Bacterial Infections Of The Nervous System PDF

รายวิชา 3000384 Clinical Neuroscience Bacterial infections of the nervous system อ.พญ.พิ ณ ทิ พ ย์ สุ ช าติ ลิ ขิ ต วงศ์ (Pediatric Infectious Diseases Specialist) Department of Microbiology, MDCU Central nervous system infections • Infections damage the nervous system :1. Directly through injury...

รายวิชา 3000384 Clinical Neuroscience Bacterial infections of the nervous system อ.พญ.พิ ณ ทิ พ ย์ สุ ช าติ ลิ ขิ ต วงศ์ (Pediatric Infectious Diseases Specialist) Department of Microbiology, MDCU Central nervous system infections • Infections damage the nervous system :1. Directly through injury of neurons or glia by the infectious agent 2. Indirectly through • Microbial toxins • Destructive effects of inflammatory responses • Immune mediated mechanisms • Principal routes by which microbes enter the nervous system :1. Hematogenous spread (the most common) 2. Direct implantation ? 3. Local extension ? 4. Transport along the peripheral nervous system (rabies, zoster virus) - Retrogade nerve Robbins & Cotran Pathologic Basis of Disease. 10th edition. 2021 Central nervous system infections • Clinical onset :• Acute : <5 days - fast come • Subacute : 5 days to <4 weeks • Chronic : >4 weeks • Sites of infection :• • • • Meningitis Encephalitis Meningoencephalitis Focal CNS syndromes (brain abscess, etc.) Central nervous system infections Type of infection Clinical syndrome Common causative agents Acute pyogenic meningitis E. coli, group B Streptococcus, N. meningitidis, S. pneumoniae, L. monocytogenes Chronic meningitis Mycobacterium tuberculosis Brain abscess Polymicrobial including streptococci, staphylococci, Gram-negative bacteria, anaerobes Meningitis Acute aseptic meningitis Enteroviruses, Influenza Encephalitis Encephalitic syndrome HSV, Enterovirus71, JE, JC, Dengue Spinal cord syndrome Acute flaccid myelitis Poliovirus Chronic meningitis Cryptococcus neoformans, Candida albicans Encephalitis Amebic encephalitis Balamuthia, Acanthamoeba, Naegleria Focal CNS Brain abscess Cysticercosis Toxoplasma gondii Taenia solium Bacterial infection Meningitis Focal CNS Viral infection Fungal infection Meningitis Parasitic infection Robbins & Cotran Pathologic Basis of Disease. 10th edition. 2021 Outline • Pathogens 1. Acute bacterial meningitis • Predisposing factors 2. Tuberculous meningitis • Pathogenesis / Pathophysiology 3. Brain abscess • Investigations • Clinical presentations • Specific treatment Meningitis • Inflammation of the meninges and subarachnoid space • Typically identified by CSF pleocytosis (WBC >5 cell/mm3) Acute bacterial (pyogenic) meningitis seen at autopsy Pus exudate covers the brain surface and thickens the leptomeninges An 8-month-old male infant and pneumonia Case: An 8-month-old infant withwith feverfever and pneumonia • Underlying condition: congenital cyanotic heart disease, taken care by a foster home • History: Low grade of fever and cough for 2 days. Developed dyspnea 2 hours ago. • PE: BT 39 ̊C, RR 60/min, SpO2 78% (baseline 88-92%), PR 140/min, BP 98/40 mmHg Lungs - subcostal retraction, no adventitious sound Heart - pansystolic murmur at LPSB Neuro - alert, no deficits - Likely Pneumonia • Immunization: missed DTwP-Hib-HBV and polio vaccine for age 6 month, never received influenza vaccine, pneumococcal conjugate vaccine • Lab: CBC - WBC 17,230 /μL (N65%, L27%), Hb 14 g/dL, Hct 44%, Platelet 186,000/μL Rapid test for influenza & RSV: negative • Diagnosis: viral pneumonia • Treatment: oxygen therapy, IV fluid, no antibiotic given - Real Case An 8-month-old maleinfant infant fever and pneumonia Case: An 8-month-old withwith fever and pneumonia • Progress note: Admission day 2, fever persists, drowsiness and