Infections of CNS

Clinical forms of CNS infections

• Acute bacterial meningitis• Acute viral meningitis• Encephalitis • Local infections:

• Brain abscess • Cerebellitis • Subdural empyema • Infectious thrombophlebitis of brain

vessels

Etiology of meningitis in different age groups

Age Causative agent

0 – 3 months Listeria monocytogenes,Group B streptococci, E. Coli and other Gram- bacteria

3 – 36 months Neisseria meningitidis,Haemophilus influenzae,Streptococcus pneumoniae,Listeria monocytogenes,Enterobacteriaceae, HSV-1, 2Group B streptococci

Older than 3 years

Neisseria meningitidis,Haemophilus influenzae,Streptococcus pneumoniae,Enteroviruses

Etiotropic therapy of meningitis depending on age Under 1 month

Listeria monocytogenes,Group B streptococci, E. Coli

Ampicillin + cefotaxim (or gentamycin)

1 – 3 months

Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae,Enterobacteriaceae, HSV,Group B streptococci

Ampicillin + cefotaxim

Older 3 months

Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae,Enteroviruses

Ceftriaxon (or cefotaxim)

Bacterial causes of meningitis and encephalitis

Aerobic bacteria

Neisseria meningitidis*Haemophilus influenzae*Streptococcus pneumoniae*Streptococcus gr. "B"Streptococcus viridansStaphylococcus aureusEnterococcusEscherichia coli

Salmonella spp., S.typhi, S.enteritidisKlebsiella pneumoniaeSerratia marcescensProteus spp.Pseudomonas aeruginosaCitrobacter diversusListeria monocytogenes

Bacterial causes of meningitis and encephalitis

Anaerobic bacteria

Bacteroides fragilisBacteroides spp.PeptostreptococcusFusobacterium meningosepticum, etc.

Clinical classification of meningitis and encephalitis

Morphology Purulent Serous

Character of appearance

Primary Secondary

Etiology Bacteria Viruses

Fungi Protozoa

Mixed

Course AcuteChronic

Fulminant

Recurrent

Predominating clinics

Basal Convexital

Total Spinal

Primary purulent meningitis

• Meningococcus

• Pneumococcus (Strep. Pneumonia)

• Haemophylus Influenza type B

Primary serous meningitis

• Acute lymphocytic choriomeningitis

• Enteroviral

• Poliomyelitis

• Parotitis

Secondary purulent meningitis

Bacterial

• Staphylococcus

• Streptococcus

• E. coli

• Salmonella

• Proteus

• Klebsiella

• Pseudomonas

• Anthrax

• Listeria

• Pasterilia

• Micoplasma

• Acinetobacter

Fungi

• Candida

• Aspergillus

Protozoa

• Ameba • Toxoplasma

Bacterial serous meningitis

• Tuberculosis

• Syphilis

• Leptospirosis

• Ornithosis

• Brucellosis

Ways of infection penetration into CNS

Hematogenous (systemic septicemia)

Axonal (HSV-1, 2)

Contact

(mastoiditis, epitympanitis, sinusitis)

Along perineural spaces of craniocerebral nerves (otits, mastoiditis)

Pathogenesis of viral neuroinfections – neuronal transmission (HSV, VZV)

Penetration and replication of the virus in skin

Replication in ganglia of dorsal radixes

Centrifugal migration of the virus

Transmission into spinal cord

Skin manifestations

Hematologic spread of bacteria into CNS

Primary replication in GI, respiratory tract, muscles

Secondary replication in Endothelium of vessels

Persistence of bacteria

Chorioid plexus Vascular endothelium

CSF

Aseptic meningitis

Viral meningitisFungi meningitis Bacterial meningitis (caused by bacteria

which can not be seen on Gram staining) Toxic meningitis (drugs, toxins) Meningitis at systemic diseasesMeningitis at neoplastic diseasesParameningeal processes

Meningococcal Infection

History

First described by Vieusseaux in 1805 as epidemic cerebrospinal fever

EpidemiologySpread All over the world Dominating

serotypes

А, W-135, Y China, Nepal, India, Mongolia, Africa, Saudi Arabia

В, С USA, Canada, Europe, Australia

Source of the infection

Symptomatic patients and carriers (up to 2000 carriers per 1 symptomatic)

Way of transmission Respiratory

Morbidity 41,19 per 100 000 (Ukraine 1998y.)

