This PPT is about tubercular meningitis

1. Tuberculous Meningitis
Moderator – Dr. Kallesh Hebbal.
Presenter – Dr. Neelesh N Jain.

2. Outline
• Introduction.
• Classification.
• Pathogenesis.
• Clinical Presentation.
• Laboratory Diagnosis.
• Treatment.

3. Introduction
• CNS tuberculosis is a devastating illness, which carries high mortality and
morbidity.
• Disease is caused by Mycobacterium tuberculosis.
• About 1% of total TB cases and 5-10% of extra pulmonary TB cases develop CNS
TB.

4. • Risk factors for CNS TB include younger age, HIV confection, malnutrition, the use
of immunosuppressive agents.
• Confection with human immunodeficiency virus (HIV) and the emergence of drug
resistant strains further complicates the disease.
• The estimated mortality of TBM in India is about 1.5/100,000 population.

5. Classification
Classification of CNS tuberculosis
Intracranial • Tuberculous meningitis
• Serous tuberculous meningitis
• Tuberculous encephalopathy
• Tuberculous vasculopathy
• Localized tuberculous meningitis
• CNS tuberculoma (single or multiple)
• Tuberculous brain abscess
Spinal Osseous spinal TB
• Pott's spine and Pott's paraplegia
Nonosseous spinal TB
• Tuberculous arachnoiditis (myeloradiculopathy)
• Tuberculomas (intradural, extramedullary tuberculoma or intramedullary)
• Spinal tuberculous abscess
• Acute myelitis

6. Pathogenesis
• CNS TB occurs as a result of secondary hematogenous spread from the site of
primary extra cranial tuberculous lesion.
• Secondary hematogenous spread occurs early in infection before immune
responses control the infection.
• Small tuberculous lesions (Rich's foci) develop around bacteria seeded in the
brain during the initial hematogenous dissemination.

7. • These initial foci may be in the meninges, the subependymal surface of the brain
or the spinal cord and are most commonly situated in the sylvian fissure.
• These foci may remain dormant for years after initial infection.
• Rupture into the subarachnoid space or into the ventricular space leads to
meningitis.
• It usually occurs within the first 3-6 months after the primary infection.

8. • After the release of tubercle bacilli from granulomatous lesions into the
subarachnoid space, dense gelatinous exudates are formed predominantly around
the sylvian fissures, basal cisterns, brainstem, and cerebellum.
• Direct contact of the exudates leads to a border zone reaction in the underlying
brain parenchyma, Blockage of CSF pathway.
• This blockade can be at basal cisterns, outflow of fourth ventricle or cerebral
aqueduct, and interference in the absorption of CSF by the arachnoid granulations.

9. • Vascular involvement is common and occurs because of inflammation, thrombosis
or external compression by exudates.
• Sylvian fissure and the basal ganglion are the most common sites of infarction.
• Cranial nerves are involved as a result of entrapment neuropathy caused by thick
exudates.

11. Clinical presentation
• Early diagnosis of TBM is difficult because of nonspecific clinical features, and
disease is often diagnosed late when brain damage has already occurred.
• Peak incidence is between 2 and 4 years.
• Typically, TBM has a sub acute onset with a gap of 1-4 weeks or more between
onset of fever and the onset of neurological symptoms.
• Early symptoms are nonspecific and include poor weight gain, low-grade fever,
vomiting, photophobia, headache and listlessness.

12. • As the disease progresses meningeal irritation signs, altered sensorium, seizures,
signs of raised intracranial pressure (ICP), cranial nerve palsies(3,6,7), focal
deficits, and abnormal movements are seen.
• Vision loss can occur due to optochiasmatic arachnoiditis, third ventricle
compression of optic chiasma or optic nerve granuloma.

14. • Fundoscopy may reveal papilledema and choroid tubercles.
• Choroid tubercles are mostly associated with miliary TB and found in only 10%
cases without miliary TB.
• These are yellow lesions with indistinct borders (single or cluster) and are
virtually pathognomonic of tubercular etiology.

