CNS Infections

1. CNS Infections Neuropathology Conference (11/5/2018) Xiaowei Su, PGY-3 & Dr. Geoffrey Murdoch Adapted from slides by jennichols and robyn massa

2. Bacterial Meningitis • Meningitis is an inflammatory disease of the leptomeninges • Abnormal number of white blood cells in the CSF • Infection of the arachnoid mater and the CSF in both the subarachnoid space and the cerebral ventricles

3. History of Meningitis • Thomas Willis described patients with "inflammation of the meninges with a continual fever“. He also described an early epidemic of meningitis in 1661 • Heinrich Quincke utilized his new technique of lumbar puncture in 1891 to analyze CSF • William Mestrezat and H. Houston Merritt compiled large series of CSF profiles, identifying three major organisms (Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenza) in the late 19th century • Vladimir Kernig and Josef Brudzinski described their eponymous signs in 1882 and 1909 • Antibiotic therapy began in the 20th century with the use of sulfonamides by Francois Schwentker and penicillin by Chester Keefer • Vaccination against meningitis debuted in the early 20th century

4. Epidemiology • Approximately 1.2 million cases per year worldwide, responsible for 135,000 deaths each year • Community Acquired Bacterial Meningitis • Strep pneumoniae, Neisseria meningitidis, Listeria monocytogenes >> Haemophilus influenzae (due to vaccines) • Healthcare associated bacterial meningitis • Usually staphylococci and aerobic gram-negative bacilli • If due to neurosurgery, can vary with whether or not antimicrobial prophylaxis was given to prevent surgical site infection • Can also occur following ventricular drains or cranial trauma, and other predisposing conditions include acute sinusitis and mastoid infections

5. Pathogenesis & Pathophysiology • Bacteria that cause meningitis are able to colonize the host mucosal epithelium, invade, survive within the bloodstream, then cross the BBB, multiplying within the CSF • Much of the damage results from cytokine release within the CSF as the host mounts an inflammatory response • Inflammatory response is initiated both in the bloodstream and the CSF, damaging the endothelium of the BBB (tight junctions)

6. Clinical Features • Patients with bacterial meningitis usually present soon after symptom onset • Classic triad • Fever, nuchal rigidity, change in mental status • More common in Pneumococcal meningitis than meningococcal meningitis (58% vs 27%) • 99 to 100% sensitive if patient has 0 of these 3 • 95% of adults presented with at least 2 of the following 4 symptoms: headache, fever, nuchal rigidity, change in mental status • Other resulting symptoms: seizures, focal neurologic deficits (CN palsies), papilledema, ischemic stroke (pneumococcal meningitis), hearing loss (late), skin manifestations (N. meningitidis)

7. Clinical Signs Brudzinski’s Sign Kernig’s Sign

8. Diagnostic Workup • Laboratory Workup • CBC: leukocytosis (majority PMNs) • 50-90% of patients have positive blood cultures • Routine blood work is usually otherwise unrevealing • Lumbar Puncture • Crucial for establishing the diagnosis, identifying causative organism, performing susceptibility testing • CT scan should be performed before LP if there is concern for increased ICP • Immunocompromised state, history of CNS disease (mass lesion, stroke, focal infection), new onset seizure within 1 week of presentation, papilledema, abnormal level of consciousness (GCS <11), focal neurologic deficit

9. CSF Findings

10. MRI Findings • T1 plus contrast: • Meningeal enhancement; especially characteristic when thicker, longer, more intensely enhancing, and if there is nodular enhancement • The degree of abnormal enhancement correlates with the degree of inflammatory cellular infiltration of the meninges • T2 FLAIR: • Leptomeningeal hyperintensities; not specific for infection vs inflammation • CSF hyperintensities, usually present in the lateral ventricles and cortical sulci • DWI: • Abscesses (Strep pneumo), especially in the subarachnoid or intraventricular regions • Resultant ischemic infarction or vasculitis

11. MRI Findings

12. Neuropathology • Streptococcal meningitis • H&E (hematoxylin stains nucleic acids blue, eosin stains amino acids red) • Gram Stain (crystal violet stains thick peptidoglycan cell walls)

13. Empiric treatment • Vancomycin 25-30mg/kg load with 15mg/kg maintenance (surgicalcriticalcare.net/Resources/vancomycin.php) • Ceftriaxone 2gm q12H (Aztreonam 2gm q6H for penicillin allergy) • Ampicillin 2gm q4H if >50-yrs (add Bactrim 15-20mg/kg/day divided q6-8H to aztreonam for allergy) • Cefepime 2gm q8H is recommended for penetrating trauma, post-NSGY, or shunt;alternative is ciprofloxacin 400mg q8H or aztreonam 2gm q6H • Acyclovir 10mg/kg q8H (ideal or adjusted body weight) if suspecting viral encephalitis • Dexamethasone for all adults with suspected bacterial meningitis not in septic shock(0.15 mg/kg q6H x4-days, first dose within 20-min prior to first antimicrobial dose) • Dexamethasone decreases mortality, neurologic complications, hearing loss for pneumococcal meningitis (most common organism >18-yrs) • Begin antimicrobials after blood cultures, do not delay for LP

