seminar Meningitis

Case study
• A 9 month old girl,presents to casuality with
history of fever,vomiting for the last 3 days.
She had h/o convulsion just before arrival at
the hospital in the form of generalized tonic
colonic siezure with uprolling of the eyes,
which settled spontaneously.
• On examination the infant is febrile (39C),
drowsy and irritable ,bulged ant
fontanel,mildly dehydrated and has cool
peripheries. Her throat is slightly inflamed.

SEMINAR ON MENINGITIS
Presented by-
• DR.MD.NAZMUS SIHAN
• DR.MAHBOBA AKHTER
• DR.SHAZIA AFREEN
• DR.MD. MYDUL ISLAM KHAN

Clinical description
Meningitis is a disease caused by the inflammation
of the protective membranes covering the brain
and spinal cord known as the meninges.
 The inflammation is usually caused by an infection
of the fluid surrounding the brain and spinal cord.
Meningitis can be life-threatening because of the
inflammation's proximity to the brain and spinal
cord; therefore the condition is classified as
a medical emergency.
4/28/2021 3

Meninges
The meninges is the system of membranes which envelops
the central nervous system.
It has 3 layers:
1. Dura mater
2. Arachnoid mater
3. Pia mater
Subarachnoid space -
is the space which
exists between the
arachnoid and the
pia mater, which is
filled with
cerebrospinal fluid.
4/28/2021 4

EPIDEMIOLOGY
 Approximately 1.2 million cases of acute bacterial meningitis,
excluding epidemics, occur every year around the world, resulting in
135,000 deaths.
 Overall mortality rates for patients with meningitis range from
2% to 30% depending on the causative microorganism, approaching
20% in most cases of bacterial meningitis.
 Generally, 30% to 50% of patients who survive meningitis may
develop neurologic disabilities.

High risk groups
Infancy
Elderly
Immunocompromised
Splenic dysfunction or Asplenia
T lymphocyte defect
Head trauma
neural surgery
Ear infections
College students living in dormitory
Military recruits

CLASSIFICATION:
A.According to eitiology-
Pyogenic or bacterial
Viral
Tubercular
Parasitic/Fungal.
B.According to duration:
Acute<4 wks-Bacterial,Viral.
Chronic>4 wks-Partially treated,TB,Fungal.
Severity/treatment of illnesses differ depending on the cause. Thus, it is
important to know the specific cause of meningitis.

Routes of Infection
• Nasopharynx
• Blood stream
• Direct spread (skull fracture, meningo and encephalocele)
• Middle ear infection
• Infected Ventriculoperitoneal shunts.
• Congenital defects
• Sinusitis

The incubation period ranges between 2 -10 days.

Subarachnoid space
BACTERIAL LYSIS
by a hematogenous
routereach the
meninges
an intense host
inflammatory response
triggered
PATHOPHYSIOLOGY

Subarachnoid
space
BACTERIAL
LYSIS
by a hematogenous
routereach the
meninges
Bacterial cell
wall
component
release
Endothelial cells
CNS macrophage cells
PATHOPHYSIOLOGY

Subarachnoid
space
BACTERIAL
LYSIS
by a hematogenous
routereach the
meninges
Bacterial cell
wall
component
release
Endothelial cells CNS macrophage cells
Cytokine
release
(IL-1, PGE2,
TNF,
PAF, etc.)
Inflammatory
response
Neurologic
damage
PATHOPHYSIOLOGY

Inflammatory response
Cont’d…
Coagulation cascade
Thrombosis
Affecting
cortical
vessels
(SIADH) with
meningitis causes
further retention of
free water

Cont’d…
Coagulation cascade
Thrombosis
Vasogenic edema Increased ICP Decreased CBF
Affecting
cortical
vessels
Cytotoxic and
interstitial
edema
Increased
CSF protein
(SIADH) with
meningitis causes
free water

Cont’d…
Coagulation cascade
Thrombosis
Affecting
cortical
vessels
Cytotoxic and
interstitial
edema
oxygen
depletion
Increased
CSF protein Decreased CSF glucose
Increased
CSF lactate
(SIADH) with
meningitis causes
free water

Neurologic damage
Affecting
cortical
vessels
(SIADH) with
meningitis causes
free water

Neurologic damage
swelling and
proliferation of the
endothelial cells of
arterioles
veins, causing
mural thrombi and
obstruction of flow
Affecting
cortical
vessels
(SIADH) with
meningitis causes
free water

Neurologic damage
swelling and
arterioles
veins, causing
mural thrombi and
obstruction of flow
an increase in intracellular
sodium and intracellular water
Affecting
cortical
vessels
(SIADH) with
meningitis causes
free water

Neurologic damage
swelling and
arterioles
veins, causing
mural thrombi and
obstruction of flow
Affecting
cortical
vessels
development of brain edema further
compromises cerebral circulation
(SIADH) with
meningitis causes
free water

Neurologic damage
swelling and
arterioles
veins, causing
mural thrombi and
obstruction of flow
Affecting
cortical
vessels
ICP secretion of ADH
(SIADH) with
meningitis causes
free water

Neurologic damage
swelling and
arterioles
veins, causing
mural thrombi and
obstruction of flow
Affecting
cortical
vessels
These factors contribute to the development of
focal or generalized seizures
(SIADH) with
meningitis causes
free water

Inflammatory response Neurologic damage
Cont’d…
Coagulation cascade
Thrombosis
swelling and
arterioles
veins, causing
mural thrombi and
obstruction of flow
Affecting
cortical
vessels
Cytotoxic and
interstitial
edema
oxygen
depletion
Increased
CSF protein Decreased CSF glucose
Increased
CSF lactate
These factors contribute to the development of
focal or generalized seizures
(SIADH) with
meningitis causes
free water