16. Grading of the severity of TBM
Severity of Tuberculous Meningitis (modified MRC scale).
Stage I Alert and orientated without focal neurological deficit.
Stage II Glasgow coma score 14-10 with or without focal neurological deficit
or Glasgow coma score 15 with focal neurological deficit.
Stage III Glasgow coma score <10 with or without focal neurological deficit.

17. Uncommon forms of TBM
1. Serous Tuberculous Meningitis.
2. Tuberculous Encephalopathy.

18. Serous Tuberculous Meningitis
• Serous TBM is characterized by signs and symptoms of mild meningitis seen
especially in Bacillus Calmette-Guérin (BCG) vaccinated children.
• These children present with fever, headache and vomiting and may be conscious
at the time of presentation
• Disease is mostly localized and CSF examination is normal.

19. Tuberculous Encephalopathy
This variant of cerebral TB has been reported in Indian children with diffuse
cerebral disorder.
Presenting symptoms were convulsions, coma, involuntary movements, and
pyramidal signs with normal CSF findings.
Postmortem - diffuse cerebral edema, perivascular myelin loss, and haemorrhagic
leukoencephalopathy.
These features may be more typical of a post infectious allergic encephalomyelitis.

20. Laboratory Diagnosis
1. Cerebrospinal Fluid analysis.
2. Neuroimaging.
3. Tests to detect evidence of TB elsewhere in the body.

21. 1. Cerebrospinal Fluid analysis
a) CSF microscopy and CSF protein and sugar estimation:
• CSF examination typically shows predominantly lymphocytic reaction (50-
500 white cells per mL) with raised protein levels (100 – 3000 mg/dl). CSF
sugar is low, mostly less than two-thirds of blood glucose concentration. CSF
lactate is about 5-10 mmol/L.
• In early TBM polymorphonuclear cells may be pre-dominant, which is
replaced by lymphocytes later on.

22. b. ZN staining/ auramine O or auramine-rhodamine stains fluorescence
microscopy for acid-fast bacilli.
• Definite diagnosis requires demonstration of tubercle bacilli in the CSF by
smear examination with Ziehl-Neelsen stain (sensitivity 10-25%)

23. c. Culture and sensitivity for Mycobacterium tuberculosis: Solid LJ medium
culture, liquid culture like Mycobacterium Growth Indicator Tube (BACTEC
MGIT) : bacterial culture (sensitivity 18-83%)

24. d. IS6110 PCR (simple PCR, multiplex PCR, and real time PCR)
• When primer against IS6110 is used for PCR, sensitivity is 76% and
specificity is 89%.
• Protein antigen B, MPB64 and 65 kDa are also targeted in PCR for TB.

25. e. Multitargeted (LAMP): GeneXpert MTB/RIF assay, GeneXpert Ultra,
Molecular line probe assays.
• Multitargeted loop-mediated isothermal amplification (LAMP) has shown
sensitivity of 77% and specificity of 99% in extrapulmonary TB.
• Xpert MTB/RIF assay have been used for rapid diagnosis of TBM and
rifampicin resistance (sensitivity 14-55% and specificity of 94-98%).

26. continuation
• World Health Organization (WHO) recommends Xpert ultra as the first
diagnostic test in TBM as it has a better sensitivity than Xpert MTB (60-76%).
• MTBDR plus line probe assay can be used for identification of drug resistance
in MTB isolates recovered from CSF samples of confirmed TBM patients.

27. Other tests
• The other tests include the evaluation of adenosine deaminase activity (ADA),
interferon-gamma (IFN-γ) release by lymphocytes, and M. tuberculosis antigens
and antibodies.
• The ADA test is a rapid test.
• It represents the proliferation and differentiation of lymphocytes as a result of the
activation of cell-mediated immunity after M. tuberculosis infection.