positive Brudzinski’s sign • Lab: Hemoculture flagged growth of the same organism in CSF at 9 hours Lumbar puncture - Bacteria Ontop CSF WBC 30/μL (PMN 96%), Protein 157 mg/dL, Glucose 23 mg/dL CSF Gram stain CSF culture Latex agglutination: negative for 5 bacterial antigens - S.pnuemo - Negative diplo cocci "Lancet" shape pneumoniae meningitis Case: AnStreptococcus 8-month-old infant with fever and pneumonia - Before given Abx - Pennicillin X A 14-year-old boy with fever and altered mental status - Spectrum of hyper-Ig E - Monocyte dominant Pathogen? - Possible - Help Dx - High effect drugh Enough antimicrobial coverage? - No improvement Complication? A 14-year-old boy with fever and altered mental status - Refer Listeria monocytogenes • Gram-positive bacilli & culturable on routine standard media • No growth in this case may be due to - MN -> PMN • Improper CSF or blood collection or transport • Meropenem activity - Bacterial Profile Rational tests? Quickest result? - Management Questions - Yes - Yes Unaffected by antimicrobial therapy? Cost effectiveness? - No - Dx Pathogen Antibiotic susceptibility testing? - Merepenem -> Culture isn't founded Acute bacterial meningitis Prognosis • Mortality rate is high (up to 20%) especially in patients with delay in diagnosis & treatment • Severe sequelae occur in ~25% of survivors, varying with the infecting organism Pathogens and susceptible age Patient age - GBS - In mother REPRO GI Under 1 month • Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes 1 – 23 months • S. agalactiae, E. coli, Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis Non-typhoidal Salmonella - Community-Acquired 2 – 50 years Over 60 years • S. pneumoniae, N. meningitidis - Maternal X • S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli - Recurrent infant disease : lower immune Handbook of Clinical Neurology, Vol. 121 (3rd series).2014 D van de Beek, et al. Lancet. 2021;S0140-6736(21)00883-7 Pathogens and predisposing factors Predisposing factors Asplenia - Have capsule - Splenectomy • S. pneumoniae, H. influenzae, N. meningitidis Complement deficiency (terminal; MAC) • N. meningitidis Cell-mediated immunity defect, HIV, Steroid use • L. monocytogenes, Non-typhoidal Salmonella - like to be in cell Mother-to-child in utero or at birth • S. agalactiae, L. monocytogenes Base of skull fracture, CSF leak • S. pneumoniae Head trauma, after neurosurgery - Skin • acquired S. aureus, coagulase-negative staphylococci, aerobic gram-negative including Pseudomonas aeruginosa - Hospital acquired CSF indwelling shunt • Coagulase-negative staphylococci, S. aureus, aerobic gram-negative including P. aeruginosa, Cutibacterium acnes Undercooked pig, pig farming, pork butchery • Streptococcus suis Contaminated food (cold meat, vegetables/fruits, • L. monocytogenes unpasteurized milk & cheese) Handbook of Clinical Neurology, Vol. 121 (3rd series).2014 D van de Beek, et al. Lancet. 2021;S0140-6736(21)00883-7 Pathogens and protective effect from vaccine Bacterial meningitis infections USA in 1971-2007 D van de Beek, et al. Nat Rev Dis Primers. 2016;2:16074 Pathogenesis of acute bacterial meningitis - local extension -> meningitis - Protein leakage - Flow lower -> Ischemia MMP; matrix metalloproteinases NO; nitric oxide http://www.pathophys.org/meningitis Ther Adv Neurol Disord. 