Bangar Raju
Dept of Microbiology KMC-IC
INFECTIONS OF THE CENTRAL NERVOUS SYTEM
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USF student Rachel Futterman, radiant and energetic
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• Thursday, when she left her restaurant job. She was excited about her recent promotion from host to server. • That night, she attended a campus wide sorority dinner and went out with friends. When she woke the next morning, she thought she had the flu. • Her Delta Gamma sorority sisters nursed her. Roommate Amber Powers brought her Gatorade to settle her stomach. • Then Saturday came. • At 7 a.m. Powers was awakened by Futterman kicking in what appeared to be a seizure, so she called 911. • Two days later, USF honored the energetic student during an outdoor memorial service on campus.
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INTRODUCTION:
• Infections of CNS are rare but life threatening • Presents special milieu for bacterial, fungal, viral, and parasitic infections • Brain and spinal cord are protected by bone and meningieal coverings • Lack intrinsic immune system • Unique compact structure
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Gross Anatomy
• Protected by bony covering • Meningieal layers give some kind of protection • Piamater and arachnoid layers are not adherent to each other • Infection can spread rapidly over cerebral hemisphere • CSF is present in subarachnoid space- true space • CSF contains little antibody or complement and few phagocytic cells • Bacteria in logarithmic phase- acute onset of bacterial meningitis
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Blood-Brain barrier
• This barrier excludes most microbes, immunocompetent cells and antibodies. • cellular configuration of cerebral capillaries, the choriod plexus and arachnoid cells. • Therefore, although the barrier deters invasion of infectious agents, it hampers their clearance once it is penetrated. • Dye-trypan blue injected into systemic circulation • Stain all tissues except the brain and spinal cord – blood brain barrier
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Immune system:
• Lacks antibodies • Antibodies found are derived from serum • IgA & IgG are found in low levels • IgM not possible due to its large size • Very few phagocytic cells found during infection- special microglial cells • Complement is almost absent • Hence clearing of pathogens difficult once entered
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• During trauma and inflammation BBB gets disrupted and inflow of antibodies seen along with serum proteins • Sometimes when inflammatory reactions sets in B cells leak into CSF and generate antibodies • PMNs are major cells found in bacterial infections • Attracted by chemotactic factors • Mononuclear cells are dominant in viral infections, sub acute infections such as tuberculosis and fungal infections. • These cells matain the infection in dormant stage and gets reactivated due to HIV, drugs and immunosupression • Organism choose specific receptors on neural cells to enter CNS
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• Blood borne invasion- Polio, Neisseria • Through peripheral nerves- Herpes simplex, Varicella-Zoster, Rabies- less common
• Local invasion- infected ears, sinuses, local injury, congenital defects (spinal bifida)
• Through olfactory tract- Amoebic meningitis.
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Pathways of spread to the central nervous system
• Direct: skull fracture, from adjacent sinus, congenital ectodermal defect, and surgical shunt Staphylococcus aureus and members of Enterobacteriacae • Neural ( via axon): tetanus toxin, rabies, Herpes • Olfactory: Herpes simplex, Naegleria fowleri • Hematogenous: H.inflenzae, streptococcus pneumoniae, Neisseria, mycobacterium, Cryptococcus, Rickettsia, Enteroviruses, plasmodium , HIV, tape worm embryos
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Terminology:
• Encephalitis: Inflammation of the brain • Myelitis: Inflammation of spinal cord • Encephalomyelitis: Inflammation of brain and spinal cord • Meningitis: Inflammation of membranous covering of the brain and spinal cord. • Meningoencephalitis: Inflammation of brain and meninges. • Epidural abscess: Inf of soft tissue • Osteomyelitis: Inf of the bones
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• • • •
Encephalitis Myelitis Encephalomyelitis Meningitis
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Meningitis
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Types of Meningitis
• • • • • • Bacterial Meningitis Viral Meningitis Fungal Meningitis Syphilitic Meningitis Carcinomatous Meningitis Drug Induced Meningitis
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Categorizing of CNS infections and etiologic agents
Acute meningitis:
bacterial- Streptococcus pneumoniae Neisseria meningitides Haemophilus influenzae type B Group B streptococci Escherichia coli viruses- Arbo viruses Entero viruses
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Chronic meningitis:
Bacterial - mycobacterium tuberculosis Fungi - Cryptococcus neoformans others
Acute encephalomyelitis
Viruses - Arboviruses Enteroviruses Herpes viruses
Acute brain abscess
staphylococcus aureus mixed anaerobic & aerobic flora group A & D streptococci
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Chronic brain abscess
Bacteria – mycobacterium tuberculosis Fungi – Cryptococcus neoformans Parasites – Taenia solium Toxoplasmosis
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Risk Factors
• Immunodeficiency states, respiratory tract infections, malnutrition, anaemia, smoking • Male > Female • Age distribution of meningitis varies from area to area • Dry season • Low socio-economic status