28. • In patients with TBM, ADA values from 1 to 4 U/L (sensitivity > 93% and
specificity < 80%) can help to exclude TBM.
• Values >8 U/L (sensitivity < 59% and specificity > 96%) can improve the
diagnosis of TBM.
• Measurement of IFN-γ release by lymphocytes stimulated by M. tuberculosis
antigens is useful for the diagnosis of latent TB and extrapulmonary TB.

29. • Interferon-gamma release assay (IGRAs) do not differentiate latent TB infection
(LTBI) from TB disease.
• IGRAs lack sufficient sensitivity and specificity in TBM.
• These tests are rapid and less expensive but have poor sensitivity and specificity.
• Detection of various M. tuberculosis antigen markers, such as lipoarabinomannan,
purified protein derivatives, heat shock protein of 62 kDa and 14 kDa, GroE, Ag
85 complex, and 38 kDa antigen have been tried to Confirm TBM diagnosis.

30. 2. Neuroimaging - MRI/CT scan of brain.
• Neuroimaging is helpful in both diagnosis and management of TBM.
• Magnetic resonance imaging (MRI) of brain is superior to a computed
tomography (CT) scan particularly when brainstem is involved.
• Diffusion-weighted MRI can detect early infarcts and border-zone encephalitis.
(cytotoxic edema that underlies the tuberculous exudates)
• Leptomeningeal tubercles are visualized in about 90% of children by the
Gadolinium-enhanced MRI.

31. • Magnetic resonance imaging is also valuable for the identification and monitoring
of associated cranial neuropathies like optochiasmatic arachnoiditis.
• MR angiography can be used to identify vascular involvement.
• Computed tomography scan brain may be normal in up to 30% cases of early
TBM but abnormal in most of the cases with late TB.

32. • CT scan reveals hyperdense basal exudates in noncontrast film.
• Contrast enhanced film shows basal meningeal enhancement, infarcts,
hydrocephalus, and tuberculomas.
• Basal meningeal enhancement, ventriculomegaly, tuberculoma, and infarcts as
characteristics to distinguish CNS TB from pyogenic meningitis and proposed that
basal meningeal enhancement, tuberculoma, or both were 89% sensitive and
100% specific for TBM.

35. 3. Tests to detect evidence of TB elsewhere in the body
a. Chest X-ray.
b. Tuberculin test.
c. M. tuberculosis AFB stain/culture from another source (i.e., sputum, lymph
node, gastric lavage, etc.
d. Commercial M. tuberculosis nucleic acid amplification test (NAAT)from
extraneural specimen.
e. CT/MR/ultrasound evidence for TB outside the CNS.

36. Treatment
1. Supportive treatment.
2. Specific treatment.
3. Surgical treatment.

37. 1. Supportive treatment
a. Maintenance of airway breathing and circulation.
b. Intravenous fluid therapy-isotonic fluids like dextrose normal saline.
c. Maintenance of acid base and electrolyte balance.
d. Antiepileptic drugs for control of seizures.
e. Treatment of raised intracranial pressure: intravenous mannitol/3% saline
infusion, acetazolamide, glycerol, and diuretics.
f. Prevention of other complications in a comatose child, e.g., exposure keratitis,
aspiration pneumonia, bed sore, etc.

38. 2. Specific treatment
• Rifampicin (R), isoniazid (INH), pyrazinamide (Z), and ethambutol (E) are the main
drugs used for TBM treatment.
• Pyrazinamide and INH are freely distributed in CSF. Rifampicin, ethambutol, and
streptomycin do not enter CSF but may penetrate inflamed meninges.
• TBM should be treated with 2 months of HRZE (intensive phase) and 10 months with
HRE (continuous phase) has per NTEP guidelines.
• The recommended daily doses include INH 10 (7-15) mg/kg, rifampicin 15 (10-20)
mg/kg, pyrazinamide 35(30-40) mg/kg, and ethambutol 20 (15-25) mg/kg.