Symptoms can be the same for Viral and
Bacterial
4/28/2021 25

Skin rashes
• Is due to small skin bleed
• All parts of the body are affeced
• The rashes do not fade under pressure
• Pathogenesis:
a. Septicemia
b. wide spread endothelial damage
c. activation of coagulation
d. thrombosis and platelets aggregation
e. reduction of platelets

What are the signs and findings in physical
examinations?
1. Bulging fontanel
2. Focal neurological signs
3. Neck rigidity
4. Ptosis, papilloedema,
5. Cushing’s triad (Bradycardia, Hypertension,
Altered respirations)
6. Positive Kernig’s and Brudzinski’s sign

Kernig’s sign - is assessed with the patient lying supine, with
the hip and knee flexed to 90 degrees. In a patient with a
positive Kernig's sign, pain limits passive extension of the knee.
Brudzinski signs -A positive Brudzinski's sign occurs when
flexion of the neck causes involuntary flexion of the knee and
hip.
4/28/2021 29

What are the investigations requied for this infant
Lumber puncture :

Condition Appearance WBC/mm3
Predominant type
Glucose Total
Protein
Normal Clear 0-5
lymphocytes
50-75
>60% of
Blood
glucose
15-40
Bacterial Turbid 100-10,000
PMN
<45 100-1000
Viral Clear 10- 2000
lymphocytes
Normal 50-100
Fungal Cloudy <300
lymphocytes
<45 40-300
TB Cloudy <500
lymphocytes
<45 100-1000
CSF Patterns in Meningitis

INDICATIONS :
• Diagnostic :
• Infectious
• Meningitis
• Encephalitis
• Inflammatory
• Multiple Sclerosis
• Gullain-Barre
syndrome
• Oncologic
• Metabolic
• Spontaneous
subarachnoid
hemorrhage
• Therapeutic :
• Analgesia
• Anesthesia
• Antibiotics
• Antineoplastics

CONTRAINDICATIONS :
• Increased intracranial pressure
• Cerebral herniation
• Impending herniation
• Possible increased ICP and focal neuro signs
• Coagulopathy
• Prior lumbar surgery
• Severe vertebral osteoarthritis or degenerative
disc disease
• Significant cardiorespiratory compromise
• Infection near the puncture site
• Space occupying lesion

COMPLICATIONS :
• Herniation
• Cardiorespiratory compromise
• Pain
• Headache (36.5%)
• Bleeding
• Infection
• Subarachnoid epidermal cyst
• CSF leakage

OTHER INVESTIGATIONS
• CBC
• Normal WBC does not rule out meningitis
• Blood cultures
• Electrolytes
• Renal function
• Serum glucose
- Useful to compare with CSF glucose
• Other relevant investigations

• CT or MRI are indicated if there are focal neurological signs,raised
ICP or prolonged fever. These are helpful in detection of CNS
complication of bacterial infections such as hydrocephalus,cereberal
infract,brain abscess and venous sinus thrombosis.

Complications
Acute complications
•Seizures
•Syndrome of inappropriate antidiuretic
hormone (SIADH) secretion
•Hemodynamic instability
•Increased intracranial pressure
•Subdural effusions
•Focal neurologic deficits

Chronic complications
•Deafness
•Seizure disorders
•Motor deficits
•Language deficits
•Behavior disorders
•Mental retardation

prognosis
• Even with appropriate antibiotics, mortality rate is
significant
• 8% H.influenza,
• 15% Neisseria meningitidis,
• 25% Pneumococcal
• Up to 35% of survivors have sequelae including
deafness, seizures, blindness, paresis, ataxia,
hydrocephalus

NEXT PRESENTER
DR.MAHBOBA AKHTER

ACUTE MENINGITIS
BACTERIAL MENINGITIS
VIRAL MENINGITIS

Age Group Causes
0-2 months Group B Streptococcus, Escherichia
coli, Listeria monocytogenes
2 months-5 years Streptococcus pneumoniae,
Neisseria meningitidis,
Haemophilus influenzae type b
5 years-15 years Neisseria meningitidis,
Streptococcus
pneumoniae,H.Influenzae.

Streptococcus pneumoniae
One of the top contributors of ear infections and can
cause Pneumococcal pneumonia.

Gram positive
containing
polysaccharide capsule
prevents the bacteria
from undergoing
phagocytosis

Listeria monocytogenes
Normally causes Listeriosis

Gram negative bacteria, has
trimeric autotransporter
adhesin or adhesion proteins
which to bind to host cells.

Through an ear infection, head trauma, neural surgery or an
compromised immune system, the chances of meningitis are
greatly increased.

The bacteria grows inside the Subarachnoid space in
cerebral spinal fluid

Bacterial Meningitis since
can be caused by many
different bacteria has an
incubation period ranging
for 2-10 days with 4 days
being the average.

Sudden onset of Headache,
fear, confusion, vomiting,
irritability, skin rashes, inability
to tolerate light or loud noises

FEATURES OF MENINGEAL INFLAMATION:
•Neck rigidity
• Kernig’s sign
•Brudzinski sign

Features of parenchymal involvement:
•Altered sensorium-stupor,coma,obtundation
•Seizures
•Focal neurological sign

Features of raised intracranial pressure
• Headace
• Photophobia
• Vomitting
• Bulged anterior fontanelle, if open
• Sixth nerv palsy
• Papilledema,seizures
• Hypertonia,extensors planter
• Altered sensorium,decorticate and decerebrate posture

Extra CNS manifestation:
• Rashes,
• petechiae,
• arthralgias,
• DIC,
• shock,
• pneumonia

Rash of Meningococcal Meningitis

Viral Meningitis
Viral meningoencephalitis is an acute inflammation of
meninges and, to a variable degree, brain tissue.
The CSF is characterized by pleocytosis and the
absence of microorganisms on Gram stain and routine
bacterial culture.

