2. Definition
Meningitis is the inflammation of the leptomeninges ( pia and
archanoid matter) surrounding the brain and spinal cord, with
involvement of the subarachnoid space.
3. Types of meningitis
Based on the onset
Acute meningitis:
• Progresses in few hours
• Acute bacterial
• Acute viral
Chronic meningitis:
• Progressively worsens over weeks (>4 weeks)
• Bacterial, viral, fungal and parasitic.
5. Acute bacterial/pyogenic meningitis
• Bacterial meningitis is an inflammation of the
leptomeninges, usually causing by bacterial infection.
• Bacterial meningitis may present acutely (symptoms
evolving rapidly over 1-24 hours), sub acutely (symptoms
evolving over 1-7days), or chronically (symptoms evolving
over more than 1 week).
6. Epidemiology
6
• Annual incidence in the developed countries is approximately 5-
10 per 100000.
• Approximately 90 per cent of cases occur in children during the
first 5 years of life.
• Cases under age 2 years account for almost 75% of all cases and
incidence is the highest in early childhood at age 6-12 months
than in any other period of life.
• There are significant difference in the incidence of bacterial
meningitis by season.
9. Etiology
Dr.T.V.RaoMD 9
Children over 2 months
Haemophilus influenza type b
Neisseria meningitides
Streptococcus pneumoniae
Children over 12 years
Neisseria meningitides
Streptococcus pneumoniae
10. Pathogenesis
• Mode of transmission – droplets from respiratory secretions
• Routes of infection:
Hematogenous spread – most common, through choroid
plexus
Direct spread – otitis media, sinusitis, mastoiditis.
Anatomical defect in CNS – surgery, trauma, congenital
defects.
12. Pathogenesis
Dr.T.V.RaoMD 12
• Susceptibility of bacterial infection on CNS in the children
– Immaturity of immune systems
• Nonspecific immune
– Insufficient barrier (Blood-brain barrier)
– Insufficient complement activity
– Insufficient chemo taxis of neutrophils
– Insufficient function of monocyte-macrophage system
– Blood levels of diminished interferon (INF) -γand
interleukin -8 ( IL-8 )
13. Pathogenesis
Dr.T.V.RaoMD 13
• Susceptibility of bacterial infection on CNS in the children
– Specific immune
• Immaturity of both the cellular and Humoral immune
systems
– Insufficient antibody-mediated protection
– Diminished immunologic response
– Bacterial virulence
14. Pathogenesis
Dr.T.V.RaoMD 14
A offending bacterium from blood invades the
leptomeninges.
Bacterial toxics and Inflammatory mediators are released.
– Bacterial toxics
• Lipopolysaccharide, LPS
• Teichoic acid
• Peptidoglycan
– Inflammatory mediators
• Tumor necrosis factor, TNF
• Interleukin-1, IL-1
• Prostaglandin E2, PGE2
15. Pathogenesis
15
• Bacterial toxics and inflammatory mediators cause
Suppurative inflammation.
– Inflammatory infiltration
– Vascular permeability alter
– Tissue edema
– Blood-brain barrier destroy
– Thrombosis
16. Pathology
16
Diffuse bacterial infections involve the leptomeninges, arachnoid
membrane and superficial cortical structures, and brain parenchyma
is also inflamed.
Ventriculitis (purulent material within the ventricles) – children.
Subdural empyema may occur.
Ventricle dilatation
Hydrocephalus
17. Pathology
17
• Blood vessel walls may infiltrated by inflammatory cells.
– Endothelial cell injury, Vessel stenosis, Secondary ischemia and
infarction.
Cerebral edema
Meningeal irritation sign is found because the spinal nerve root is
irritated.
Cranial nerve may be damaged
18. Clinical manifestation
18
• Toxic symptom all over the body
– Hyperpyrexia
– Headache
– Photophobia
– Painful eye movement
– Fatigued and weak
– Malaise, myalgia, anorexia,
– Vomiting, diarrhea and abdominal pain
– Cutaneous rash
– Petechiae, purpura
22. Kernig's sign.
22
• One of the physically
demonstrable symptoms
of meningitis is Kernig's
sign.
• Severe stiffness of the
hamstrings causes an
inability to straighten the
leg when the hip is
flexed to 90 degrees.