39. Drugs Intensive phase (2
months)
Continuous phase (10
months)
CSF Penetration Dosage and adverse
effect
Rifampicin (R) Yes Yes Bactericidal, Poor but penetrate
inflamed meninges.
15 (10-20) mg/kg.
Similar to INH,
Hepatotoxic.
Isoniazid (INH) Yes Yes Bactericidal, good CSF
penetration.
10 (7-15) mg/kg.
Neurotoxicity, Anemia,
Rashes.
Pyrazinamide (Z) Yes No Bactericidal, good CSF
penetration.
35(30-40) mg/kg.
Hepatotoxic,
Hyperuricemia.
Ethambutol (E) Yes Yes Bacteriostatic, Poor but
penetrate inflamed meninges.
20 (15-25) mg/kg.
Loss of visual acuity/
colour vision.

40. Drug Formulations and dosages
Paediatric formulation
H50, R75, Z150, E100 (separate tablet)
Adult formulation
H75, R150, Z400, E275
Children up to the weight of 39kg would be managed as per the
various weight bands available for children
Children ≥ 40kg would be managed as per the various weight bands
available for adults.
Weight band (Kg) Dose from 0 – 18
Years
4 – 7 kg 1 P + 1 E
8 – 11 kg 2 P + 2 E
12 – 15 kg 3 P + 3 E
16 – 24 kg 4 P + 4 E
25 – 29 kg 3 P + + 3 E + 1 A
30 – 39 kg 2 P + + 2 E + 2 A
Weight category IP –FDC (HRZE)
(75/150/400/275)
CP – FDC (HRE)
(75/150/275)
25 – 34 kg 2 2
35 – 49 kg 3 3
50 – 64 kg 4 4
65 – 75 kg 5 5
> 75 kg 6 6

42. Multidrug-resistant Tuberculous Meningitis
• In high burden countries, probability of a patient with TBM having MDR TB
would be 0.1-1.4%.
• Association of MDR TBM with Beijing strains and drug resistance related
mutations in katG and rpoB genes has been found.
• CSF NAATs and detection of genetic mutations that confer drug resistance, e.g.,
Xpert MTB are the only way to diagnose drug resistance quickly.

43. • Fatality rate of MDR TBM was found 57% with significant functional impairment
in most of the survivors.
• MDR TBM is treated with extended course of second-line drugs.
• These drugs are less effective and have more side-effects than a rifampicin and
INH based regime.
• Choice of drug should be determined by probable susceptibility and CSF
penetration.

44. • Ethionamide and cycloserine have good CNS penetration, they are used as part of
intensive-phase treatment regimen in patients with MDR TBM.
• According to recent NTEP guidelines, MDR/XDR CNS TB treatment:
Intensive phase (6-9 months) Continuation phase (18 months)
Amikacin, High-dose Moxifloxacin,
Linezolid, Clofazimine, Ethionamide,
and Cycloserine.
High-dose Moxifloxacin, Linezolid,
Clofazimine, and Cycloserine

45. • Shorter MDR treatment regime and bedaquiline/ delamanid - based regime are not
recommended for MDR CNS TB.
• INH mono-resistant disease requires addition of another drug with better CSF
penetration.
• Mono-resistance to INH is treated by uniphasic regime including levofloxacin,
rifampicin, pyrazinamide, and ethambutol for 9-12 months.

46. Recommended daily dosage of second – line anti - tuberculous drugs for treatment of drug-resistant
tuberculous meningitis in infants and children (below 15 years of age).
Name of the drug Doses CSF penetration
Ethionamide 15-20 mg/kg/day (maximum 1g) oral single dose Good
Cycloserine 15-20 mg/kg/day (maximum 1g) oral single daily dose Good
Streptomycin 20-40 mg/kg/day (maximum 1g) IM or IV single daily
dose
Poor but penetrate inflamed
meninges
Para - aminosalicylic
acid
200-300 mg/kg/day orally in 2 divided doses No Data
Capreomycin 15-20 mg/kg/day (maximum 1g) orally single daily dose No Data
Amikacin and
Kanamycin
15-20 mg/kg/day (maximum1 g/day) IM or IV as a single
daily dose
Poor but penetrate inflamed
meninges
High dose INH 15-20 mg/kg Good
Levofloxacin 15-20 mg/kg (maximum 500 mg) orally single daily dose Good
Moxifloxacin 7.5-10 mg/kg/day (maximum 400 mg) orally single daily
dose
Good
Linezolid 15 mg/kg once a day (maximum 600 mg) Good
Clofazimine 2-5 mg/kg; maximum 100 mg Poor