2009; 2(6):401-12 Step I: Mucosal colonization Involves combination of bacteria adhering to host cell surfaces and avoidance of defense mechanisms • Respiratory tract : S. pneumoniae, H. influenzae, N. meningitidis • Gastrointestinal or genital tracts : S. agalactiae, L. monocytogenes - Capsule Upper respiratory tract epithelium Bacterial factors: IgA protease, Polysaccharide capsule, Pneumolysin, Fimbriae or pilli e.g. type IV pili (tfp), Endotoxin (lipopolysaccharide) Host factors: Ciliary activity, Anticapsular antibodies, Secretory IgA McGill F, et al. Lancet.2016;388:3036-47 Step II: Intravascular survival To evade opsonophagocytosis and/or the complement system Bacterial factors • • • Polysaccharide capsule Pneumococcal surface proteins (PspA, PspC) Pneumolysis (Ply) • • • • • Polysaccharide capsule Outer membrane proteins factor H-binding protein (fHbp) Neisseria surface protein A (NspA) Porin B Autotransporter Na1P D van de Beek, et al. Nat Rev Dis Primers. 2016;2:16074 Step II: Intracellular survival Immunoglobulins and complement are relatively unimportant for protecting the host against L. monocytogenes. Instead, cell-mediated immunity serves as the host’s primary defense. Adhere by internalins (bacterial surface proteins) mediated by listeriolysin O exotoxin Actin-based locomotion Filopods formation • Entry into macrophages after passage through GI lining carries the bacteria to liver and spleen, leading to disseminated disease. • Genes responsible for membrane lysis, intracellular replication, and directional movement are clustered, and regulated by, a single gene, prfA, or positive regulatory factor - Psuedolegf Southwick FS, Purich DL. NEJM. 1996;334(12):770-6 Murray PR, et al. Medical Microbiology. 9th Edition. 2021 Step III : Meningeal invasion (1) • Blood-Brain or Blood-CSF Barrier is formed by microvascular endothelial cells that are fused together by tight junctions to restrict paracellular invasion by bloodborne pathogens. Blood-CSF barrier Neurovascular unit Barichello T. Blood-Brain Barrier. 2019 D van de Beek, et al. Nat Rev Dis Primers. 2016;2:16074 Step III : Meningeal invasion (2) - TB Listeria Ecoli Burkellei Routes of CNS access: via transcellular, leukocyte-facilitated (Trojan-horse), paracellular, contiguously spread from surrounding tissue or via nerve endings - Macrophage - BBB Forrester JV, et al. Nat Rev Neurosci. 2018;19:655-71 Step IV: Host immune response in subarachnoid space Once pathogens enter SAS, host defense are inadequate to control the infection despite early influx of neutrophils • Low complement and immunoglobulins in CSF (blood-CSF IgG = 800:1) • Inefficient opsonophagocytosis and bactericidal activity - Orchesta meningitis TLR=Toll-like receptor; HMGB1 = high mobility group box 1 protein DAMP=damage-associated molecular pattern; PAMP=pathogen-associated molecular pattern D van de Beek, et al. Lancet. 2021;S0140-6736(21)00883-7. Clinical presentations (1) - Stiff neck - Found only 20-30% Classic triad : fever, nuchal rigidity, altered mental status (found only 2/3) - 1/4 -> Suspect Fever >80% Meningismus 5-75% - Stiff neck Altered mental status - Kernig >75% Headache >85% Vomiting 35% Seizures 30% Focal neurologic deficits 10-35% Papilledema <5% *Absence of this does not rule out diagnosis of bacterial meningitis - Brudzinski Although commonly tested on physical examinations, the sensitivity and specificity of Kernig’s and Brudzinski’s signs are uncertain. Both may be absent in very young or elderly patients, immunocompromised individuals, or patients with a severely depressed mental status. Cervical spine disease in older individuals may result in false-positive tests for nuchal rigidity. Netter’s Illustrated Human Pathology. updated edition. 2014 Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Edition 9. 