CNS Infections Neuropathology Conference (11/5/2018) - PowerPoint Presentation

Slide1

CNS Infections

Neuropathology Conference (11/5/2018)

Xiaowei Su, PGY-3 & Dr. Geoffrey Murdoch

Adapted from slides by

jen

nichols

and

robyn

massa

Slide2

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

Slide3

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

Slide4

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

Slide5

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)

Slide6

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

)

Slide7

Clinical Signs

Brudzinski’s Sign Kernig’s Sign

Slide8

Diagnostic Workup

Laboratory Workup

CBC: leukocytosis (majority PMNs)

50-90% of patients have positive blood culturesRoutine 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

Slide9

CSF Findings

Slide10

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

Slide11

MRI Findings

Slide12

Neuropathology

Streptococcal meningitis

H&E

(hematoxylin stains nucleic acids blue

, eosin stains amino acids

red

)

Gram Stain

(crystal

violet

stains thick peptidoglycan cell walls)

Slide13

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

Slide14

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

Slide15

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

)

Slide16

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

Slide17

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

Slide18

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

Slide19

Imaging

Slide20

Neuropathology

Slide21

Neuropathology

Slide22

Neuropathology

Slide23

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

)

Slide24

Imaging

Slide25

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%

Slide26

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)

Slide27

Treatment

Slide28

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

Slide29

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

)

Slide30

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