Con…
In most instances, the infections are self-limited.
In some cases, substantial morbidity and mortality
occur.

Viral Meningitis
•Enteroviruses
•Herpes Simplex virus (HSV)
•HIV
•Lymphocytic Choriomeningitis virus (LCM)
•Mumps
•Other less common causes include West Nile, St Louis
Encephalitis, and California Encephalitis (although most
commonly assoc. with encephalitis). May also accompany
primary VZV, outbreaks of herpes zoster, EBV, CMV, and
adenoviruses.

Pathology and pathophysiology:
Tissue sections of the brain generally are characterized by meningeal
congestion and mononuclear infiltration, perivascular cuffs of
lymphocytes and plasma cells, some perivascular tissue necrosis with
myelin breakdown, and neuronal disruption .

Cont….
•The cerebral cortex, especially the temporal lobe, is often
severely affected by HSV
• The arboviruses tend to affect the entire brain
• Rabies has a predilection for the basal structures.
Involvement of the spinal cord, nerve roots, and peripheral
nerves is variable.

Investigations:
• CSF study
• Complete blood count
• Blood culture-reveals bacteria in 80-90% cases
• C-reactive protein
• S.electrolyte
• Blood for bacterial antigen

CSF STUDY:
PRESSURE(mmH20
)50-80
LEUKOCYTES(mm3
)<5,≥75%LYMPHO
CYTES
PROTEIN(mg/dl)20
-45
GLUCOSE(mg/dl)>
50(75%Serum
Glucose)
COMMENTS
Acute bacterial
meningitis
Usually
elevated(100-300)
100-10,000 or
more,usually300-
2,000;PMNs
predominate
Usually100-500 Decreased,usually
<40(or<
50% serum
glucose)
Organism seen on
Gram stain and
recovered by
culture
Partially treated
bacterial
meningitis
Normal or
elevated
5-10,000;PMNs
predominate
Usually100-500 Normal or
decreased
Organism may be
seen on Gram
stain
Viral meningitis Normal or slightly
elevated(80-150)
Rarely>1000
cells;PMNs early
but mononuclear
cell most ly
Usually50-200 Normal Not seen on Gram
stain

Others
• Latex particle agglutination: detects presence of bacterial antigen in the
spinal fluid and useful for detection of H. influenza type B, S. pnemoniae, N.
meningitidis, E. coli.
• Concurrent Immuno-Electrophoresis (CIE): used for rapid detection of H.
influenza, S. pneumoniae & N. meningitidis.
• Smears: taken from purpuric spots may show meningococci
• PCR: for detection of bacteria.
• Urinary antigen

Neuroimaging
• Indications of neuroimaging :
• No response to treatment
• Head trauma
• Immunocompromised state
• Coma
• Presence of a CSF shunt
• Focal neurological deficit
• Hydrocephalus

Cont….
• USG of brain(if fontanelle open)
• Urine culture
• Coagulation profile
• Chest X-ray
• Blood gases
• EEG

Therapeutic principle
• Immediate management
• Specific management with antimicrobial therapy
• Corticosteroid treatment
• Supportive care
• Treatment of complication

Immediate Management
• Assurance of adequate ventilation and cardiac perfusion
• Treatment of septic shock, if present.
• Administration of dexamethason prior to antibiotic therapy.
• Administration of first dose empiric antibiotic
• .After culture report give according to culture and sensitivity.
• Treatment of acidosis and coagulopathy.

Corticosteroid Therapy:
• Inj Dexamethasone :0.15mg/kg every 6 hrly for 2 days.
• Limits production of inflamatory mediator.
• Should started before antibiotic therapy.
• Effective in meningitis caused by H. influenzae.
• Rapid killing of bacteria release toxic cell products after cell lysis that precipitate
the cytokine mediated injury leads to edema formation nurologic injury which
worsen CNS signs symptoms.

Emperic Antibiotic Therapy:
• Inj:Cefotaxime-200mg/kg/day;6 hrly
OR
• Inj:Ceftriaxone-100mg/kg/day;single
PLUS
• Inj Vancomycin-60mg/kg/day;6 hrly.
• Inj Ampicillin-200mg/kg/day;6 hrly(If L.monocytogens is suspected.

Pt allergic to β-lactum antibiotics:
• Inj:Meropenam-120mg/kg/day;8 hrly
OR
• Inj-Chloramphenicol-100mg/kg/day;6hrly
PLUS
• Inj-Vancomycin-60 mg/kg/day;6 hrly

Duration of therapy:
Organism Duration
Neisseria meningitis 5-7 days
H.Influenzae 7-10 days
S.pneumoniae 10-14 days
Other gram negative
bacilli(E.coli,Pseudomonas)
3 weeks or 2weeks after CSF
sterilization

Prognosis:
• Overall mortality rate beyond the neonatal period is
<10%.
• Highest mortality rates with pneumococcal meningitis.
• Severe neurorodevelopmental sequelae in 10-20% of
case.