2020 Clinical presentations (2) Vary based on age, underlying diseases, host response, pathogens and duration of illness In neonates, symptoms can be subtle and nonspecific and may not have signs of meningeal irritation - Extreme age(Immunocompromised) -> More subtle only 1/3, late Elderly are less likely to have headache, photophobia, nausea and meningeal signs, but more likely to present with fever, sepsis and late neurologic deficits such as hemiparesis, seizures, or coma https://doctorsaustralia.com.au/th/topic/general-report/meningitis Clinical presentations (3) Vary based on age, underlying diseases, host response, pathogens and duration of illness N. meningitidis •Person-to-person transmission occurs through droplets from the respiratory tract and requires close contact. •Household contacts of cases have 500-800 times the rate of disease. - Rapid progression • Usually, manifests as septicemia/meningococcemia (40% of cases), meningitis (50%), or both. In fulminant cases, purpura, limb ischemia, coagulopathy, pulmonary edema, shock, coma, and death can ensue within hours despite appropriate management. • Rash - commonly found - rapid evolution within hours (dermal seeding of organisms with endothelial damage) ‘Purpura fulminans’ ➢ ➢ ~ MP Rash Peripheral ischemia/ gangrene Diffuse MP exanthem Petechial/purpuric rash -> 1-2 hr -> Postexposure chemoprophylaxis - Red flags : Bad prognosis Laboratory-acquired infection (work in a biosafety cabinet) Red Book. Edition 32. 2021-2024. - Skin scraping Infections of the central nervous system (Scheld). Edition 4. 2014. Clinical presentations (3) Vary based on age, underlying diseases, host response, pathogens and duration of illness - Cold tolerance L. monocytogenes • - Teratogenic •Transmission : predominantly foodborne, mother-to-fetus (transplacental following maternal bacteremia, inhalation of infected amniotic fluid and infection ascending from vaginal colonization) Usually, manifests as invasive listeriosis • Amnionitis, abortion, preterm delivery, neonatal sepsis (early-onset: pneumonia, septicemia, granulomatosis infantisepticum; late-onset: meningitis) • Other population: bacteremia, meningitis+/- parenchymal brain involvement, rhombencephalitis, brain abscess, endocarditis - Enceph in romben - Granuloma Red Book. Edition 32. 2021-2024. Clinical microbiology reviews. 2001;14:584-640. Clinical presentations (4) Vary based on age, underlying diseases, host response, pathogens and duration of illness - Late Intracranial complications Increased ICP - Subdural effusion/empyema - Cortical thrombophlebitis - Ventriculitis - Venous thrombosis - Cerebral infarction - Reduced level of consciousness - Generalized seizures (early, easily controlled) - CN VI, III palsies - Papilledema - Decerebrate posturing - Cushing reflex (HR, BP, irregular RR) - very late - Cerebral herniation Extracranial complications Long term sequelae - Syndrome of inappropriate antidiuretic hormone secretion; SIADH (serum Na, euvolemia) due to non-osmotic stimuli e.g., ICP, IL-6, pain, hypoxia - Cerebral salt wasting (serum Na, hypovolemia) - Sensorineural hearing loss Weakness - S.suis Epilepsy Intellectual impairment Behavioral disorder Delayed development Hydrocephalus Investigations for acute meningitis - Steps by steps Hemoculture Don’t delay antibiotic - Invasive procedure • Always do first before initiating antibiotic • Use: finding pathogens (50-80% positive H/C) - If not -> Don't delay Abx • Most useful; should be done if no contraindications and before initiating antibiotic Lumbar puncture • Use: CSF analysis & finding pathogens Brain imaging Slide courtesy of Neurologist P, facebook • Diffuse meningeal enhancement but not diagnostic (disease with BBB permeability) • Use: search for alternative diagnosis & complications • CT brain prior to LP when suspicion for intracranial mass or brain edema → potential risk for brain herniation ❑ ❑ ❑ ❑ Suspected intracranial mass Focal neurologic deficits New-onset seizures Reduced mental status ❑ ❑ ❑ ❑ Immunocompromised state CNS disease such as stroke Papilledema Signs of brain herniation Photo courtesy of Mikael Haggstrom, Wikiversity Journal of Medicine.2014 Photo courtesy of Jonathan Trobe, MD University of Michigan Kellogg Eye Center Fundoscopic exam Collection tube number for tests on CSF specimens Landmark: L3-4 or L4-5 Clinical Microbiology Procedures Handbook, 5th Edition. ASM books. 