24. Clinical manifestation
24
Seizures occur in about 20%-30% of children with bacterial
meningitis.
Seizures is often found in Haemophilus influenza and
pneumococcal infection.
Transient or permanent paralysis of cranial nerves and limbs
may be noted.
Deafness or disturbances in vestibular function are relatively
common.
Involvement of the optic nerve, with blindness, is rare.
Paralysis of the 6thcranial nerve, usually transient, is noted
frequently early in the course.
Skin rashes
25. Symptom and signs of the infant under the age of 3 months
– Only irritability, restlessness, dullness, vomiting, poor
feeding, cyanosis, dyspnea, jaundice, seizures, shock
and coma may be noted.
– Bulging fontanel may be found, but there is not
meningeal irritation sign.
25
26. Complications
Dr.T.V.RaoMD 26
• Subdural effusion
– 10%-30% of children with bacterial meningitis.
– Subdural effusions - age of 1 year - Haemophilus
influenza and pneumococcal infection.
– Clinical manifestations are enlargement in head
circumference, bulging fontanel, cranial sutures diastasis
and abnormal trans illumination of the skull.
• Cerebellar hyponatremia
– Syndrem of inappropriate secretion of antidiuretic hormone
(SIADH)
31. Cytological and biochemical parameters in CSF of normal
individuals and in different types of meningitis
Characteristics Normal individual Pyogenic meningitis Tuberculous meningitis Viral meningitis
CSF pressure
(mm of water) Normal (50–150) Highly elevated (>180) Moderately elevated Slightly elevated/normal
TLC (per mm3 ) 0–5 100–10,000 10–500 25–500
Predominant
cell type Lymphocytes Neutrophils Lymphocytes Lymphocytes
Glucose (mg%) 40–70 < 40 mg/Dl 20-40 absent
Total proteins 15-45 >45 100–500 mg/dL 20–80 mg/dL
( mg%) (moderately increased) (markedly increased) (mild increase)
32. • CSF microscopy ( gram stain):
- Heaped smear
- Centrifugation
• Direct antigen detection:
-From CSF: supernatant- latex agglutination test - S. pneumoniae,
S.agalactiae, N.meningitidis, H.influenza or E.coli
-From urine: ICT – C-polysaccharide antigen of S. pneumoniae.
• Culture: chocolate agar, blood agar and MacConkey agar.
33. Culture and identification properties of common bacterial agents of
pyogenic meningitis
Streptococcus pneumoniae:
• Culture: It produces α-hemolytic colonies on blood agar, described
as draughtsman-shaped or carrom coin appearance
• Biochemical identification: It shows bile soluble, ferments inulin and
sensitive to optochin.
Neisseria meningitidis:
It produces non- hemolytic colonies on blood agar, which on smear
shows gram-negative diplococci.
• Biochemical identification: Meningococci are catalase and oxidase
positive. They ferment glucose and maltose but not sucrose
• Serogrouping: Slide agglutination serogrouping (SASG) test is done to
identify the serogroups of meningococci isolates by using appropriate
antisera.
Haemophilus influenzae:
• Culture: Blood agar with S. aureus streak line shows satellitism.
• Biochemical identification: Disk test for X and V factor requirement
shows growth surrounding combined XV disk.
37. Streptococcus agalactiae:
• Culture: It produces β-hemolytic colonies on blood agar, which on
smear shows gram-positive cocci in short chain.
• Biochemical identification: It shows CAMP test positive and
resistance to bacitracin
• Serogrouping with group specific antisera shows Lancefield group B.
Gram-negative bacilli meningitis:
• Escherichia coli and Klebsiella produce lactose-fermenting colonies
on MacConkey agar; identified by ICUT tests
• Non-fermenters: Pseudomonas is oxidase positive, whereas
Acinetobacter is oxidase negative. They produce non-lactose
fermenting colonies; identified by ICUT tests.
Listeria monocytogenes:
• Motility: It shows tumbling type of motility at 25°C but nonmotile at
37°C (called differential motility, which is due to temperature
dependent flagella expression)
• Culture: It grows on blood agar (β-hemolytic colonies), and chocolate
agar.