Prevention
• Haemophilus vaccine (HiB vaccine) in children.
• The pneumococcal conjugate vaccine is now a routine
childhood immunization and is very effective at preventing
pneumococcal meningitis.
• Household members and others in close contact with people
who have meningococcal meningitis should receive preventive
antibiotics.
4/28/2021 81

Chemoprophylaxis:
H.Influenzae –Rifampicin 20mg/kg/day single dose for 4
days.
Meningococcus-Rifampicin 20 mg/kg/day in 2 divided
doses for 2 days
or
Ciprofloxacin 500 mg orally single dose

NEXT PRESENTER
DR.SHAZIA AFREEN

CHRONIC MENINGITIS
• Persistence of symptoms and signs of meningitis for more than
4 weeks associated with CSF pleocytosis.
• Chronic meningitis can have either an acute or
insidious onset.
ref:Veena Kalra practical pediatric neurology

ETIOLOGY
INFECTIOUS NON-INFECTIOUS
Bacterial Collagen vascular disease
Tuberculosis, Partially treated meningitis SLE, PAN
Syphilis, Brucellosis, Leptospirosis,
Lyme boreliosis
Wegener's granulomatosis,
Fungal Sarcoidosis
C.neoformans ,Candida,Coccidioidis
immitis
Chemotherapeutic agents
Viral Malignancies
CMV, HIV Leukaemia,Lymphoma
parasite

INTRODUCTION
• The most common form of CNS tuberculosis .
• Serious complication of childhood tuberculosis
• Complicates 0.3% of untreated TB in children
• Causes substantial morbidity and mortality in adults & children.

INCIDENCE
• Global : In 2014, an estimated 9.6million incident cases of TB
• 1.5 million people died from the disease (1.1 million deaths among people
who were HIV-negative and 360 000 among people who were HIV-positive).
• Bangladesh: Incidence 227 per 100000 population
• In developing countries, 10-20% of people who die of TB are children.
• Bangladesh ranks 7th among countries with the highest burden of TB
WHO global TB report 2015

M. TUBERCULOSIS
• Straight or slightly curved rods
• Arranged either singly or in small
groups.
• Non-spore forming,
• Non capsulated
• Non flagellated
• Non-motile.
• Acid fast, gram positive.
• Strict aerobe, slow growers.
• Mycolic acid is the principle
constituent of cell wall & is
responsible for acid fastness of
bacterium.

RISK FACTORS
• Age : 6months to 4 years
• 43% in infants (children < 1year)
• 25% in children aged one to five years
• 15% in adolescents
• 10% in adult
• Malnutrition
• Overcrowding
• Exposure to high risk adult (close contact)
• History of TB with in 1 yr
• Immunosuppression particularly HIV infection

• Tuberculous meningitis is always a secondary lesion with
primary usually in the lungs
• Meningitis results from formation of a metastatic caseous
lesion in the cerebral cortex, meninges and choroid plexus
during the process of initial occult lympho-hematogenous
spread of primary infection.
• Then Caseous foci form on the surface of brain (Rich’s
foci). They increase in the size and discharge bacilli in CSF.
PATHOGENESIS

• A thick, gelatinous exudate may infiltrate the cortical or
meningeal blood vessel , which produces an intense
hypersensitivity reaction giving rise to inflammatory changes,
obstruction or infarction .
• Most commonly involved site is the brain stem causing
frequent involvement of 3rd , 6th and 7th cranial nerves.
• Basal cisterns are obstructed causing communicating
hydrocephalus.
• Accompanying inflammation may cause cerebral edema.
Cont…..

CLINICAL FEATURE
Clinical progression : 2 types
• Rapid
• Gradual

RAPID
• Less common presentation
• More common in infant and young children
• Few days fever, lethargy followed by acute onset of
hydrocephalus, seizure, cerebral edema .

GRADUAL
• Classical
• Present as sub acute or chronic meningitis
• Over several weeks

Symptoms progresses over 3 stages
• 1st Stage : Prodromal stage
Lasts over 1-2 wks
Nonspecific symptoms like –
.Fever
.Headache
.Irritability
.Drowsiness
.Malaise
.Loss interest in play
GCS score of 15/15 with absence of focal neurological sign
Infants may experience a stagnation or loss of developmental milestone

2nd stage : stage of meningitis
• 2a: GCS of 15 with no neurological deficit or GCS 13-14 with or
without neurological deficit.
• 2b: GCS score of 10-12 with or without neurological deficit.
• Onset is more abrupt.

CONT
• Lethargy
• Sign of meningeal irritation(25%)
• Seizure(50%)
• Hypertonia
• vomiting
• Cranial nerve palsies(20-30%) and other focal neurologic signs.
• Hydrocephalus
• Raised ICP(20%)

CONT
Some children have no evidence of meningeal irritation but
can have signs of encephalitis such as disorientation,
movement disorders or speech impairment
Fundoscopy: papilloedema, choroid tubercle

3rd stage : stage of coma
Stage of downhill course(if not treated)
• GCS score <10.
• Rapidly become comatose
• High grade irregular fever & convulsion.
• Hemiplegia
• Paraplegia
• Extreme neck stiffness, opisthotonus develop with decerebrate posturing &
pupil become dilated & fixed.
• Deterioration of vital signs specially hypertension.
• Death may occur if treatment started late in this stage.
Refined MRC Scale; source- Central Nervous System Infections of Childhood, edt Protibha Singhi,Nelson
textbook of pediatrics,20th edition.

COMPLICATIONS
• Hydrocephalus
• Seizure
• Blindness
• Deafness
• Cranial nerve palsy
• Ataxia
• Hemiparesis
• Cerebral palsy
• Endocrinopathies
• Mental retardation,
• Psychiatric disorder

• The diagnosis of CNS TB can be difficult early in its course.
• Require high degree of suspicion
• History
• Clinical feature
• Examination
• Lab investigations
DIAGNOSIS

INVESTIGATIONS
• Complete blood count with ESR
• Hb : decreased
• ESR: raised
• S.electrolytes: Mild to moderate hyponatremia in case of SIADH

Investigation contd.
• Tuberculin test:
• Reactive 10—50 % cases for CNS TB
• Recent study shows sensitivity-75%
J F Schoeman , R van Toorn. Central Nervous System Infections in Childhood. Mac Keith press2014: 202-210.