14. Viral encephalitis • Clinical course is more slowly progressive, altered level of awareness, personality changes, headache may worsen over days to >1-week • HSV & VZV encephalitis treated with acyclovir • CMV in immunocompromised patients treated with ganciclovir • EBV responds with supportive therapy alone • Arboviruses (West Nile, St. Louis, Japanese), lymphocytic choriomeningitis virus (LCMV), enteroviruses (acute flaccid myelitis) have no targeted treatments Radiopaedia.org

15. Neuropathology • Enteroviral meningitis • H&E (hematoxylin stains nucleic acids blue, eosin stains amino acids red) • CMV radiculitis • H&E (hematoxylin stains nucleic acids blue, eosin stains amino acids red)

16. Fungal Meningitis - Cryptococcal • Encapsulated saprophytic yeast, transmitted by inhalation • C. neoformans - most common, 82% of disease worldwide • C. gattii - immunocompetent individuals in tropical & subtropical regions (sporadic cases in North America) • Mostly affects those with impaired cell-mediated immunity • HIV - 95% in middle to low income countries, 80% in high income countries • Immunosupressant medications • Immunocompetent hosts - autoimmune disease, malignancy, occult immune deficiencies

17. Clinical Features • Subacute headache • Confusion • Increased ICP  CN palsies, seizures • Meningismus <20% of patients • Cryptococcomas (granulomas)  hydrocephalus • Ocular (papilledema, uveitis, chorioretinitis, optic nerve dysfunction) • Pulmonary, cutaneous, and bloodstream infections also occur

18. Diagnosis • Lumbar puncture • Elevated opening pressure (can fluctuate) • Lymphocytic pleocytosis, low glucose, elevated protein (can be normal, especially in HIV) • India ink staining under light microscopy (low sensitivity) • CSF cryptococcal antigen >93% sensitive and >93% specific, urine antigen less specific • Fungal culture on Sabouraud media, grows after 36 hours • Radiology • Cryptococcomas and pseudocysts in midbrain or basal ganglia • Low sensitivity for symptomatic hydrocephalus and dilated perivascular spaces

19. Imaging

20. Neuropathology

21. Neuropathology

22. Neuropathology

23. Neuropathology • Cryptococcus meningitis • H&E (hematoxylin stains nucleic acids blue, eosin stains amino acids red) • PAS (period acid oxidizes polysaccharides, creating aldehydes that stain purple with Schiff reagent) • Mucicarmine (stains mucopolysaccharide capsules red) • GMS (methanamine oxidizes mucopolysaccharides, creating aldehydes that reduce silver reagent black)

24. Imaging

25. IRIS • Host immune recovery triggers inflammatory response to antigens • Paradoxical unmasking after initial response to antifungals • Occurs after starting ART or pausing anti-rejection medications • May occur in immunocompetent hosts as their immune system recovers from high fungal burden • Risk factors: severe disease, slow fungal elimination • Benefit of steroids is unclear • Mortality up to 36%

26. Neuropathology • Immune reconstitution inflammatory syndrome • H&E (hematoxylin stains nucleic acids blue, eosin stains amino acids red) • CD3 (anti-CD3 binds T-cells, which turns brown with biotin-based detection) • IBA1 (anti-IBA1 binds microglia, which turns brown with biotin-based detection)

27. Treatment

28. Treatment • Amphotericin B • Side effects: nephrotoxicity, hypokalemia, hypomagnesemia • Liposomal formulations are less nephrotoxic • Greatest early fungicidal activity • Flucytosine • Side effects: bone marrow suppression • Reduction of raised ICP • Serial LPs, CSF drainage catheter, VP shunt (acetazolamide may cause harm) • Changes in exam are the earliest indication of worsening ICP • Management of immune reconstitution inflammatory syndrome (IRIS) • ART for HIV patients: start 4-10 weeks after initiating antifungal treatment

29. Other Fungal Meningitis • Aspergillus • H&E (hematoxylin stains nucleic acids blue, eosin stains amino acids red) • GMS (methanamine oxidizes mucopolysaccharides, creating aldehydes that reduce silver reagent black) • Tuberculosis • H&E (hematoxylin stains nucleic acids blue, eosin stains amino acids red) • FITE (carbol fuchsin stains cell walls red, other cells destained by acid-alcohol and counterstain blue)

30. Questions “The brain is a wonderful organ. It starts working the moment you get up in the morning and does not stop until you get into the office.” - Robert Frost