Note: Selective media such as PALCAM agar (containing mixture of
38. Small, β-hemolytic colonies of
L. monocytogenes on Blood
agar Umbrella-shaped zone of motile
growth after 24 hrs in semisolid
motility medium at 25°C.
L.monocytogenes
40. Antibiotic Therapy
40
• Selection of antibiotic
– Not Certainly Bacterium
• Community-acquired bacterial infection
• Nosocomial infection acquired in a hospital
• Broad-spectrum antibiotic coverage as noted below
– Children under age 3 months
» Cefotaxime and ampicillin
» Ceftriaxone and ampicillin (children over age 1months)
– Children over 3 months
» Cefotaxime or Ceftriaxone or ampicillin and
chloramphenicol
41. Antibiotic Therapy
41
• Certainly Bacterium
– Once the pathogen has been identified and the antibiotic
sensitivities determined, the most appropriate drugs
should selected.
• N meningitides : penicillin, - cephalosporin
• S pneumoniae: penicillin, - cephalosporin, Vancomycin
• H influenza: ampicillin, cephalosporin
• S aureus: penicillin, nefcillin, Vancomycin
• E coli: ampicillin, chloramphenicol, - cephalosporin
42. Antibiotic Therapy
Dr.T.V.RaoMD 42
• Course of treatment
– 7 days for meningococcal infection
– 10 ~ 14 days for H influenza or S pneumoniae
infection
– More than 21 days for S aureus or E coli infection
– 14 ~ 21 days for other organisms
43. General and Supportive Measures
43
Treatment of hyperpyrexia and seizures
– Pyretolysis by physiotherapy and/or drug
– Convulsive management
• Diazepam
• Phenobarbital
Treatment of increased intracranial pressure
– Dehydration therapy
• 20%Mannitol 5ml/kg vi q6h
• Lasix 1-2mg/kg iv
Treatment of septic shock and DIC
44. Complication Measures
• Subdural effusions
– Subdural pricking
• Ependymitis
– Ventricular puncture — drainage
• Pressure in ventricle be depressed.
• Ventricular puncture may give ventricle an injection of
antibiotic.
• Hydrocephalus
– Operative treatment
• SIADH (Cerebral hyponatremia)
– Restriction of fluid
44
45. Prognosis
45
• Appropriate antibiotic therapy reduces the
mortality rate for bacterial meningitis in children,
but mortality remain high.
• Overall mortality in the developed countries ranges
between 5% and 30%.
• 50 percent of the survivors have some sequelae of the
disease.
47. Definition
• It is characterized by persistence of signs and symptoms as well as the
CSF abnormality for >4 weeks.
Agents of chronic meningitis:
Bacterial agents
Common bacterial agents • Partially treated suppurative meningitis •
Parameningeal infections (e.g. otitis media) • Mycobacterium
tuberculosis • Borrelia burgdorferi (Lyme disease) • Treponema
pallidum (secondary, tertiary syphilis)
Rare bacterial agents: Nocardia, Actinomyces, Tropheryma whipplei,
Leptospira, Brucella.
Viral agents
Some of the agents of acute viral meningitis may also present as
chronic meningitis.
Examples: Mumps, echoviruses, herpesviruses, HIV and lymphocytic
choriomeningitis virus.
49. TUBERCULOUS MENINGITS (TBM)
• Most common form of CNS tuberculosis
• If untreated, high frequency of Neurologic sequelae and Mortality
• TBM complicates 0.3% of untreated TB infections in children.
• Common between 6 months and 4 years of age
• Clinical progression of TBM may be rapid or gradual
Rupture of 1 or more Subependymal tubercle
• Rapid progression more often in infants and young children
• Occasionally, TBM occurs many years after the infection
2
50. DIAGNOSIS
• TST – Nonreactive in up to 50% of cases
• CXR - 20-50% of children have a normal findings
• HIV serology
• Lumbar CSF study
• Polymerase chain reaction (PCR)
• Cultures of other body fluids can help confirm the diagnosis
• Other Radiographic studies
7
51. CSF Study
Specimen: CSF – centrifuge - aliquots of the sediment transferred to appropriate
culture media.
Low-volume fluid samples can be added directly to broth and incubated.
