterial meningitis:

• Trauma to skull
• HIV
• Diabetes mellitus
• Organ transplant
• Immunosuppresion

• Genetic polymorphism in the individuals may determine the susceptibility to develop bacterial meningitis, the severity of infection and the ability to recover.^[4]
• Single nucleotide polymorphism in the complement system may determine the increased or decreased susceptibility to develop bacterial meningitis in these patients^[5][6]

Gross pathological findings of bacterial meningitis may include:^[10]

• Clouded appearance of meninges
• Presence of exudate
• Obliteration of sulci
• Pus
• Petechiae
• Cerebral hemorrhages

Microscopic pathological findings in bacterial meningitis may include the following:^[10]

• Neutrophilic exudate seen in meninges
• Prominent dilated blood vessels
• Edema and focal inflammation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

The causative agent for bacterial meningitis varies according to age group. Common causative agents for bacterial meningitis may include Group B Streptococcus, Streptococcus pneumoniae, Escherichia coli, Listeria monocytogenes, Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b (Hib).^{[1][2][3][4][5][6]}

The causative bacterial agent for bacterial agent may vary according to the age group:^{[1][2][3][4][5][6]}

The most common causes of bacterial meningitis include the following in order of decreasing frequency:^[3]

• Streptococcus pneumoniae- most common in all age groups
• Neisseria meningitis
• Hemophilus influenza
• Group B streptococcus
• Listeria monocytogenes

The rare causes of bacterial meningitis include:

• Staphylococcus aureus
• Group B streptococcus
• Klebsiella
• Peudomonas
• E coli
• Listeria monocytogenes
• Kingella Kingae^[7]
• Mycobacterium tuberculosise
• Trepenoma pallidum
• Diphtheroids
• Propionibacterium acnes
• Serratia marcescens
• Salmonella species
• Borrelia burgdoferri
• Brucella sp
• Nocardia
• Francisella tularensis
• Streptococcus suis

Meningococcal meningitis may lead to bilateral adrenal hemorrhage causing shock and death.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

The differential diagnosis of bacterial meningitis includes two step approach. First is differentiating bacterial meningitis from other diseases which have similar clinical presentation as bacterial meningitis such as encephalitis, brain abscess, subarachnoid hemorrage, and brain tumour. Second step involves CSF examination and differentiating bacterial meningitis from viral, fungal and other causes of meningitis.^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]}

Bacterial meningitis may mimick other diseases in terms of clinical signs and symptoms. It is important to differentiate meningitis from other diseases with similar presentation. Once the diagnsis of meningitis is confirmed, the next step may be to differentiate different types of meningitis on the basis of CSF examnination:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]}

Bacterial meningitis may be differntiated from other causes of meningitis by cerebrospinal fluid examination:^{[21][22][23][24][25]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

Worldwide, the bacterial meninigtis epidemics affects more than 400 million people living in the 26 countries of the extended “African meningitis belt” (from Senegal to Ethiopia). However, from 2010 to 2014 cases have been steadily decreasing, with approximately 24 000 cases in 2010 to 11 500 cases in 2014.^[1] The annual incidence of bacterial meningitis is 4,100 cases and 500 deaths between the year 2003-2007 in USA.^[2] The frequency of different causative agents causing bacterial meningitis varies with different age groups.The incidence of Hemophilius influenza meningitis is higher in children younger than 5 years of age, rate estimated to be 31 cases per 100,000.^[3] The incidence of Streptococcus pneumoniae in very young and very old individuals is estimated to be 17 cases per 100,000 making it the most common cause of meningitis in this age group.^[4]

• Worldwide, the bacterial meninigtis epidemics affects more than 400 million people living in the 26 countries of the extended “African meningitis belt” (from Senegal to Ethiopia). However, from 2010 to 2014 cases have been steadily decreasing, with approximately 24 000 cases in 2010 to 11 500 cases in 2014.^[1]
• There may be approximately 1.2 million cases of bacterial meningitis and 135,000 deaths that occur annually throughout the world.
• In USA, the annual incidence of bacterial meningitis is 4,100 cases and 500 deaths between the year 2003-2007.^[2]
• In USA, the overall incidence of bacterial meningitis has decreased significantly since the emergence of vaccine against Hemophilus influenza and Streptococcus pneumoniae.^[5]

Age

• The frequency of different causative agents causing bacterial meningitis varies with different age groups
• There is increased incidence of bacterial meningitis with increasing age
• In USA, the incidence rate is 0.66 cases per 100, 000 in age groups from 18 to 34 years compared to 1.92 cases per 100, 000 in age group >65 years of age.^[5]
• The case fatality rate in USA in age group 18-34 years of age is 16.4 percent compared to 22.7 percent in individuals >65 years of age
• The incidence of Hemophilius influenza meningitis is higher in children younger than 5 years of age, rate estimated to be 31 cases per 100,000.^[3]
• The incidence of Streptococcus pneumoniae in very young and very old individuals is estimated to be 17 cases per 100,000 making it the most common cause of meningitis in this age group.^[4]