• X-ray chest
• Normal in 20-50% cases
• Others may show mediastinal lymphadenopathy
• Sign of TB infection in lung parenchyma
• Pleural effusion
Nelson textbook of Paediatrics: 20th Ed,

Investigation
• The most useful guide to diagnose TBM is CSF study
Pressure Elevated/ normal
Appearance Clear / Slightly turbid
On standing there may be a cobweb like clot of the
fluid
Cell count Leukocytosis :10-500/ cmm
In early stage elevated PMNs
Later lymphocyte predominant
Protein Raised, 400-5000mg/dl
Sugar Typically Less than 50 mg/dl
Rarely less than 20 mg/dl

CSF study contd.
• Definitive diagnosis of TBM is made by detection of tubercle bacilli
in the CSF either by smear examination or bacterial culture.
• CSF culture
• Culture of CSF for AFBs remains the "gold standard“ to make the
diagnosis TBM.
• Needs 4-8 wks to identify the organism
• Drug susceptibility testing requires an additional 4 wks.
• Culture is positive in 50-70% of cases

CSF study contd.
• Rapid culture method
• Semi automated radiometric culture system
such as BACTEC 460
• Require 1-3 wks to yield the growth
• Drug susceptibility determined in an additional
3-5 days.
• Acid fast stain of CSF
• Positive up to 30% of cases

Investigation Cont..
• How to increase Mycobacterial isolation in CSF :
• Examination of the deposits on centrifugation of 5—10 ml CSF
• Smear prepared from the cobweb
• Examination for at least 30 min before reporting as negative
• Examination of several samples obtained over several days
• Several daily large volume (10–15 mL) lumbar punctures are
often needed for microbiologic diagnosis; sensitivity increases to
>85% when four spinal taps are performed.
Nelson textbook of Paediatrics: 20thh Ed,
Cherian A, Thomas SV, Kennedy DH, Fallon RJ. Central nervous system tuberculosis .African Health Sciences 2011; 11(1):264–8.

• ADA: CSF Adenosine Deaminase activity (ADA)
• marker of cell-mediated immunity.
• It was found that ADA values less than 4 U/L excludes
TBM and greater than 8 U/L are suggestive of TBM. CSF
ADA 10 U/ L has >90% sensitivity and specificity of
diagnosing TBM .
• However, false-positive ADA can be found in
• HIV, cryptococcal meningitis,malaria,CNS lymphoma and
cytomegalovirus disease.
• It is not recommended as a routine diagnostic test for TBM.

Antibody detection:
• ELISPOT(Enzyme linked immunospot assay) to detect antibody in CSF
Antigen detection
o ELISA( Enzyme Linked Immune Sorbent Assay
o Dot immunobinding assay
o Latex agglutination test sensitivity-88%, specificity-95% ((J. Med.
Microbiol. 20:239–247)
o Radioimmune assay

PCR
 Sensitive
 Rapid
 Reliable
Identify mycobacterial nucleic acid amplification (RNA or DNA
sequence ) in CSF

Xpert MTB/RIF assay: The Xpert MTB/RIF
• A new fully automated diagnostic molecular test
• simultaneously detects the presence of multidrug resistant tuberculosis
(MTB) and Rifampicin resistance in specimens, using nested real-time
(sensitivity 67-85%, specificity 94-98%) .
• The advantages are the ease of use for inexperienced staff and
rapid turnover time (about 2 h).
World Health Organization, “Automated real-time nucleic acid amplification technology for rapid and simultaneous
detection of tuberculosis and Rifampicin resistance: Xpert MTB/RIF system,” Policy Statement, 2011.

Investigations
• Interferon-γ Release Assays
• Two blood tests (T-SPOT.TB and QuantiFERON-TB) detect IFN-γ
generation by the patient’s T cells in response to specific M.
tuberculosis antigens (ESAT-6, CFP-10, and TB7.7).
• The QuantiFERON-TB test measures whole blood concentrations of
IFN-γ and
• The T-SPOT.TB test measures the number of lymphocytes producing
IFN-γ.

IMAGINGS
• CT scan and MRI may be normal during the early stage
• Findings:TRIAD
• Basal enhancement
• Ventricular enlargement
• Infarcts
100% specific & 11% sensitive for diagnosis of TBM.
Andronikou et al,pediatr radiolo 34:867-85,2004

• Carotid and MR angiogram:
• Uniform narrowing of large segments.
• Small segmental narrowing.
• Irregular beaded appearance and
• Complete occlusion of vessels due to vasculitis or compression
by basilar exudates.

Diagnostic criteria for classification of definite, probable, possible, and
not tuberculous meningitis
Tuberculousmeningitis: a uniform case definition for use inclinical research. Lancet Infect Dis 2010; 10:803–12.

Diagnostic criteria for classification of definite, probable, possible, and
not tuberculous meningitis
Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis 2010; 10:803–12.

Consensus tuberculous meningitis diagnosis
• Clinical entry criteria
• Symptoms and signs of meningitis including one or more of the following:
Headache, irritability, vomiting, fever, neck stiffness, convulsions, focal
neurological deficits, altered consciousness, lethargy.

• Definite tuberculous meningitis
Patients should fulfill criterion A or B:
A) Clinical entry criteria plus one or more of the following: acid-
fast bacilli seen in the CSF; Mycobacterium tuberculosis
cultured from the CSF or a CSF positive commercial nucleic
acid amplification test.
B) Acid-fast bacilli seen in the context of histological changes.
Consistent with tuberculosis in the brain or spinal cord with
suggestive symptoms or signs and CSF changes or visible
meningitis (on autopsy).

• Probable tuberculous meningitis
• Clinical entry criteria plus a total diagnostic score of 10 or more
points (when cerebral imaging is not available) or 12 or more
points (when cerebral imaging is available) plus exclusion of
alternative diagnoses. At least 2 points should either come from
CSF or cerebral imaging criteria.