• CSF cells - leukocyte 10-500 cells/µl
Lymphocytes predominates
• CSF glucose - <40 mg/dl
• CSF Protein - markedly high (400-5,000 mg/dl)
• Early stage 1
Viral aseptic meningitis then progress severely
• Success of CSF study related to its volume
• 5-10 mL of lumbar CSF
Acid-fast stain positive in up to 30% of cases
culture is positive in 50-70% of cases
8
52. Direct microscopy by acid-fast staining:
Ziehl-Neelsen (ZN) technique—long slender, beaded, less uniformly stained red
color acid-fast bacilli
Kinyoun’s cold acid-fast staining
Fluorescent (auramine) staining
Conventional culture media—take 6–8 weeks
Lowenstein Jensen (LJ) medium—shows rough, tough and buff colored colonies in
6–8 weeks, Middlebrook media.
Automated culture methods—take 3–4 weeks
MGIT system: Detects growth as well as resistance to antitubercular drugs (ATDs)
Automated identification—by MALDI-TOF MPT 64 antigen detection—by ICT
Molecular methods
PCR detecting IS6110 gene
CBNAAT (GeneXpert) and Truenat—for identification and detection of
resistance to rifampicin; has a turnaround time 2 hours
Line probe assay (e.g. Genotype TB)—for identification and detection of
resistance to 1st and 2nd line ATDs; has a turnaround time of 2–3 days
56. Internationally accepted ATT for TBM/Tuberculoma
• Intensive phase
Four drugs (RHZE/S) are recommended for 2 months
• Continuation phase
Isoniazid and Rifampicin are recommended for 10 months
• Corticosteroids (usually prednisone)
HIV Negative
All children with TB meningitis at 2 mg/kg daily for 4 weeks
Then gradually tapered over 1– 2 weeks before stopping
HIV Positive
Advised in the absence of life threatening opportunistic infections
20
58. Aseptic Meningitis
• It is the inflammation of subarachnoid space due to viral etiology.
• It is the second most common type of meningitis, next to acute
bacterial meningitis.
• It is often less severe than bacterial meningitis and has a better
prognosis.
• Etiological Agents:
-Enteroviruses (Coxsackie's and echovirus): most common.
-Adenovirus
-Arbovirus
-LCM virus
-Measles virus
-Herpes Simplex Virus
-Varicella
58
59. Viral Meningitis
Dr.T.V.RaoMD 59
Reservoirs:
-Humans for Enteroviruses, Adenovirus, Measles, Herpes Simplex,
and Varicella
-Natural reservoir for arbovirus birds, rodents etc.
Modes of transmission:
-Primarily person to person and arthopod vectors for
arboviruses
Incubation Period:
-Variable. For enteroviruses 3-6 days, for arboviruses 2-
15 days
Treatment:
No specific treatment available.
Most patients recover completely on their own.
60. Non Polio Enteroviruses
Dr.T.V.RaoMD 60
Types:62 different types known:
-23 Coxsackie A viruses,
-6 Coxsackie B viruses,
-28 echoviruses, and 5 other
Non-polio enteroviruses - most common cause of viral meningitis.
Cases - sporadic or occur in clusters
Examples - Coxsackieviruses, echoviruses, parechoviruses and Enterovirus 71.
Mode of trsnsmission:
• Virus present in the respiratory secretions & stool of a patien
• Direct contact with secretions from an infected person.
• Parents, teachers, and child care center workers may also become infected by
contamination of the hands with stool.
61. Enteroviruses :
• Transmitted by feco-oral route.
• Multiply in the intestine - do not cause any intestinal manifestations.
• Associated with various systemic manifestations
Coxsackieviruses
• spread through an infected person’s nasal and throat secretions, fluid from
blisters or scabs.
• Inoculating into tissue culture - Cytopathic effect can be observed within
5-14 days.
• PCR targeting specific genes (e.g. VP1) is highly useful as it is rapid,
more sensitive and serotype-specific
• Serology is performed to detect neutralizing antibodies.
62. Echoviruses
• (enteric cytopathogenic human orphan viruses) infect humans by feco-
oral route.
• Associated with aseptic meningitis, encephalitis, rashes, common cold,
and ocular disease.
Arboviruses
• sometime cause meningitis, especially in individuals – recently
travelled to the areas where these viruses are endemic.
• Transmitted by the bite of their arthropod vectors.