2023. CSF findings in infectious meningitis - Ratio Types - RBC/500 = WBC (Criteria) Normal Viral Bacterial Tuberculous Cryptococcal Opening pressure (cmH2O) 6 – 20 Normal or slightly elevated Usually elevated Usually elevated Usually elevated WBC (cell/mm3) 0–5 10 – 1,000 <100 – >10,000 25 – >100 40 – 400 Cell predominate MN Protein (mg/dL) 20 – 45 Glucose (mg/dL) CSF: Blood ratio > 40 > 0.6 MN** PMN* MN** - Early : PMN - Except Listeria (MN->PMN) 50 – 200 100 – >500 100 – 3,000 Normal1 - Except HSV(Low) Low4 MN 20 – 500 Low Low - Glucose transporter inhibition Direct staining N/A Not done > 85% (Gram)2 < 30% (AFB) < 50% (India ink) Culture N/A Not done > 95%3 < 30% ~ 75% N/A PCR Latex, PCR PCR (highest yield) Crypto Ag (+ve 90%) - Slow Additional testing *Mononuclear cells predominate can be found in Listeria meningitis (30%) **Polymorphonuclear cells predominate can be found in early stages 1 Low glucose can occur in meningitis caused by HSV 2 Typical negative CSF gram stain in Listeria meningitis 3 Lower yield of culture when CSF is collected after antibiotic 4Hypoglycorrhachia could be from increased glucose catabolism by WBCs, organisms, or brain parenchyma, and inhibited glucose transporter-1 across inflamed meninges. CSF profile in acute bacterial meningitis - Abx -> Culture X • Antibiotic therapy initiated a few hours prior to LP will not significantly alter CSF WBC and glucose, nor prevent pathogen detection by Gram stain or PCR • Administration of IV glucose a few hours prior to LP is unlikely to alter CSF glucose Nucleic acid testing Update 3 Sep 2022 Detection by PCR or 16S rRNA gene sequencing • PCR is increasingly used for rapid, sensitive diagnosis of meningitis, especially when organisms are low numbers, difficult to grow, or when patients are partially treated with antimicrobial agents. • However, PCR should not replace culture and are best collaborated with diagnostic stewardship. Harrison’s Principles of Internal Medicine. Edition 21. 2022 Clinical Microbiology Procedures Handbook, 5th Edition. ASM books. 2023 Bacterial antigens detection by latex agglutination Principle: antibody-coated particle capable of binding to specific bacterial polysaccharide surface antigens, resulting in macroscopically visible agglutination - Use: rapid test in Gram stain–negative meningitis or previously treated patients Limitations: - detect only 5 bacteria; unable to differentiate between N. meningitidis B/E. coli - low sensitivity (0-25%) in culture-negative meningitis sensitivity up to 50-100% in gram stain- or culture-positive cases https://www.thermofisher.com/order/catalog/product/R30859602 Bailey & Scott’s Diagnostic Microbiology, 15th Edition. Elsevier [2021] Nucleic acid testing : multiplex PCR - Dx Case - Expensive Principle: Double PCR reaction (multiplex PCR followed by nested PCR) with DNA melting curve analysis Pooled sensitivity 90.2% (95%CI 86.2–93.1) Pooled specificity 97.7% (95%CI 94.6–99.0)* BioFire® FilmArray® Meningitis/Encephalitis (ME) Panel - Choose primers *Pediatr Emerg Care. 2020; 36(8): 397–401 Antibiotic therapy in bacterial meningitis - High dose , Parenteral -> BBB Considerations • • • • • • Begin antibiotic ASAP Antibiotic choice depending on possible causative pathogen, drug resistance, adequate CSF penetration High CNS dosage Parenteral administration Simplify or modify following the result of susceptibility testing Sufficient total duration based on pathogen-specific for uncomplicated meningitis - prevent relaspe Principles and Practice of Pediatric Infectious Diseases. Edition 5. 