• Possible tuberculous meningitis
• Clinical entry criteria plus a total diagnostic score of 6–9 points
(when cerebral imaging is not available) or
• 6–11 points (when cerebral imaging is available) plus exclusion of
alternative diagnoses.
• Possible tuberculosis cannot be diagnosed or excluded without
doing a lumbar puncture or cerebral imaging.
• Not tuberculous meningitis
• Alternative diagnosis established, without a definitive diagnosis of
tuberculous meningitis or other convincing signs of dual disease.

TREATMENT
• Treatment must be started as soon as there is a reasonable
suspicion of the diagnosis
• Treatment must not be delayed while waiting for confirmation of the
diagnosis.
• The children with TBM should be hospitalized.

Treatment contd..
• There is no general consensus about the form of chemotherapy or
optimal duration of treatment.
• WHO put CNS TB under treatment category I and recommended
• Initial phase(1st 2months): INH, RIF , PZA , EMB followed by
• Continuation phase(next 10 months): INH, RIF

Treatment cont..
• Centre for Disease Control(CDC) America recommended
• Initial phase (1st 2months): INH, RIF, PZA
Ethambutol or streptomycin may be added if the response is
not satisfactory
• Continuation phase(Next 4 months)
INH, RIF
Total duration at least 6 months
May be extended up to 12 months

National Guideline for TBM (Bangladesh)
2(HRZ)S +10(HR)

Treatment cont..
• Pyridoxine is not routinely prescribed.
• Pyridoxine should be added to prevent INH induced peripheral
neuropathy specially in severe malnourished children, HIV infected
children on antiretroviral treatment, chronic liver disease and renal
failure.
• Older children: 12.5—25 mg /day
• Infants: Multivitamins syrup

Anti TB therapy : 1st line drugs
Drugs Dose mg/kg Maximum
(mg)
Main toxicity
Isoniazide 10 (5-15)mg/kg 300 Hepatitis, peripheral
neuropathy
RIF 15(10-20) 600 Hepatitis, orange colour
urine, drug interaction
PZA 35( 30-40) 2000 Hepatitis, arthralgia
Strep. 15(12-18) 1000 Oto and nephrotoxic
EMB 20(15-25) 1200 Visual disturbance

Multiple drug resistant TBM
• Resistance to both INH and RIF (2nd line)
Drugs Dose mg/kg max Duration (mo) Main toxicity
Cycloserine 10-20 1gm 18-24 Psychosis ,
depression,
convulsion
Ethionamide 15-20 1gm 18-24 Hepatitis,
hypothyroidism
Amikacin/kan
amycin
15-30 1 gm 6 Oto and
nephrotoxicity

Multiple drug resistant TBM contd.
Drug Dose mg/kg max Duration(mo
nth)
Main toxicity
Capreomycin 15-30 1gm 6 Oto and
nephrotixicity
Paraaminosalicy
lic acid
150-200 12 gm 18-24 Hypothyroidism,
diarrhea, vomiting
Levofloxacin 7.5-10 18-24 insomnia
Moxifloxacin 7.5-10 18-24
Ofloxacin 15-20 18-24

STEROID THERAPY
• Reduce mortality
• Improvement in neurological secquelae
• Better intellectual outcome
• Enhance resolution of
• Basal exudates
• Intracranial oedema and
• tuberculoma

Steroid therapy
Drug Dose Duration
Prednisolone 2mg/kg/day 4 wks then
tapering over 1-2
wks
Dexamethasone 0.4 mg/kg/day- 1st wk
0.3 mg/kg/day- 2nd wk
0.2 mg/kg/day- 3rd wk
0.1 mg/kg/day- 4th wk
Tapering with oral
dexamethasone 4 mg/day for 1
wk
3m/day—1wk
2mg /day—1wk
1mg/day—1wk Ref: UpToDate 2005; TB meningitis.
Ref: National guideline Bangladesh

Treatment of Complications
• Hydrocephalus
• Seizure
• Ataxia
• Hemiparesis
• Cerebral palsy
• Endocrinopathies
• MR
• Psychiatric disorder

PROGNOSIS
Stage I good
Stage II 50%-78% recovery
Stage III 20% recovery

PREVENTION
• BCG vaccination
• Prevents CNS TB
• Efficacy 75-85%

NEXT PRESENTER
DR.MD. MYDUL ISLAM KHAN

Fungal meningitis
• Fungal meningitis is a rare, life-threatening disease. It can be
caused by a variety of fungi although the most likely are
Cryptococcus neoformans and Candida albicans.
• Fungal meningitis usually only occurs in immunocompromised
patients.
• Fungal meningitis is not transmitted from person to person. The fungi
are usually inhaled and then spread by the blood to the central
nervous system; fungi may also be directly inserted into the central
nervous system by medical techniques or enter from an infected site
near the central nervous system.

Most common causative Fungi include:
• Fungi
• Cryptococcus neoformans
• C immitis
• B dermatitidis
• H capsulatum
• Candida species
• Aspergillus species

Presentations:
• Fever
• Headache
• Stiff neck
• Nausea and vomiting
• Photophobia
• Altered mental status

Diagnosis:
• CSF Study
• Culture
• Other specific lab tests can be performed, depending on the type of
fungus suspected.