47. Corticosteroids in Central Nervous System Tuberculosis
• It should be used irrespective of patient's age and stage of the disease.
• In unstable patients IV dexamethasone is given till oral steroids can be added.
• Prednisolone in dose of 2-4 mg/kg given for 4 weeks followed by tapering dose.
• Response is dramatic with rapid improvement in headache, sensorium, and CSF
abnormalities.

48. 3. Surgical treatment
a. Ventriculoperitoneal shunt or endoscopic third ventriculotomy for
hydrocephalus if indicated.
b. Surgical decompression in case of Pott's paraplegia.
c. In case of large tuberculoma causing mass effect and tuberculous brain abscess.

49. Treatment of Complications
• Hyponatremia.
• Acute seizures.
• Raised ICP.
• Vasculitis.
• Hydrocephalus.

50. Hyponatremia
• Low serum sodium levels are found in 35-65% cases of TBM.
• Causes of hyponatremia in TBM include cerebral salt wasting syndrome (CSWS),
syndrome of inappropriate antidiuretic hormone secretion (SIADH), and increased
renal sensitivity to ADH.
• Volume and sodium replacement for the treatment of CSWS and Mineralocorticoid
supplementation has also been shown to be effective.
• For SIADH fluid restriction is done.
• In case hyponatremia is severe, 3% normal saline along with furosemide is added.

51. Acute Seizures
• Acute seizures occur in about 50% of children.
• Phenytoin is the most frequently used antiepileptic drug (AED) for acute
management of seizures.
• Many AEDs interact with antitubercular drugs and may affect metabolism of each
other.
• Some AEDs are hepatotoxic (sodium valproate) as are antitubercular drugs.

52. Raised Intracranial Pressure
• Multiple factors are responsible for increased ICP and include cerebral edema due
to encephalitic process, infarcts with edema, hydrocephalus, tuberculomas, and
electrolyte disturbances.
• Osmotic agents such as hypertonic saline and mannitol are used to lower the ICP
particularly in those patients who do not require surgery.

53. Vasculitis
• Corticosteroids may be beneficial because of their anti-inflammatory effect.
• Dexamethasone (0.08 – 0.3mg/kg/day)

54. Hydrocephalus
• Hydrocephalus is found in >80% of children with TBM at presentation.
• About 80% of children with communicating hydrocephalus can be managed by
the medical treatment (acetazolamide and furosemide)
• Only failed medical treatment and noncommunicating hydrocephalus are the
indications for the ventriculoperitoneal shunting.
• Endoscopic third ventriculostomy has become an alternative surgical option to
divert CSF flow without complications of shunt.

55. OUTCOME AND PROGNOSIS
• Clinical stage of TBM at which treatment has been started is the single most
important determinant of the outcome for survival and sequelae.
• Young age, malnutrition, hydrocephalus, focal neurological deficit, miliary
disease and HIV infection are associated with bad prognosis.
• Mortality and morbidity is very low if treated in stage I.
• In stage III almost 50% of patients die, and survivors have some form of
neurological deficit.

56. • Various sequelae occur in 10-85% of cases of TBM, they are intellectual
disability, epilepsy, neurological deficits, cranial nerve palsy (commonly 7th, 3rd,
and 6th cranial nerves), blindness, deafness, behavior problems, and
hydrocephalus.
• Intracranial calcifications, which are detectable after 2-3 years, are found in 20-
48% of patients with TBM.

57. Fungal Meningitis

58. Introduction
• Fungal meningitis in pediatric patients is a rare but serious.
• It usually occurs in immunocompromised individuals, although healthy children
can also be affected.
• Invasive fungal infections have a very high mortality rate (90%) as compared to
bacterial, viral or parasitic.
• The most common causative organisms are Cryptococcus neoformans, Candida
species, Histoplasma capsulatum, Coccidioides immitis, Aspergillus species.