2018 แนวทางเวชปฏิบตั ขิ องโรคเยือ่ หุม้ สมองและเนื้อสมองอักเสบเฉียบพลัน สมาคมโรคติดเชือ้ ในเด็กแห่งประเทศไทย พ.ศ. 2557 Antibiotic therapy in bacterial meningitis • Empirical therapy - Age = Clue • Specific therapy - +GBS Harrison’s Principles of Internal Medicine. Edition 20. 2018 - Suppress inflammation Adjunctive steroid therapy Antibiotic Bacterial cell lysis in CSF Influx and stimulation of macrophages and microglia cells Inflammatory cytokines TNF-α, IL-1, IL-6 Dexamethasone • Pros meningeal inflammation, mortality,  sensorineural hearing loss in acute meningitis caused by S. pneumoniae in adults & H. influenzae type b in children - HiP • Cons meningeal inflammation → penetration of vancomycin into CSF - Prevent healing loss (from Orchesta) Impaired BBB CSF outflow obstruction Neuronal injury • Regimen 0.15 mg/kg/dose (max 10 mg) IV 20 min before or concurrent with the first dose of antibiotic every 6 h for 4 days Red Book. Edition 31. 2018 - 2021 Harrison’s Principles of Internal Medicine. Edition 20. 2018 Principles and Practice of Pediatric Infectious Diseases. Edition 5. 2018 Tuberculous meningitis - CSF Finding Pathogen - Studied Mycobacterium tuberculosis • • • • Mycobacterium tuberculosis complex (>9 species) Aerobic acid-fast bacilli (AFB) size 2-4 µm long, 0.2-5 µm wide Presence of medium-to-long chains of mycolic acid in cell wall Slow growth (generation time 15-20 hrs) Airborne transmission Closeness of contact Infectiousness of source Inhalation of droplet nuclei containing tubercle bacilli Pathogenesis - Studied - Break out • Blockage of basal subarachnoid cisterns by adhesion formation, obstructing CSF flow, leading to hydrocephalus and ICP. • Obliterative vasculitis of small arteries, leading to brain ischemia • Perineuritis, resulting in CN palsies • Direct parenchymal involvement - Quarantine Manyelo CM, et al. J Clin Microbiol. 2021;59(3):e01771-20. Epidemiology - Prevalence in 1 yrs infant radiopaedia.org • Incubation period : 2-6 months after initial infection • Develop in one of every 300 untreated patients • Most frequently in patients under 6 years of age • Accompanying miliary tuberculosis in ~50% of cases → - Hematogenous spreading Miliary TB : a form of lymphohematogenous spread of tubercles; usually arising from caseous focus (lymph node) into pulmonary veins. Within 3 weeks after the onset of symptoms, tubercles can be seen evenly distributed throughout both lung fields. Feigin & Cherry's textbook of pediatric infectious. 8th Edition. 2019. Timetable of tuberculosis Feigin & Cherry's textbook of pediatric infectious. 8th Edition. 2019. Clinical presentations - Hard to Dx (except late stage) ▪ Clinical course : subacute - chronic (5 – 30 days) ▪ Non-specific prodrome for weeks and gradually evolve to include more-recognizable symptoms and signs of meningitis e.g. fever, headache, vomiting and neck stiffness ▪ Advanced disease may present with more severe headache, prominent meningeal signs, altered mental status, stroke, hydrocephalus, and cranial nerve palsies CSF findings in infectious meningitis Types Normal Viral Bacterial Tuberculous Cryptococcal Opening pressure (cmH2O) 6 – 20 Normal or slightly elevated Usually elevated Usually elevated Usually elevated WBC (cell/mm3) 0–5 10 – 1,000 <100 – >10,000 25 – >100 40 – 400 Cell predominate MN MN** PMN* MN** MN Protein (mg/dL) 20 – 45 50 – 200 100 – >500 100 – 3,000 20 – 500 Glucose (mg/dL) CSF: Blood ratio > 40 > 0.6 Normal1 Low4 Low Low Direct staining N/A Not done > 85% (Gram)2 < 30% (AFB) < 