CSF findings in Fungal meningitis
• Pressure: Usually elevated
• Cells: 5-500; PMNs early but mononuclear cells predominate through
most of the course. Cryptococcal meningitis may have no cellular
inflammatory response
• Protein: 25-500mg/dl
• Glucose: <50mg/dl; decreases with time if treatment is not provided
• Others:Budding yeast may be seen. Organisms may be recovered in
culture. Cryptococcal antigen (CSF and serum) may be positive in
cryptococcal infection

C. neoformans
• an encapsulated yeast-like fungus that
found in high concentrations in aged
pigeon droppings
• 50-80% of cases occur in
immunocompromised hosts
• The infection is characterized by the
gradual onset of symptoms, the most
common of which is headache.
• The onset may be acute, especially
among patients with AIDS

Diagonosis of cryptococcal meningitis
Diagnosis : identification of the pathogen in the CSF
• C neoformans culture from CSF
• India ink preparation : sensitivity of only 50%, but highly
diagnostic if positive
• CSF cryptococcal antigen : sensitivity of greater than 90%
• blood cultures and serum cryptococcal antigen to determine if
cryptococcal fungemia is present.

C. neoformans in India ink preparation:
(source: Lange Microbiology)

cryptococcal meningitis in patients without
AIDS
• Induction/consolidation: Administer amphotericin B (0.5-1
mg/kg/d) plus flucytosine (100 mg/kg/d) for 2 weeks.
Then, administer fluconazole (6-12 mg/kg/d) for a
minimum of 10 weeks.
• A lumbar puncture is recommended after 2 weeks to
document sterilization of the CSF. If the infection persists,
longer therapy is recommended. Solid organ transplant
recipients require prolonged therapy.

AIDS-related cryptococcal meningitis
• Induction therapy: amphotericin B (0.5-1 mg/kg/d IV) for at least
2 weeks
• Consolidation therapy: fluconazole (12 mg/kg/d for 8 wk).
Itraconazole is an alternative
• Maintenance therapy: Long-term antifungal therapy with
fluconazole (6-12 mg/kg/d)
• In case of increased ICP. Make an effort to reduce such
pressure by repeated lumbar puncture, a lumbar drain, or shunt

Treatment options for other Fungal meningitis
• C. immitis
• oral fluconazole (6-12mg/kg/d) or
• Itraconazole
• Duration of treatment usually is life long.
• H capsulatum
• Amphotericin B at 0.5-1 mg/kg/d to complete a total dose
of 35 mg/kg
• Fluconazole (6-12 mg/kg/d) for an additional 9-12 months
may be used to prevent relapse.
• Candida species
• amphotericin B (0.5mg/kg/d)+/- Flucytosine (25 mg/kg qid)
for 30 days.

Prognosis:
• Prognosis of meningitis caused by opportunistic pathogens
depends on the underlying immune function of the host. Many
of the survivors require lifelong suppressive therapy (eg, long-
term fluconazole for suppression in patients with HIV-associated
cryptococcal meningitis).

Parasitic meningitis
Free-living amoebas eg,
 Acanthamoeba,
 Balamuthia,
 Naegleria
• infrequent but often life-threatening illness
• In the 10 years from 2003 to 2012, 31 infections were reported in
the U.S. All were fatal.

N fowleri
• is the agent of primary
amebic meningoencephalitis
(PAM)
• Infection occurs when
swimming or playing in the
contaminated water
• invade the CNS through the
nasal mucosa, invade the
cribriform plate, and reach the
subarachnoid space.

• PAM occurs in 2 forms.
• an acute onset of high fever, photophobia, headache, and
change in mental status, similar to bacterial meningitis with
involvement of the olfactory nerves sensation. Death occurs
in 3 days in patients who are not treated.
• subacute or chronic form, is an insidious onset of low-
grade fever, headache, and focal neurologic signs.
• Acanthamoeba and Balamuthia cause granulomatous
amebic encephalitis (GAE), which spreads
hematogenously from the primary site of infection (skin or
lungs)

Hemorrhage in the frontal cortex due to Primary
Amebic Meningoencephalitis.

multiple variable-sized haemorrhagic and
necrotic lesions in GAE
• Case report:Emergence of balamuthia mandrillaris
meningoencephalitis in India
S Khurana, V Hallur1, MK Goyal2, R Sehgal, BD Radotra3 (Indian
journal of Medical microbiology)

Diagnostic tools:
• CSF study
• Antigen detection in CSF.
• Biopsy & histopathology of tissue specimen.
• Tissue-based polymerase chain reaction (PCR) assay
• Imaging study.

CSF in PAM
• lumbar puncture for CSF analysis is the primary diagnostic tool
in PAM. CSF analysis is indistinguishable from that in acute
bacterial meningitis, except that Gram stain findings are always
negative.
• If PAM is suspected, light microscopy with phase contrast on
fresh, still-warm CSF may reveal motile trophozoites.

CSF indices (in N fowleri)include the following:
• CSF protein levels are elevated.
• CSF glucose levels are within the reference range or reduced.
• CSF WBC count is elevated (1000-10,000 cells/µL).
• CSF RBC count is high, and the CSF is often hemorrhagic.
• CSF Gram stain results are negative for bacteria.
• CSF wet mount is positive for motile trophozoites and is of
paramount importance for the diagnosis.

CSF In GAE
• lumbar puncture for CSF analysis is the primary diagnostic tool in
GAE. CSF analysis typically demonstrates less inflammation than
that observed in individuals with PAM, and no trophozoites appear
in the CSF. Opening pressure is elevated.
• CSF analysis mimics that of aseptic meningitis, with low to
moderate, primarily mononuclear white blood cells (WBCs);
elevated protein levels; and often, near-normal or slightly
decreased glucose levels.