59. Cryptococcus neoformans Candida Histoplasma capsulatum
Coccidioides immitis Aspergillus

60. Fungi infecting the CNS
Pathogenic fungi Opportunistic fungi
Cryptococcus neoformans Candida species (candida albicans, C. tropicalis, C.
lusitaniae)
Histoplasma capsulatum Aspergillus species
Blastomyces dermatitidis Zygomycetes (mucormycosis)
Coccidioides immitis Trichosporon
Paracoccidioides brasiliensis
Sporothrix species

61. Risk Factors
• Immunocompromised children and Organ transplantation.
• HIV/AIDS: risk for cryptococcal meningitis.
• Chemotherapy: patients undergoing chemotherapy or stem cell transplants.
• Neonates: Especially premature infants and ELBW.
• Environmental exposure: In regions endemic to fungi like Coccidioides or
Histoplasma, children might be at risk through soil or animal droppings.

62. Pathogenesis
The pathophysiology of fungal meningitis in children involves several stages, which are
influenced by the type of fungus involved and the immune status of the child.
1. Fungal Invasion and Entry into the CNS
• Hematogenous Spread: Fungal organisms typically enter the CNS through the
bloodstream, particularly in immunocompromised patients.
For example, Cryptococcus, Candida, Aspergillus, and Histoplasma are common
fungal pathogens that can invade the brain and meninges.

63. • Direct Invasion: Fungi may also reach the CNS through direct extension from
adjacent structures, such as the sinuses, ears, or after trauma or neurosurgical
procedures.
• Inhalation: Certain fungi like Histoplasma or Coccidioides can be inhaled,
causing respiratory infections that may later spread to the CNS in
immunocompromised children.

64. 2. Immune Response and Host Factors
• In children with immunodeficiency fungal organisms can proliferate unchecked in
the CNS, leading to severe infection.
• Granulomatous Inflammation: Certain fungal infections, such as Cryptococcus,
provoke a granulomatous inflammatory response, characterized by the formation
of clusters of macrophages and other immune cells around the infection site.
This can lead to tissue damage and the formation of abscesses or cysts in the brain
and meninges.

65. • Cerebral Vasculitis:
Some fungi (e.g., Aspergillus) can cause vasculitis (inflammation of blood
vessels), leading to impaired blood flow, ischemia, and potentially, infarcts.

66. 3. Blood-Brain Barrier (BBB) Disruption
• Fungal pathogens have the ability to cross the blood-brain barrier.
• The fungi can produce various enzymes and molecules that break down the BBB,
allowing the infection to spread to the brain and meninges.
• In particular, Cryptococcus can pass through the BBB more easily due to its
ability to form a thick polysaccharide capsule, which helps it evade host immune
responses.

67. 4. Inflammatory Response and Tissue Damage
• Once the fungi enter the CNS, they trigger an inflammatory response.
• The immune system reacts by releasing pro-inflammatory cytokines (such as TNF-α,
IL-1, and IL-6), causing inflammation in the meninges and surrounding brain tissue.
• This cause changes in cerebrospinal fluid (CSF), including elevated white blood cells
(pleocytosis), increased protein levels, and decreased glucose levels and
hydrocephalus.

68. Clinical Features
• Fungal meningitis in children often has an insidious onset.
• Persistent fever, Vomiting, Neck stiffness, Photophobia (in older children)
• Headache (in older children, this can be reported, but in infants, signs like
irritability and poor feeding may be seen)
• Altered mental status: Lethargy, irritability, or in severe cases, seizures.

69. • Neurological findings: Cranial nerve palsies or signs of increased intracranial
pressure (ICP) such as papilledema.
• Severe cases, fungal infections can lead to abscesses, necrosis,
• Developmental delays and hydrocephalus.