50% (India ink) Culture N/A Not done > 95%3 < 30% ~ 75% Additional testing N/A PCR Latex, PCR PCR (highest yield) Crypto Ag (+ve 90%) *Mononuclear cells predominate can be found in Listeria meningitis (30%) **Polymorphonuclear cells predominate can be found in early stages 1 Low glucose can occur in meningitis caused by HSV 2 Typical negative CSF gram stain in Listeria meningitis 3 Lower yield of culture when CSF is collected after antibiotic 4Hypoglycorrhachia could be from increased glucose catabolism by WBCs, organisms, or brain parenchyma, and inhibited glucose transporter-1 across inflamed meninges. Brain imaging • CT brain with contrast 4 patterns - Specific 1. Basilar arachnoiditis 2. Tuberculoma - Enhance 3. Cerebral infarction 4. Hydrocephalus A. Pre-contrast basal hyper density and hydrocephalus B. Post-contrast CT scan showing basal meningeal enhancement Marais S., et al. Lancet Infect Dis 2010;10: 803–12 Diagnosis Symptoms & Signs Confirmed TB disease Radiology or Pathology - Significant contact > 8 hr / day or > 120 hr / mth History of TB exposure and/or Positive TST or IGRAs - Used to infected Microbiology (molecular or culture) Treatment in tuberculous meningitis • Standard therapy for susceptible TB: 2 IRZE / 10 IR • isoniazid (I), rifampicin (R), pyrazinamide (Z), ethambutol or ethionamide (E) • Adjunctive steroid: prednisolone 2-4 mg/kg/day for 4-6 weeks • symptoms of inflammation, brain edema, survival, paradoxical reaction • Management for ICP • Medication, repeat tapping, VP shunt Brain abscess Pathological process • Intact brain parenchyma is resistant to infection, thus preexisting focal areas of hypoxemia, ischemia, or necrosis in brain parenchymal tissue usually occur before established infection Necrotic center Day 1-3 Pus collection Marked edema Day 4-9 - Ring enhancment Ring-enhancing capsule on imaging study Day 10-13 Well-formed dense collagenous capsule; Surrounding edema regress but marked gliosis Day >14 - Founded Harrison’s Principles of Internal Medicine. Edition 20. 2018 Atlas of Infections in Neurosurgery and Spinal Surgery. 2017 Pathogenesis 3 main routes 1.Contiguous spread from parameningeal foci (~50%) e.g. middle ears, mastoids, sinuses, orbits, teeth 2.Hematogenous spread (~30%) from remote site e.g. lung, heart, abdomen, pelvic, skin and bone 3.Following neurosurgery or head trauma (~10%) • Cryptogenic : ~25% without apparent source • Rare complication of bacterial meningitis Brouwer MC, et al. NEJM.2014;371:447-56 Contiguous spread Otogenic brain abscess Temporal lobe Otitis media Cerebellum Mastoiditis Acute Severe Complications of Otitis Media in Children and Adults. 2016 Contiguous spread (Axial CT) A man with frontal brain abscess following untreated frontal and maxillary sinusitis Atlas of Infections in Neurosurgery and Spinal Surgery. 2017 Hematogenous spread Cyanotic congenital heart disease, producing right-to-left shunt (such as tetralogy of Fallot or transposition of great vessels) would allow bloodborne bacteria to bypass pulmonary capillary bed and reach brain directly - Common Focal areas of cerebral ischemia, thus providing a nidus for organisms that bypassed pulmonary circulation to form an abscess Hall A, et al. Int J Surg Case Rep. 2016;20:138-41 Hematogenous spread - Stroke territory • Predilection for territory of middle cerebral arteries and located at graywhite junction • Usually multiple and multi-loculated abcesses (Axial CT) Multiple brain abscesses on both sides in a patient with infective endocarditis Atlas of Infections in Neurosurgery and Spinal Surgery. 