Epidemic cycle 8-30 years

Epidemiology

• Serogroups A, B, C, W135, X, Y, and Z – by capsular polysaccharide antigen.

• Most strains causing meningococcal disease have the of groups A, B, or C.

EpidemiologyContagiousness 10-15% in non-vaccinated

Seasonal morbidity

January-March

Age distribution

<2 years – 50%

15-19 years – 15%

>30 years– 25%

Mortality (Ukraine 1998y.)

In total infectious pathology - 9,1%

From meningococcemia - 20,1%

From meningococcal meningitis - 5,2%

Epidemiology

Carriage rate 5-10%

Carriage rate during epidemics in closed populations

100%

Higher risk of meningococcal

infection • Freshmen college students,

especially living in dormitories • Viral infections (facilitate invasion) • Smoking and smoke exposure• Crowded living conditions• Underlying chronic diseases• Low socioeconomic status

Every year about 250 000 children die from meningococcal infection in the world

70% of all cases are generalized ones45% of all home-acquired sepsis cases are

caused by N. meningitidis30-40% cases of primary meningitis in children

are due to N. meningitidisAbout 86% children with invasive forms of

meningococcal infection require immediate emergency care

25% of patients are misdiagnosed primary and 70% receive inadequate emergency care

Importance

Microbiology

1. Polysaccharide capsule → resist phagocytosis

2. Lipo-oligosaccharide endotoxin → fever, shock

3. Immunoglobulin A1 protease → cleavage of lysosomal membrane glycoprotein-1 → intracellular surviving

4. Fimbria → adhesion to epithelium

N.meningitidis – Gram negative incapsulated dyplococcus

N.meningitidis

• Gram-negative • Intra- and extracellular bacteria • not stable to outer influence • Serogroups А and В typically give

generalized infections • Serogroup A is responsible for

epidemics • Can autolyse – endotoxin is released

Different Forms of Meningococcal Infection

Mucosal colonization

Carriage

Local invasion

Bacteriemia Meningococcemia (occult)

Local infection

Meningitis, pneumonia, osteomyelitis, pericarditis,

Myocarditis, Iridocyclitis

Sepsis

Meningococcemia

Chronic meningococce

mia

N.meningitidis

Exanthem Fulminant

Meningococcemia

Combined forms

Nasopharyngitis, conjunctivitis, uretritis, pneumonia, epiglottitis

Development of meningococcemiaAbsence of antimeningococcal antibody

↓Bacteriemia

↓Interaction with phagocytes + adhesion to endothelial

cells ↓

Complement system activation + attachment of white blood cells to endothelium

↓Production of multiple proinflammatory cytokines (TNFa, IL-1ß, IL-6, and IL-8) + activation of both the

extrinsic and intrinsic pathways of coagulation↓

Development of meningococcemiaCapillary leak and disseminated intravascular

coagulopathy (DIC) ↓

Leukocyte-rich fibrin clots in small vessels↓

Focal hemorrhage and necrosis in any organ system

↓Heart, CNS, skin, mucous and serous membranes,

and adrenals are affected in most fatal cases↓

Multiple organ system failure, septic shock, and sometimes death

Development of meningococcemia

Fatal cases typically have higher concentrations of TNFa and ILs

TNFa and ILs levels decrease rapidly once antibiotics are given

_______________________________Fatality risk is higher in children

capable of strong immune response

Development of meningococcemia

Meningococcal survival is enhanced by:

• Polysaccharide capsule, which helps resist phagocytic killing

• Iron scavenging system that can use host transferrin and lactoferrin

Predisposition

• Complement component deficiencies → increased susceptibility to and recurrent cases of meningococcal infections