West Nile virus
Saint Louis encephalitis virus
Tick-borne encephalitis
California encephalitis virus
63. HIV meningitis
Meningitis in HIV infection may occur following primary infection in
5–10% of cases and less commonly at later stages of illness.
• Cranial nerve palsies - involving cranial nerves V, VII, or VIII, are
more common in HIV meningitis than in other viral infections.
MUMPS meningitis:
• Meningitis in mumps - secondary to parotitis.
• Mumps meningitis - more common in the late winter or early spring,
especially in unvaccinated children with a male preponderance.
LCM meningitis
• Lymphocytic choriomeningitis (LCM) virus affects people with
history of contact with rodent droppings or urine.
64. Laboratory criteria for diagnosis:
Normal or slightly elevated protein level (20–80 mg/dL)
• Normal glucose level
• Normal or mildly elevated CSF pressure (100–350 mm H2O)
• Cell count - 25–500/μL, in some viral meningitis (e.g. LCM virus and mumps) the cell
counts of several thousands/μL may be seen.
• Pleocytosis: Lymphocytes – predominant cell type, although neutrophils may predominate
in the first 48 h of illness in some viral meningitis (e.g. West Nile virus)
• Organisms are not seen on Gram staining of CSF.
VIRAL CULTURE
• Sensitivity of CSF cultures - generally poor.
• In addition to CSF, specific viruses – isolated from throat swabs, stool, blood, and urine
• Isolation of enteroviruses from stool – not diagnostic
65. • The CSF analysis showed higher values of lactate level in bacterial
meningitis with comparison to viral meningitis 8.35 ± 3.18 mmol/L
and 3.4 ± 5.62 mmol/L (p value)
• The CSF glucose level was found to be lower in bacterial meningitis
than in viral meningitis, 9.63 ± 0.57 mg/dl and 57.96 ± 14.11 mg/dl.
• The CSF protein level was high in bacterial than viral meningitis
patients, with mean 298.33 ± 88.32 and 95.05 ± 49.42 mg/dl.
• The CSF protein and lactate values, as well as CSF glucose value,
can rapidly differentiate between bacterial and viral meningitis
when conventional Gram's staining and culture are negative.7
66. Cytological and biochemical parameters in CSF of normal
individuals and in different types of meningitis
Characteristics Normal individual Pyogenic meningitis Tuberculous meningitis Viral meningitis
CSF pressure
(mm of water) Normal (50–150) Highly elevated (>180) Moderately elevated Slightly elevated/normal
TLC (per mm3 ) 0–5 100–10,000 10–500 25–500
Predominant
cell type Lymphocytes Neutrophils Lymphocytes Lymphocytes
Glucose (mg%) 40–70 < 40 mg/Dl 20-40 absent
Total proteins 15-45 >45 100–500 mg/dL 20–80 mg/dL
( mg%) (moderately increased) (markedly increased) (mild increase)
67. Treatment
Treatment of almost all cases of viral meningitis is primarily
symptomatic:
Analgesics, antipyretics, antiemetics and fluid and electrolyte
replacement.
Oral or intravenous acyclovir may be of benefit in patients with
meningitis caused by HSV-1 or 2 and in cases of severe EBV or VZV
infection.
Patients with HIV meningitis should receive highly active antiretroviral
therapy.
68. Parasitic infections of central nervous system
Protozoan infections of CNS
• Free-living amoebae infections of CNS*
• Toxoplasma encephalitis*
• Cerebral malaria (Plasmodium falciparum)*
• African sleeping sickness (Trypanosoma brucei)*
• Chagas’ disease (meningoencephalitis, Trypanosoma cruzi)
• Cerebral amoebiasis (E. histolytica)
Cestode infections of CNS
• Neurocysticercosis (Taenia solium)*
• Others: Taenia multiceps, Spirometra and Echinococcus
Trematode infections of CNS
• Schistosoma mansoni and S. japonicum infections
• Cerebral paragonimiasis
Nematode infections of CNS
• Hyperstrongyloidiasis syndrome (Strongyloides)
• Eosinophilic meningitis (Angiostrongylus cantonensis)
• Others: Loa loa (meningoencephalitis), Trichinella spiralis, Toxocara, Baylisascaris procyonis and
Gnathostoma infections
69. Fungal agents causing CNS infections
Primary CNS pathogen: Cryptococcus neoformans
Fungi which primarily cause infections of other body sites, rarely cause CNS
infections
• Agents of systemic mycoses: Blastomyces dermatitidis, Histoplasma
capsulatum and Coccidioides immitis
• Agents of subcutaneous mycoses: Sporothrix schenckii, Pseudallescheria
boydii and Cladophialophora bantiana
• Opportunistic fungal agents : Candida albicans, Aspergillus species and
Mucor (rhinocereberal mucromycosis)
• Others: Microsporidia
70. Cryptococcal meningitis
Cryptococcal meningitis is caused by a capsulated yeast called
Cryptococcus neoformans, which is capable of producing potentially
fatal meningitis in HIV infected people.