2017 Pathogens and host immunity Mostly mixed organisms - aerobic & anaerobic bacteria Immunocompetent Immunocompromised • Streptococcus spp. including anaerobic and viridans streptococci (40%) - Oral / IE • Nocardia spp. • Enterobacteriaceae* (20%) • Anaerobes** (30%) • Staphylococcus aureus (10%) *Proteus, E. coli, Klebsiella, Citrobacter koseri, Enterobacter, Serratia marcescens **Bacteroides, Fusobacterium, Prevotella, Clostridium, Actinomyces - Rare / Fungus-like • Toxoplasma gondii • Candida spp. • Cryptococcus neoformans • Aspergillus spp. Harrison’s Principles of Internal Medicine. Edition 20. 2018 Infections of the Central Nervous System. Edition 4. 2018 Linkage between pathogenesis and pathogens R. Sonneville, et al. Clin Microbiol Infect. 2017;23(9):614-620. Clinical presentations - Mass effect ≈ Tumor + fever • Classic triad : fever, headache (constant, dull-aching, progressive), focal neurologic deficits • Neurologic signs depend on the site of the abscess and can be subtle for days to weeks. - Hemiparesis • Average time from the onset of symptoms to hospital : 10 days - Lobe-dependent • The abrupt onset of meningeal signs, associated with worsening of headache and neurological status may indicate the rupture of brain abscess into ventricles; ventriculitis (mortality >50%) Widdrington JD, et al. Infection. 2018;46:785–792 Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Edition 9. 2020 Investigations for brain abscess Brain imaging - CT with contrast after 2 wks Microbiological   Obtain abscess material & underlying foci   Note: also benefit for evidence of distant source infection: sinusitis, otitis media, mastoiditis, fracture, malformation, foreign body, etc Additional 1. Staining (direct smear) 2. Culture (for aerobes & anaerobes, mycobacteria, fungi) 3. Nucleic acid-based testing - Mixed • Hemoculture for aerobe & anaerobe (10-30%) • Peripheral leukocytosis (50%) - Hemoculture • ESR, CRP (60-80%) ineffective • Echocardiography (Rt to Lt shunt, vegetation) • Chest x-ray (lung abscess, empyema) • Dental exam organism Never lumbar puncture Note: because of risk of herniation from ICP and low likelihood to identify pathogen from CSF Weinberg GA. Pediatr Rev. 2018; 39(5): 270–272. Treatment in brain abscess Antimicrobial Therapy ASAP Long duration of high-dose IV therapy is typically 6-8 weeks and sometimes followed by additional 2-3 month course of oral antimicrobial therapy - Suppressive therapy Cefotaxime/ceftriaxone + metronidazole would be recommended in most settings Neurosurgical management For microbiological documentation and drainage of lesion - Drug can't reach  Abscess size >2.5 cm  Symptomatic cerebral edema  Ventricular rupture  Accessible location R. Sonneville, et al. Clin Microbiol Infect. 2017;23(9):614-620. Specific antimicrobial therapy in brain abscess Brouwer MC, et al. NEJM.2014;371:447-56 Summary Acute bacterial meningitis (emergent) • Organisms: S. pneumoniae, N. meningitidis, L. monocytogenes, Hib • Pathogenesis: Nasopharyngeal colonization → Intravascular survival → Meningeal invasion → SAS inflammation • Triad: fever, nuchal rigidity, altered mental status • W/U: H/C, CSF analysis (wbc, PMN, glucose, protein, Gram, Culture) Z Tuberculous meningitis • Pathogenesis: inhaled tubercles → lymphohematogenous spread → rupture of Rich foci → SAS inflammation • Clinical: subacute to chronic, non-specific prodrome → evolving S&S of meningitis, stroke, CN palsies, hydrocephalus • W/U: TST or IGRAs, CSF analysis (wbc, MN, glucose, protein, AFB, TB Culture, PCR), brain imaging, miliary CXR Brain abscess • Organisms: polymicrobial agents, fungi and protozoa in immunocompromised host • Pathogenesis: contiguous spread, hematogenous spread, following neurosurgery or head trauma • Triad : fever, headache, focal neurologic deficits • W/U: brain imaging, obtain abscess material & 1ry foci, NEVER LUMBAR PUNCTURE