• Immunoglobulin G2 subclass deficiency → recurrent meningococcemia

• Hereditary properdin deficiency → predisposition to meningococcal disease

Natural immunity against N. meningitidis

• After repeated colonization with different serogroups or serotypes

• From gastrointestinal colonization with enteric bacteria that express cross-reactive antigens

• Infants also have high carriage rates of the unencapsulated, nonpathogenic neisserial strain, N. lactamica → immunity against meningococci

• Protective effects of maternal IgG during only the first 3 months of life

Classification of meningococcal infection

Form Localized GeneralizedRare forms

Course AcuteSubacuteFulminantRecurrent

Severity MildModerateSevere

Forms of meningococcal infection

Localized forms: Carriage Nasopharyngitis Generalized forms: Meningococcemia Meningitis MeningoencephalitisMeningococcemia

with meningitis

Rare forms:Endocarditis Arthritis Iridocyclitis Pneumonia Urethritis Otitis Conjunctivitis

Meningococcemia (meningococcal sepsis)

Accounts for 15-20% of all invasive cases of meningococcal infection.

Mortality is 20 - 40%.Superacute meningococcal sepsis

develops in 10-20% of cases.Mortality from Superacute

meningococcal sepsis is over 90%.

Clinical PresentationsMain :Hemorrhagic rash Fever, chills

Additional:Pale, mottled or cyanotic skin (capillary refill >2 sec.)

Irritation and crying or lethargy (till coma)Seizures Vomiting, nausea, diarrheaFeeding refusal Myalgias and Arthralgias Decreased urination

Meningococcal rash

Hemorrhagic rash with uneven borders and central necrosis, first appear on lower extremities and buttocks

Meningococcal rash

Meningococcal rash

Meningococcal rash

Meningococcal rash

The glass test

Waterhouse-Friderichsen syndrome

• In fulminant cases, the disease progresses rapidly over hours to septic shock characterized by hypotension, DIC, acidosis, adrenal hemorrhage, renal failure, myocardial failure, and coma.

Criteria of severity

Damroshe Scale (1966)

1. Appearance of hemorrhagic rash within 12 hours from the beginning of the diseases

2. Presence of shock (systolic pressure <70 mm.Hg.)3. Absence of meningitis (CSF cytosis <20

cells/mm3)4. WBC count in peripheral blood <10х109/l5. ESR normal or low (<10 mm/h)

Every index has 1 point. 3 points: case fatality rate is 85,7%, ≥ 4 points: 100%

Criteria of severity

Niklasson Scale (1971)

1. Absence of meningitis (CSF cytosis <100 cells/mm3)

2. Hypotension (systolic pressure <70 mm.Hg.)3. Appearance of hemorrhagic rash within 12 hours

from the beginning of the diseases4. WBC count in peripheral blood <15х109/l5. Fever > 40°С6. Thrombocytopenia (<100 000 /mm3)

Every index has 1 point. ≥ 4 points: case fatality rate is 100%

Criteria of severity

Glasgow Meningococcal Septicemia Scale (1991)

8 points– fatality rate 73%, 10 points – 87,5%, 12 and more – 100%

Systolic pressure < 75 mm.Hg. (under 4 years), < 85 mm.Hg. (older 4 years)

3 points

Gradient of skin-rectal temperature >3°С 3 points

Glasgow Coma Scale < 8 points 3 points

. “Every hour” previous worsening of condition

2 points

Absence of Meningeal signs 2 points

Spread hemorrhagic rash with large elements

1 point

Base deficit (pH>8,0) 1 point

Differential diagnosis

Scarlet fever Measles Rubella Exanthema subitum Dengue Fever Gonococcal infectionInfluenza Mycoplasma infections Rocky Mountain Spotted Fever

Streptococcal Group A & B infections Thrombocytopenic Purpura Ebola Virus Enterovirus Infective Endocarditis Malaria Drug reactions Poisonings