C.Neoformans
C.Gattii
71. Pathogenesis and Virulence factors
• Infection is acquired by inhalation of aerosolized forms of
Cryptococcus.
• Polysaccharide capsule—It is the principal virulence factor of the
fungus. It is antiphagocytic and also inhibits the host’s local immune
responses
• Ability to make melanin by producing an enzyme called phenyl
oxidase
• Production of other enzymes such as phospholipase and urease.
• CNS spread: The unique feature of Cryptococcus is its ability to
cross blood-brain barrier which occurs by the yeast cells either they
migrate directly across the endothelium or carried inside the
macrophages as “Trojan horse”
72. Lab diagnosis
• Specimens: CSF, blood or skin scrapings.
• Direct Detection Methods
1. Negative staining: Modified India ink stain (added with 2%
mercurochrome) and nigrosin stain - demonstrate the capsule -
refractile delineated clear space surrounding the round budding
yeast cells against black background.
2. Gram staining may show gram-positive round budding yeast cells.
3. Other stains include:
Mucicarmine stain: It stains the carminophilic cell wall of C.
neoformans Masson-Fontana stain: It demonstrates the production of
melanin
Alcian blue stain: To demonstrate the capsule.
4. Antigen detection: The capsular antigens can be detected from
CSF or serum by latex agglutination test. It is a rapid and sensitive
(95% sensitivity) and specific method.
74. Confirmation of Cryptococcus species is made by:
• Niger seed agar and bird seed agar: They are used to demonstrate
melanin production (brown colored colonies).
• Growth at 37°C .
• Urease test is positive
• Assimilation of inositol and nitrate
• Mouse pathogenicity test
• Automated identification system such as MALDI-TOF
75. TREATMENT
• Treatment depends upon the type of cryptococcosis.
• Cryptococcosis without CNS involvement: Fluconazole is the drug of
choice.
• HIV-infected patients with CNS involvement:
- The recommended regimen is induction phase for two weeks
(amphotericin B ± flucytosine)
- followed by oral fluconazole therapy till CD4 T cell count raises
>200 /µL for 6 months.
76. References
1. Koneman EW, Allen SD, Janda WM, Schreckenberger PC, Winn WC. Diagnostic
microbiology,6th edition, Philedelphia: Lippincott-Raven Publishers(2017), pg.1075-
145.
2. Scott Bailey, Forbes Betty A, et al. Diagnostic Microbilogy, 12th edition, St. louis,
Missouri: Mosby Inc (2007).
3. Jawetz, Melnick, Adelberg’s. Medical Microbiology, 28th edition, McGraw-Hill
Education eBooks (2019).
4. Mandell, Douglas, Bennett’s. INFECTIOUS DISEASE ESSENTIALS,
Philadelphia:Elsevier Inc.(2017).
5. Janagond, Anand & Sastry, Apurba & Bhat, Sandhya & Rajshekar, Deepashree. (2018).
Essentials of Medical Microbiology, 2nd Edition.
6. M. Knipe, David, M. Howley, Peter, et al. F I E L D S Virology, 6th edition,
Philadelphia: Lippincott Williams & Wilkins, a Wolters Kluwer business(2013).
7. Ahmed S, Rakib A, Nasrin F, Chowdhury RH, Azad AK, Hasan CM. Assessment of
cerebrospinal fluid (CSF) to differentiate between bacterial meningitis and viral
meningitis. Journal of Advances in Medical and Pharmaceutical Sciences. 2018 Sep
6;17(4):1-7.