70. Diagnosis
Cerebrospinal fluid (CSF) analysis:
• Elevated white blood cells [5-500] (pleocytosis, usually lymphocytic in fungal
infections)
• Elevated protein levels, (25 - 500)
• Low glucose levels (< 50; though glucose can be normal in some fungal infections
like Cryptococcus)

71. • India Ink preparation: This is used to identify Cryptococcus neoformans in CSF,
though it has lower sensitivity.
• Fungal cultures (Sabouraud’s agar): Culture from CSF, blood, or other body fluids
can help confirm the diagnosis.

72. Computed tomography (CT) and magnetic resonance imaging (MRI)
• Cryptococcus meningitis:- MRI better than CT identifies cryptococcal leasions,
Cryptococcomas, pseudocysts, meningeal enhancement, intracerebral nodules.
• Candida:- MRI or CT scan shows punctate nodules, microabscesses, vasculitis and
infarcts.
• Coccidioides:- widespread basal cisterns, hydrocephalus and cervical
subarachnoid meningeal involvement.

73. • Aspergillus:- MRI scan can be useful to characterize paranasal sinus and CNS
leasions.

74. • Zygomycetes:- MRI or CT demonstrate mucosal thickening and opacification of
paranasal sinuses, bony erosion with intravascular thrombosis, infarcts, emboli,
abscesses in frontal or temporal lobe and cavernous sinus thrombosis.
• Reverse halo (opacity surrounded by ring of consolidation) is seen in case of
mucormycosis.

75. • PCR: Polymerase chain reaction (PCR) assays can identify specific fungal
pathogens.
• Fungal antigen testing: For certain fungi like Cryptococcus, serum and CSF
antigen tests (e.g., cryptococcal antigen)
• Urine examination for fungal hyphae and cultures.

76. Antifungal drugs
1. Amphotericin B:-
• It remains the most used and successful drug for fungal infections of CNS,
although concentrations of the drug in the CSF is generally low or even
immeasurable.
• Lipid formulation of amphotericin B, such as liposomal amphotericin B may be a
better alternative to conventional amphotericin B,
• It is used to treat infections caused by Candida, Blastomyces, Coccidioidies,
Cryptococcus, and Histoplasma.

77. 2. Flucytosine:-
• It penetrates well into CSF, has long half life and achieves 75% of simultaneous
serum concentrations.
• Administering flucytosine alone is associated with treatment failure due to
development of resistance.
• It has a synergistic action with amphotericin B or fluconazole in the treatment of
meningitis.
• Flucytosine is effective against Cryptococcus and Candida.

78. 3. Itraconazole:-
• Itraconazole has potent antifungal activity against a broad-spectrum of fungi
including Aspergillus.
• It has very limited penetration into the CSF.
• Used in treatment of cryptococcal meningitis in patients with AIDS.

79. 4. Fluconazole:-
• It is effective against Cryptococcus and Candida.
• It crosses blood brain barrier and has long half life.
• CSF sterilization is slower as compared to an amphotericin – B.

80. 5. Voriconazole:-
• Voriconazole is a broad-spectrum triazole which has a remarkable activity against
aspergillus, Fusarium fungi.
• Penetration into the CSF and early favorable clinical improvement.
• Voriconazole the drug of choice in CNS Aspergillosis.

81. 6. Caspofungin:-
• Caspofungin, an echinocandin is effective against Candida spp. and active against
Aspergillus.
• Activity against Fusarium, Rhizopus, and Trichosporon is limited.
• The utility of the echinocandins in CNS infections is not clear given due to poor
CSF penetration.

82. Treatment
• Supportive care:-
Children may require intensive care for managing raised intracranial pressure,
seizures, and other neurological complications.
• The choice of antifungal agent depends on the organism identified.
• Treatment duration depends on pathogen and clinical response.