Diseases with hemorrhagic rash

• Neisseria meningitidis • Haemophilus influenzae • Streptococcus pneumoniae• Neisseria gonorrhoeae

Diagnosis in children with fever and hemorrhagic rash (Baker R.C. et al, Pediatrics, 1989)

Bacterial sepsis 39 (12,2%)Neisseria meningitidis 26 (8,2%)Haemophilus influenzae type b 9 (2,8%)Streptococcus pneumoniae 2 (0,6%)Staphylococcus aureus 2 (0,6%)Other bacterial infections 68 (21.3%)Bowel infection caused by Escherichia coli 3 (0,9%)Streptococcal tonsillitis 23 (7,2%)M. pneumoniae pneumonia 1 (0,3%)Pneumonia of unknown etiology 11 (3.4%)Acute otitis media 30 (9,4%)Ricketsiosis 1 (0,3%)Viral infections 195 (61,1%)Enteroviral infection 9 (2,8%)Aseptic meningitis 16 (5%)Adenoviral infection 1 (0,3%)

Diagnosis in children with fever and hemorrhagic rash –cont.

RS-infection 12 (3,8%)Human methapneumovirus 11 (3,4%)Rotavirus 1 (0,3%)

HHV-6 (exanthema subitum) 1 (0,3%)Probable viral infection 144 (45,1%)Other causes 25 (7,9%)Hemorrhagic vasculitis 2 (0,6%)Kawasaki disease 1 (0,3%)Thrombocytopenic purpura 1 (0,3%)Vaccination reaction 3 (0.9%)Acute leukemia 2 (0,6%)Febrile seizures 5 (1,6%)Partially treated meningitis 2 (0,6%)Partially treated septicemia 2 (0,6%)Exudative tonsillitis 2 (0,6%)Reaction to ampicillin 1 (0,3%)Unknown 4 (1,3%)

Occult meningococcemia

• Fever with or without associated symptoms that suggest minor viral infections

• Resolution may occur without antibiotics, but some cases will develop meningitis

Chronic meningococcemiaRare form : Intermittent Bacteriemia illness that

lasts from at least one week to as long as several months

– Intermittent fever, with afebrile periods ranging from 2-10 days, during which the patient seems entirely healthy → febrile periods occur more frequently, fever may become continuous;

– Headache, arthritis can develop;– Eventually, skin hemorrhages or signs of

meningitis appears during a febrile episode;– Blood cultures may initially be sterile.

Meningitis

Inflammation of soft meningeals of viral,

bacterial or fungi etiology or as a complication or

presentation of systemic septicemia

Current epidemiology of meningitis

• Streptococcus pneumoniae –50 %

• Neisseria meningitidis - 25 % • Group B streptococci – 15 %• Listeria monocytogenes - 10 %• Haemophilus influenzae < 10 %

(vaccination !)

Meningococcal meningitis

• Meningococcal meningitis - 50-60% of all invasive cases of meningococcal infection

• Case fatality rate is 3 - 10%• About 30% of cases are

combined with meningococcemia

Clinical Signs - main Fever Headache Positive Meningeal signs : - Neck stiffness - Brudzinski sign - Kernig sign - Lessage’s sign - Fontanel bulging

- Position of the “kicking dog” - Lobzin’s sign - Guillain’s sign - Flatau’s sign

Clinical Signs – additional Irritability Somnolence Vomiting (repeated regurgitations) Groaning crying High-pitch cry at irritation Light fear Decreased feeding Decreased consciousness Delirium Convulsions Craniocerebral nerves involvement Pain in joints and muscles

Meningeal signs – cont.

