seminar Meningitis

seminar Meningitis

1. 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.

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

3. 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 . 1/27/2016 3

4. Meninges The meninges is the system of membranes which envelops the central nervous system. It has 3 layers: Dura mater Arachnoid mater Pia mater Subarachnoid space - is the space which exists between the arachnoid and the pia mater, which is filled with cerebrospinal fluid. 1/27/2016 4

5. 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.

6. 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

7. 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.

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

9. The incubation period ranges between 2 -10 days .

10. Subarachnoid space BACTERIAL LYSIS by a hematogenous route reach the meninges an intense host inflammatory response triggered PATHOPHYSIOLOGY

11. Subarachnoid space BACTERIAL LYSIS by a hematogenous route reach the meninges Bacterial cell wall component release Endothelial cells CNS macrophage cells PATHOPHYSIOLOGY

12. Subarachnoid space BACTERIAL LYSIS by a hematogenous route reach 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

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

14. Inflammatory response 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 further retention of free water

15. Inflammatory response Cont’d… Coagulation cascade Thrombosis Vasogenic edema Increased ICP Decreased CBF Affecting cortical vessels Cytotoxic and interstitial edema oxygen depletion Increased CSF protein Decreased CSF glucose Increased CSF lactate (SIADH) with meningitis causes further retention of free water

16. Neurologic damage Affecting cortical vessels (SIADH) with meningitis causes further retention of free water

17. 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 further retention of free water

18. Neurologic damage swelling and proliferation of the endothelial cells of arterioles veins, causing mural thrombi and obstruction of flow an increase in intracellular sodium and intracellular water Affecting cortical vessels (SIADH) with meningitis causes further retention of free water

19. Neurologic damage swelling and proliferation of the endothelial cells of arterioles veins, causing mural thrombi and obstruction of flow an increase in intracellular sodium and intracellular water Affecting cortical vessels development of brain edema further compromises cerebral circulation (SIADH) with meningitis causes further retention of free water

20. Neurologic damage swelling and proliferation of the endothelial cells of arterioles veins, causing mural thrombi and obstruction of flow an increase in intracellular sodium and intracellular water Affecting cortical vessels development of brain edema further compromises cerebral circulation ICP secretion of ADH (SIADH) with meningitis causes further retention of free water

21. Neurologic damage swelling and proliferation of the endothelial cells of arterioles veins, causing mural thrombi and obstruction of flow an increase in intracellular sodium and intracellular water Affecting cortical vessels development of brain edema further compromises cerebral circulation ICP secretion of ADH These factors contribute to the development of focal or generalized seizures (SIADH) with meningitis causes further retention of free water

22. Inflammatory response Neurologic damage Cont’d… Coagulation cascade Thrombosis Vasogenic edema Increased ICP Decreased CBF swelling and proliferation of the endothelial cells of arterioles veins, causing mural thrombi and obstruction of flow an increase in intracellular sodium and intracellular water Affecting cortical vessels Cytotoxic and interstitial edema oxygen depletion Increased CSF protein Decreased CSF glucose Increased CSF lactate development of brain edema further compromises cerebral circulation ICP secretion of ADH These factors contribute to the development of focal or generalized seizures (SIADH) with meningitis causes further retention of free water

23. Symptoms can be the same for Viral and Bacterial 1/27/2016 25

24. 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

25. Meningococcemia - Petechiae

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

27. 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. 1/27/2016 29

28. What are the investigations requied for this infant Lumber puncture :

29. Condition Appearance WBC/mm 3 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

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

31. 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

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

33. 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

34. 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.

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

36. Chronic complications Deafness Seizure disorders Motor deficits Language deficits Behavior disorders Mental retardation

37. 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

38. NEXT PRESENTER DR.MAHBOBA AKHTER

39. ACUTE MENINGITIS BACTERIAL MENINGITIS VIRAL MENINGITIS

40. 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 .

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

42. Gram positive containing polysaccharide capsule prevents the bacteria from undergoing phagocytosis

43. Listeria monocytogenes Normally causes Listeriosis

44. Neisseria meningitidis

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

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

47. The bacteria grows inside the Subarachnoid space in cerebral spinal fluid

48. 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.

49. PATHOGENESIS:

50. PATHOGENESIS AND PATHOLOGY:

51. CONT….

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

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

54. Kernig’s Sign

55. Brudzinski’s Neck Sign

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

57. 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

58. Papilledema

59. Extra CNS manifestation: Rashes, petechiae , arthralgias , DIC, shock, pneumonia

60. Rash of Meningococcal Meningitis

61. 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.

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

63. 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.

64. PATHOGENESIS AND PATHOLOGY:

65. 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 .

66. 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.