Treatment for PAM
• The treatment of choice for PAM is amphotericin B, at
maximally tolerated doses, with adjunctive rifampin and
doxycycline. Successful treatment may also require intrathecal
amphotericin B.
• Sulfisoxazole, phenothiazine, and artemisinin may have some
benefit.
• In addition, studies have suggested some role for azithromycin
as an adjunct to amphotericin B.
(source: Medscape)

Treatment for PAM
• Recently an investigational anti-leishmania drug, miltefosine ,
has shown some promise in combination with some of these
other drugs. Miltefosine has shown ameba-killing activity
against free-living amebae, including Naegleria fowleri, in the
laboratory.
• Miltefosine has also been used to successfully treat patients
infected with Balamuthia and disseminated Acanthamoeba
infection
(source: CDC)

Treatment of Granulomatous amebic encephalitis
(GAE)
• Ketoconazole and amphotericin B (alone or in combination), as
well as sulfadiazine, may be indicated in GAE.
• A case report described successful treatment of Balamuthia GAE
with miltefosine, fluconazole, and albendazole.
• Another case report described successful treatment of
Acanthamoeba GAE with trimethoprim-sulfamethoxazole (TMP-
SMZ), fluconazole, pentamidine, miltefosine, and hyperbaric
oxygen.
• Finally, a combination of voriconazole and miltefosine has been
used.
(Source:Medscape)

Eosinophilic Meningitis
• Eosinophilic meningitis is defined as 10 or more
eosinophils/mm3 of CSF.
• The most common cause worldwide of eosinophilic pleocytosis
is CNS infection with helminthic parasites.
• Eosinophilic meningitis may also occur as an unusual
manifestation of more common viral, bacterial, or fungal
infections of the CNS.
• Noninfectious causes of eosinophilic meningitis include multiple
sclerosis, malignancy, hypereosinophilic syndrome, or a
reaction to medications or a ventriculoperitoneal shunt.

Common Helminths causing eosinophilic
Meningitis:
• Angiostrongylus
cantonensis(most common)
.
• Gnathostoma spinigerum
(dog and cat roundworm)
• Baylisascaris procyonis
(raccoon roundworm),
• Ascaris lumbricoides (human
roundworm),
• Trichinella spiralis,
• Toxocara canis,
• T. gondii,
• Paragonimus westermani,
• Echinococcus granulosus,
• Schistosoma japonicum,
• Onchocerca volvulus, and
• Taenia solium.

Angiostrongylus cantonensis
is found in Southeast Asia, the South
Pacific,Japan, Taiwan, Egypt, Ivory Coast,
and Cuba. Infection is acquired by eating
raw or undercooked freshwater snails,
slugs, prawns, or crabs containing
infectious 3rd-stage larvae.
• cause eosinophilic meningitis (pleocytosis
with >10% eosinophils)
• present with nonspecific and self-limited
abdominal pain caused by larval migration
into the bowel wall.
• On rare occasions, the larva can migrate
into the CNS and cause eosinophilic
meningitis

Gnathostoma spinigerum
•Gnathostoma infections are found in Japan,
China, India, Bangladesh,and Southeast Asia.
cause eosinophilic meningoencephalitis
•acquire the infection following ingestion of
undercooked or raw infected fish, frog, snake
meat, bird or poultry.

Diagnosis of Helminthic Meningitis
• The presumptive diagnosis of helminth-induced eosinophilic
meningitis is made by travel and exposure history in the
presence of typical clinical and laboratory findings.
CSF study:
• CSF findings indicative of angiostrongyliasis include cloudy
CSF, elevated opening pressure, an increased protein level, a
normal glucose level, and an elevated absolute leukocyte count
with eosinophilia

• Analysis of CSF specimens from
patients with gnathostomiasis
usually reveals xanthochromia, an
elevated opening pressure in one-half
of infected patients, pleocytosis with
eosinophilia, normal glucose levels,
and normal or elevated protein levels
(Source:Eosinophilic Meningitis due to
Angiostrongylus and Gnathostoma Species
Lynn Ramirez-Avila, Sally Slome, Oxford journal)

Treatment of Helminthic Meningitis
• Treatment is supportive, because infection is self-limited and
anthelmintic drugs do not appear to influence the outcome of
infection.
• Analgesics should be given for headache and radiculitis,and
CSF removal or shunting should be performed to relieve
hydrocephalus, if present.
• Steroids may decrease the duration of headaches in adults
with eosinophilic meningitis.

Spirochetal meningitis
T pallidum
• modes of transmission:
• sexual contact
• direct contact with an active lesion
• passage through the placenta
• blood transfusion (rare)
• Three stages of disease are described, and involvement of the CNS can
occur during any of these stages.
• Syphilitic meningitis usually occurs during the primary or secondary
stage. Its presentation is similar to other agents of aseptic meningitis.

• CNS syphilitic syndromes include
• meningovascular syphilis
• parenchymatous neurosyphilis
• gummatous neurosyphilis
and the symptoms are dominated by focal syphilitic arteritis
(ie, focal neurologic symptoms associated with signs of
meningeal irritation), typically in absence of fever.

Diagnosis of Syphilitic Meningitis
• The CSF is characterized by mild lymphocytic pleocytosis.
• elevated CSF protein levels & decreased glucose levels may be
observed in 10-70% of cases.
• Demonstrate the spirochete by using dark-field or phase-contrast
microscopy on specimens collected from skin lesions (eg, chancres and
other syphilitic lesions).
• CSF VDRL : sensitivity of 30-70% (a negative result does not rule out
syphilitic meningitis) and a high specificity (a positive test result
suggests the disease).
• serologic tests to detect syphilis : VDRL test ,FTA-Abs ,TPHA

Treatment of Syphilitic Meningitis:
• penicillin G (2-4 million U/d IV q4h) for 10-14 days, often
followed with benzathine penicillin G 2.4 million U IM.
• Alternative : administer procaine penicillin G (2.4 million
U/d IM) plus probenecid (500 mg PO qid) for 14 days,
followed by IM benzathine penicillin G (2.4 million U).
• Repeat CSF examination : cell count , serologic titers
• Because penicillin G is treatment of choice, patients who
are allergic to penicillin should undergo penicillin
desensitization

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