Neck stiffness Inability to touch sternum with chin

Kernig Flexed in hip and knee joints leg can not be straightened in knee joint

Brudzinski (upper)

At head bending the legs are flexed in hip and knee joints

Brudzinski (lower)

At Straightening of the flexed in hip and knee joints leg, the second leg is flexed

Lessage’s At lifting up, the infant flexes legs and remains in this position

Meningeal signsPosition of the “kicking dog”

The patient is lying on the back with thrown back head and legs flexed to the bowel

Guillain’sCompression of leg’s quadriceps causes other leg’s flexion hip and knee joints

Lobzin’s Pain increase at pressure on the eyeballs

Flatau’s Pupils’ widening at head flexion

Amoss’

Leaning on hands behind when sitting, inability to touch knee with lips

Herman’s Passive head flexion to the sternum causes extension of toes

Levinson’s Mouth opening at head flexion to the sternum

Neck stiffness irritability or lethargy

Particularities of meningitis clinics

in infants • Irritability / somnolence • Mild fever • “Brain cry” – headache equivalent • Large fontanelle bulging • Lessage’s sign• Head retroflexion • Tonic and clonic seizures• Transient diarrhea

Meningitis diagnosis

• The only way to exclude/diagnose neuroinfection is to investigate CSF

• Pleocytosis proves a CNS

infection

Differential diagnosis

Encephalitis and meningitis caused by other viruses or bacteria

Acute bowel infections Pneumonia Septic shock RhinosinusitisAcute poisoning Encephalopathies

Differential diagnosis – cont.

Acute myositis Infectious delirium Retropharyngeal abscesses Shaken baby syndrome Subdural haematoma CSF hypertension syndrome Brain blood circulation damage Hypertensive crisis

Required tests at meningitis

• CSF• CBC • Signs of brain edema:

– Eye fundus examination (edema) – CT, MRI

• Blood electrolytes• Glucose of blood and SCF• CRP

CSFIndexes Healthy

Meningitis Encephalitis

Encephalo-pathy Purulent Serous

Pressure(mm Н2О)

<150 Increased Increased Increased Increased

Cytosis <5x106

/l>1000x106/l

10-1000x106/l

10-1000x106/l

<5x106/l

Lymphocytes

60-70% 20-30% 90-100% 90-100% 60-70%

Monocytes 30-50% 10-20% 0-10% 0-10% 30-50%

Neutrophils No >60% No No No

Glucose (mmol/l)

2,8-4,4 Decreased

Normal Normal Normal

Glucose gradient (%)

>60 <60 Normal Normal Normal

Protein (g/l) <0,45 Increased Increased Increased Normal

Etiologic diagnosis Test Material Comments

Gram’s stain

CSF, aspirate from skin rash or sinovial fluid or other sterile material

Rapid test CSF Sensitivity – 65%Skin rash sensitivity - 30-70%

Culture

CSF, blood, aspirate from skin rash or sinovial fluid or any other sterile material

“Golden” standard for diagnosis

Result in 1-2 days CSF Sensitivity – 95% (without antibiotics)

Blood culture Sensitivity – 50% (without antibiotics)

Nasopharyngeal secretion

Confirms carriage

Etiologic diagnosis – cont.

Test Material Comments

PCR CSF, blood

CSF: Sensitivity - 89%, Specificity– 100%

Blood: Sensitivity – 81%, Specificity -97%

Serology Blood

Specific IgM or Ab titer increase 4 times and more (low informativity and sensitivity)

Antigen test CSF

Low sensitivity, additional test to Gram’s staining

Complications

• Disseminated intravascular coagulation • Vasomotor collapse and shock • Seizures or deafness in the acute

stages of meningitis • Ependimatitis • Postmeningitic epilepsy (rare) • Coma • Thrombocytopenia • Septic arthritis

Complications – cont.

