Tubercular Meningitis in pediatrics.pptx

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.

10. 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.

11. 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.

12. 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.

13. 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.

14. Uncommon forms of TBM Serous Tuberculous Meningitis. Tuberculous Encephalopathy.

15. 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.

16. 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.

17. Laboratory Diagnosis Cerebrospinal Fluid analysis. Neuroimaging. Tests to detect evidence of TB elsewhere in the body.

18. Cerebrospinal Fluid analysis 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.

19. 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%)

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

21. 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.

22. 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 %).

23. 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.

24. 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 .

25. In patients with TBM, ADA values from 1 to 4 U/L (sensitivity > 93% and specificity < 80 %) can help to exclude TBM. V alues >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.

26. 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. 

27. 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.

28. 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 .

29. 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.

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

31. Treatment Supportive treatment . Specific treatment. Surgical treatment.

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

33. 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.

34. 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.

35. 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

36. 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 .

37. 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.

38. 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

39. 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.

40. 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

41. 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.

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

43. Treatment of Complications Hyponatremia. Acute seizures . Raised ICP . Vasculitis . Hydrocephalus.

44. 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. I n case hyponatremia is severe, 3% normal saline along with furosemide is added.

45. Acute Seizures Acute seizures occur in about 50% of children. P henytoin 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. S ome AEDs are hepatotoxic (sodium valproate) as are antitubercular drugs.

46. 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.

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

48. 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) O nly f ailed 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.

49. 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.

50. 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.

51. Fungal Meningitis

52. 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.

53. Cryptococcus neoformans Candida Histoplasma capsulatum Coccidioides immitis Aspergillus

54. 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

55. 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.

56. 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.

57. 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.

58. 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.

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

60. 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.

61. 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 .

62. 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 .

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

64. 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)

65. 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.

66. 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.

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

68. 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.

69. 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.

70. Antifungal drugs 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.

71. Flucytosine:- It penetrates well into CSF, has long half life and achieves 75 % of simultaneous serum concentrations. A dministering 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.

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

73. 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.

74. 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.

75. 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.

76. 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.

77. SPECIFIC TREATMENT

78. Cryptococcosis T he most commonly used regimen is intravenous amphotericin B deoxycholate (1 mg/kg/day) and flucytosine (100 mg/kg/day QID) for 2 weeks. F ollowed 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.

79. 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.

80. 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.

81. 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.

82. 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.

83. 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.

84. Blastomycosis A mphotericin 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.

85. 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.

86. 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.

87. 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.

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