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

68. CSF STUDY: PRESSURE(mmH20)50-80 LEUKOCYTES(mm3)<5,≥75%LYMPHOCYTES 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

69. 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

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

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

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

73. 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 .

74. 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.

75. 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.

76. 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

77. 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

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

79. 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. 1/27/2016 81

80. 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

81. NEXT PRESENTER DR.SHAZIA AFREEN

82. 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

83. 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 agen ts Viral Malignancies CMV, HIV Leukaemia,Lymphoma parasite

84. TUBERCULAR MENINGITIS

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

86. 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

87. M. TUBERCULOSIS Straight or slightly curved rods A rranged either singly or in small groups. Non-spore forming, N on capsulated Non flagellated N on-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.

88. 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

89. 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

90. 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 , 6 th and 7 th cranial nerves. Basal cisterns are obstructed causing communicating hydrocephalus . Accompanying inflammation may cause cerebral edema . Cont…..

91. Clinical progression : 2 types Rapid Gradual

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

93. Classical Present as sub acute or chronic meningitis Over several weeks

94. 1 st Stage : P rodromal stage L asts 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

95. 2 nd 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.

96. 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%)

97. 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

98. 3 rd 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,20 th edition.

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

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

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

102. 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.

103. 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 : 20 th Ed,

104. 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 2 mg/dl Nelson textbook of Paediatrics : 20 th Ed,

105. 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 Nelson textbook of Paediatrics : 20 th Ed ,

106. 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 Nelson textbook of Paediatrics : 20 th Ed,

107. How to increase M ycobacterial 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 : 20th h Ed, Cherian A, Thomas SV, Kennedy DH, Fallon RJ. Central nervous system tuberculosis .African Health Sciences 2011; 11(1):264–8.

108. 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.

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

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

111. 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.

112. 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. Nelson textbook of Paediatrics : 19 th Ed,

113. 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

114. 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.

115. 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.

116. 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.

117. 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.

118. 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. Tuberculousmeningitis : a uniform case definition for use inclinical research. Lancet Infect Dis 2010; 10:803–12.

119. 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). Tuberculousmeningitis : a uniform case definition for use inclinical research. Lancet Infect Dis 2010; 10:803–12.

120. 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. Tuberculousmeningitis : a uniform case definition for use inclinical research. Lancet Infect Dis 2010; 10:803–12.

121. 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. Consensus tuberculous meningitis diagnosis Tuberculousmeningitis : a uniform case definition for use inclinical research. Lancet Infect Dis 2010; 10:803–12.

122. 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 .

123. 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(1 st 2months): INH, RIF , PZA , EMB followed by Continuation phase(next 10 months): INH, RIF

124. Treatment cont.. Centre for Disease Control(CDC) America recommended Initial phase (1 st 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

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

126. 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

127. Anti TB therapy : 1 st 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

128. Multiple drug resistant TBM Resistance to both INH and RIF (2 nd 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 / kanamycin 15-30 1 gm 6 Oto and nephrotoxicity

129. Multiple drug resistant TBM contd. Drug Dose mg/kg max Duration(month) Main toxicity Capreomycin 15-30 1gm 6 Oto and nephrotixicity Paraaminosalicylic 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

130. Reduce mortality Improvement in neurological secquelae Better intellectual outcome Enhance resolution of Basal exudates Intracranial oedema and tuberculoma

131. 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- 3 rd wk 0.1 mg/kg/day- 4 th 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

132. Treatment of Complications Hydrocephalus Seizure Ataxia Hemiparesis Cerebral palsy E ndocrinopathies MR Psychiatric disorder

133. PROGNOSIS Stage I good Stage II 5 0%-78% recovery Stage III 2 % recovery

134. BCG vaccination Prevents CNS TB Efficacy 75-85%

135. NEXT PRESENTER DR.MD. MYDUL ISLAM KHAN

136. 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.

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

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

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

140. 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

141. 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

142. 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.

143. C. n eoformans in India ink preparation : (source: Lange Microbiology)

144. 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.

145. 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

146. 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.

147. 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).

148. 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.

149. Acanthamoeba

150. Balamuthia

151. 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.

152. 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)

153. Hemorrhage in the frontal cortex due to Primary Amebic Meningoencephalitis .

154. multiple variable-sized haemorrhagic and necrotic lesions in GAE Case report:Emergence of balamuthia mandrillaris meningoencephalitis in India S Khurana , V Hallur 1 , MK Goyal 2 , R Sehgal , BD Radotra 3 (Indian journal of Medical microbiology)

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

156. 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 .

157. 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.

158. 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.

159. 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 )

160. 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)

161. 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 )

162. 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 .

163. 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 .

164. 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

165. 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.

166. 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

167. 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)

168. 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.

169. 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.

170. 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.

171. 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

172. 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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