• Herpes labialis (5-20% of patients) • Immune complex arthritis of multiple

joints • Pericarditis • Bacterial endocarditis • Myocarditis • Gangrene • Urethritis and endometritis • Osteomyelitis • Purulent conjunctivitis and sinusitis

Complications by age

Age Early Late Any Septic

shockHyponatremiaSeizures Brain edema

Subdural empyema Hyponatremia Ventriculitis Cerebral hypotension Seizures

Under 3-6 months

HypoclycemiaApnoe

Uncommon manifestations of meningococcal disease

• Endocarditis• Purulent pericarditis• Pneumonia (in 15% + pleural effusion or

empyema)• Endophthalmitis• Mesenteric lymphadenitis• Osteomyelitis• Sinusitis• Otitis media• Periorbital cellulitis• Primary purulent conjunctivitis • Urethritis, cervicitis, vulvovaginitis, proctitis

Antibiotic therapy before hospitalization for

meningococcal, pneumococcal and hemophylus infections

(Writing Group for Therapeutic Guidelines: Antibiotic 11-th edition: Therapeutic Guidelines LTd. 2000. Melbourne)

Drug Age Dosage

Ceftriaxon

Under 10 years

Older 10 years and adults

Once, IV or IM 100mg/kg (not exceed 2 g)

Once, IV or IM, 1000mg

Treatment before hospitalization at the

presence of meningitis and gemorrhagic rash

1. Dexamethazone – 4 mg IM once 2. Ceftriaxon – 100mg/kg IM once – 15’

later3. Analgin 0.1ml/year at fever > 38 C4. IV normal saline (10-20ml/kg/hour)

Etiologic treatment

• Start antibiotic – ceftriaxon (100mg/kg/d) or cefotaxim (200 mg/kg/d)

• Reserve antibiotic – meropenem (120mg/kg/d)

Length of therapy – 10-14 days, till clinics disappearance and normal cytosis of CSF (50 cells are admissible if lymphocytes)

Etiologic treatment

Proved meningococcal infection: Penicillin G – starting dose • Meningococcemia – 300 000 U/kg/d• Meningitis - 500 000 U/kg/d

Maximal allowed dose - 1 000 000 U/kg/d

Pathogenic therapy for meningitis

Septic shock

•Bolus 0.9% NaCl, start with 20ml/kg, then –10 ml/kg every hour before hematocrit → 33 %;•Cardiotonic drugs (dopamin)

Brain edema

•Osmotic dehydratation: mannitol, manit •Hyperventilation

Seizures • Barbiturates, benzodiazepins• Hyponatremic seizures: 3 % NaCl –

10-12 ml/kg/h• Hypoglycemic seizures (under 3 mo):

5-10 % glucose

Deafness prophylaxis

•Dexametazone 0,15 mg/kg every 6 h – 2 days, first dose - 15 minutes before antibiotics

Chemoprophylaxis of contacts of meningococcal, pneumococcal and

hemophylus infections (2000 Red Book: Report of the Committee on Infection Diseases 25th

Edition)Drug / age Dosage Course

Rifampicin< 1 month> 1 month and adults

Per os:5 mg/kg bid 10 mg/ kg bid(max – 600 mg)

2 days2 days

Ceftriaxon < 12 years > 12 years

Intramuscular :125 mg250 mg

Once Once

Ciprofloxacin > 16 years(not recommended for pregnant and children under 16 years)

Per os:500 mg

Once

Specific prophylaxis

Total vaccination against meningococcal infection is not performed routinely in Ukraine.

Vaccination is indicated to patients older 18 months with: Functional or anatomical aspleniaComplement components insufficiency Properdin insufficiency Factor B insufficiency People from endemic areas

Specific prophylaxis

Vaccination is indicated to patients older 18 months with (cont.):

• Hemoglobinopathies• Nephrotic syndrome• CSF shunting • Cellular and humoral

immunodeficiencies• HIV infection • Chronic diseases of cardiovascular,

respiratory systems and liver

Specific prophylaxis

Characteristics of vaccine (Meningitis Vaccine Project, 2007)

Characteristics Tetravalent polysaccharide (MPSV4)

Tetravalent conjugated (MCV4)

Composition Pure polysaccharides A,C,Y,W-135

Pure polysaccharides A,C,Y,W-135, conjugated to Diphhteria toxoid

Immunogenic in children Low High

Bactericidal activity of Аb in children Low High

Immunologic memory induction No Yes

Nasopharyngeal carriage

Transitory and incomplete

Documented decrease