83. SPECIFIC TREATMENT

84.  Cryptococcosis
• The most commonly used regimen is intravenous amphotericin B deoxycholate (1
mg/kg/day) and flucytosine (100 mg/kg/day QID) for 2 weeks.
• Followed by oral fluconazole 10–12 mg/kg/day × 8 weeks in both HIV and non-
HIV patients.
• Liposomal amphotericin B and flucytosine combination can also be used as an
alternative.
• In HIV patients secondary prophylaxis of fluconazole (6 mg/kg/day) is given till
antiretroviral therapy is started.

85.  Aspergillosis
• Voriconazole is the primary recommendation for CNS Aspergillosis.
• Dose 8 mg/kg/day 12 hourly for children 2–12 years of age.
• 4 mg/kg/day 12 hourly for children 12 years or older.
• Duration of treatment is 6–12 weeks depending upon the degree of
immunosuppression, site involved and clinical improvement.
• Maintenance therapy or secondary prophylaxis may be required in patients with
immunosuppression.

86. • Alternatively, liposomal amphotericin-B (dose 3–5 mg/kg/day) can also be used as
primary or salvage therapy in patients where Voriconazole cannot be given.
• Echinocandins can be used as salvage therapy and in combination and not in
isolation. Intravenous Caspofungin (70 mg on day 1, followed by 50 mg per day).
• Intravenous micafungin and oral posaconazole can also be used.
• Surgical excision should be done in cases of space occupying lesions not
responding to antifungal therapy or in case of infected paranasal sinuses.

87.  Candidasis
• Amphotericin B deoxycholate (1.0 mg/kg/day IV) along with flucytosine 100
mg/kg/day 6 hourly is the treatment of choice for systemic candida infections.
• Fluconazole is used as an alternative in patients who have not used fluconazole
prophylaxis.
• Liposomal amphotericin B (5 mg/kg/day) are recommended for children with
compromised renal function.
• Therapy should be continued for 2–4 weeks or longer until symptomatic improvement
or clearance of CSF and radiological abnormalities.

88.  Coccidioidomycosis
• Fluconazole (6 - 12mg/kg/day) and Itraconazole (5 -10 mg/kg/day) are effective in
cococcidioidal meningitis.
• Fluconazole is the primary therapy and intravenous or intrathecal amphotericin B
(3 - 5 mg/kg/day) can be given in severe disseminated cases till clinical
improvement.
• This can be followed by maintenance therapy till 1 year.

89.  Histoplasmosis
• liposomal amphotericin B (5 mg/kg/day for 4–6 weeks) followed by Itraconazole
for 1 year or until resolution of clinical symptoms and antigen tests.
• Both conventional and liposomal derivative of amphotericin B can be used.
• Monitoring of Itraconazole levels along with renal and liver functions.
• Posaconazole and Voriconazole have also been used but are not routinely
recommended.

90.  Blastomycosis
• Amphotericin B deoxycholate and liposomal amphotericin B for 4–6 weeks.
• Followed by oral Itraconazole for at least 12 months until resolution of symptoms
or CSF.
• Fluconazole (800 mg per day) or Voriconazole (200–400 mg twice per day) can
also be used.

91.  Rhinocerebral disease caused by zygomyces
• Liposomal amphotericin B (5 mg/kg/day) is the drug of choice for CNS
mucormycosis in children.
• Posaconazole can be used as a salvage therapy.
• Surgical debridement of the devitalized tissue along with intravenous
amphotericin B is necessary.

92. Neurosurgical intervention
It must be considered in following cases:-
• Space occupying lesions of the brain - large abscesses or granuloma with mass
effect or not responding to antifungal therapy.
• Insertion of lumbar drains or shunts in case of cryptococcal and
Coccidioidomycosis to relieve raised ICP or hydrocephalus.
• Aneurysms with subarachnoid hemorrhage.

93. Prognosis
The prognosis of fungal meningitis in children largely depends on:
Early identification and initiation of appropriate antifungal therapy are critical to
improving outcomes.
The extent of CNS involvement and the child’s overall immune status influence the
prognosis.
Children with significant immunocompromised (e.g., from HIV, cancer treatment,
or organ transplantation) are at greater risk for poor outcomes.

94. THANK YOU