Race
There is no known racial predilection for bacterial meningitis. However, in USA, increased incidence of bacterial meningitis has been reported among African Americans compared to Hispanics and whites.
Geographical distribution

• The frequency of different bacterial causes of meningitis may vary in different parts of the world.^[6]
• Meningococcal meningitis is commonest cause of meningitis epidemic in developing world. However, it is relatively uncommon cause of meningitis in USA and Europe.^[7][8][9]
• In African countries the streptococcus pneumoniae is the most common cause of high mortality rates due to bacterial meningitis.
• Streptococcus suis is the new emerging cause of bacterial meningitis in Asia.^[10]
• In USA, the incidence of bacterial meningitis is estimated to be 1.33 cases per 100,000 each year. ^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

Common risk factors for bacterial meningitis may include extremes of age groups, immunosuppression, recent exposure to person suffering from meningitis, disruption of normal anatomical CNS barrier, medical conditions such as lupus, complement deficiency, sepsis, infective endocarditis, people living in close groups such as college campuses and dorms, alcohalism, smoking and injection drug abuse.^{[1][2][3][4][5]}

Common risk factors of bacterial meningitis may include:^{[1][2][3][4][5][6][7][8]}
Age

• Extremes of age predispose to bacterial meningitis such as infants and old age
• Type of bacteria affecting affecting different age groups varies

Community setting

• People living in dorms
• Military personnel
• Large gatherings in college campuses

Certain medical conditions

• Recent respiratory or ear infection
• Otorrhea or rhinorrhea
• Lupus
• Infective endocarditis

Working with meningitis-causing pathogens

• Microbiologists
• Lab personnel

Travel

• Recent travel to endemic area such as sub-Saharan Africa
• Travel to Mecca during the annual Hajj and Umrah pilgrimage

Immunosuppression

• Prolonged steroid therapy
• Complement deficiency
• Diabetes mellitus
• Hypogammaglobulinemia
• Human immunodeficiency virus (HIV) infection

Disruption of anatomical CNS barrier

• Basilar skull fracture
• Neurosurgery
• CNS implants such as intracerebral pressure monitors
• CSF shunts
• Choclear implants

Other risk factors

• Smoking
• Alcoholism
• Injection drug abuse
• Sepsis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

Bacterial meningitis is a medical emergency and need urgent medical treatment. If left untreated, the bacterial meningitis may be associated with significant morbidity and mortality. Common complications which may result from bacterial meningitis may include seizures, focal neurological deficit, sensorineual hearing loss, vision loss, cranial nerve palsies and intellectual impairment.^{[1][1][2][3][4][5][6]}

If left untreated, the bacterial meningitis may cause severe neurological complications such as altered mental status, cranial nerve palsy, increased intracranial pressure, seizures, brain abscess, herniation of cerebellar tonsil and death. ^[1]

Common complications of bacterial meningitis may be divided into common and uncommon complications:^{[1][2][3][7][8][9][10][11][12][13][14][15][16]}

• Papilledema
• Vision loss
• Hearing loss
• Cranial nerve palsies
• Sepsis
• Seizures
• Focal neurological deficit
• Cerebral infarction
• Shock
• Learning disabilities in infants
• DIC
• Intracerbral hemorrhage

• Spinal cord infarction
• Transverse myelitis
• Multiple brain abscess
• ARDS
• Subdural empyema
• Subdural effusions
• Ventriculitis
• Intracranial aneurysm
• Hydrocephalus

• Shock
• DIC
• Cardiac arrythmia
• Stroke
• Exacerbation of chronic disease
• Hyponatremia (SIADH)
• ARDS
• Intracranial aneurysm

Bacterial meningitis is a medical emergency and require urgent treatment. Prognosis of this disease largely depends on the duration between acquisation of disease and onset of treatment. Case fatality rate of bacterial meningitis in USA in children more than one month is estimated to be 0 to 15 percent. The mortality rates of bacterial meningitis are significantly high in the infants and old patients. However, there is a decline in mortality in midlife. Despite effective medical treatment, the rate of neurological complications is as high as 30 percent in patients who survive bacterial meningitis. Poor prognositc factors associated with bacterial meningitis which may lead to significant morbidity and mortality may include the following:^{[4][5][6][17][18][3][19]}

• Decreased level of consciousness at the time of admission
• Immunosuppression
• Presence of complications such as seizures, focal neurological deficit
• Presence of other medical conditions such as diabetes mellitus, CHD
• Low CSF glucose concentration
• Infants and old age
• Poor nutritional status
• Infective organism such as Pneumococcal and meningococcal meningitis

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