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ENTRY, REPLICATION AND SPREAD
Infectious agents can invade the CNS using one of three routes: • Hematogenous spread • Neural pathways - less common • Direct inoculation
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Hematogenous spread of organisms • Most of the viruses and bacteria invade by this route • Gain access to blood stream following colonization and penetration mucosal surfaces- respiratory • Sometimes the bite of the arthropod, bite of the mammal or transplacentally • Penetrates the blood brain barrier elaborating different virulence factors • Can enter even through places where tight junctions between endothelial cells are less significant
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• Direct entry through choriod plexus- mumps virus • Arboviruses directly infect endothelial cells including the microvascular circulation the brain • Symptoms or manifestations depend on the microbial load in blood stream meningococcal meningitis arboviruses meningitis rabies , mumps viruses staphylococcus aureus etc………
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Spread by neural route:
• Organisms use special neural pathways
Rabies HSV Varicella- Zoster • Some use only olfactory nerves endings to reach the brain Naegleria fowleri- Meningoencephalitis
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Bacterial evasion mechanisms to host responses
Pathogenic Event
Colonization and mucosal invasion,
Host Defense
Bacterial Evasion Mechanism
IgA protease secretion Ciliostasis Adhesive pili Blockage of Alternative Compliment Pathway by Mechanisms on the cell surface Passage through tight junctions between cells, mechanism unknown Rapid bacterial replication
1. Secretory IgA 2. Cellular cilia activity 3. Mucosal epithelium
Survival in the blood stream
Activation of Complement Pathways
Crossing the bloodbrain-barrier
Cerebral endothelium
Survival within the CSF
Poor opsonic activity
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Damage:
• Death of CNS cells is due to action of
bacterial toxins, lytic cycles of viral replication, intracellular growth of bacteria immune response of the host Multiplication and spread – elicits inflammatory response, less intense that other areas Infiltration of microglial cells and astrocytes - vascular edema due to increased vascular permeability Neutrophils and macrophages infiltrate and phagocytize the organisms. Lysis of infiltrating neutrophils releases enzymes, leading to further tissue destruction Focal lesions are important to diagnose the CNS diseases
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Anatomical basis of localization of symptoms
• Frontal lobe:
frontal sinusitis headache memory defects attention loss diminished intellectual performances
• Temporal lobe:
personality changes visual field defects focal seizures
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• Basilar (base of the brain):
sub occipital headache
neck stiffness diplopia cranial nerve palsies
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Viral Meningitis
• Acute onset • Meningeal signs and symptoms • CSF abnormalities typical of meningitis • Absence of bacteria on smear/culture of CSF • Self limiting, benign course
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Fungal Meningitis
• Most common in the immunosupperssed due to: – AIDS – Organ transplantation – Immunosuppressive chemotherapy – Chronic corticosteroid therapy • Meningeal signs and symptoms may occur up to 3 – 6 months after initial infection
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Clinical Features of Fungal Meningitis
• Usually mild meningeal symptoms
– – – – – – Headache Fever Photophobia Nausea / Vomiting Skin lesions Cranial nerve palsies
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Syphilitic Meningitis
• 6 types of neurosyphilitic syndromes • Acute syphilitic meningitis one of them – Meningeal symptoms typically develop within 1 year – Usual symptoms: • Headache • Nausea / Vomiting • Stiff neck • Papilloedema
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Carcinomatous Meningitis
• Dissemination of malignant cells throughout the leptomeninges • Adenocarcinoma and malignant melanoma are the most common solid tumours to metastasize to leptomeninges • Mechanism for how tumour cells reach the leptomeninges is unknown
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Bacterial meningitis:
• Also called as septic or pyogenic meningitis • Virus meningitis is a self-limiting condition • Bacterial meningitis far less common but lifethreatening • Rare causes - spirochetes, fungi • Early acute-influenza-like syndrome, (fever, severe head ache, stiff neck, lethargy.) • In elderly immunocompromised, confusion, agitation, disorientation, coma • Bacterial meningitis is a severe life threatening infection that requires prompt diagnosis and treatment –uncommon • Viral meningitis more common – less serious • Agent of bact meningitis varies with age
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Etiology of bacterial meningitis by patient category age
Birth to 3 months
Most common
Strep agalactiae ( group B)
others
E coli Listeria monocytogenes N. meningitidis H. influenzae type B
3- 60 months
Strep pneumoniae
>60 MONTHS
Strep pneumoniae
N. meningitidis L. monocytogenes
Staphylococcus epidermidis Pseudomonas and GNB GNB & pseudomonas
Any age
Staphylococcus aureus
Any age
L. monocytogenes
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Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae
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Predisposing Conditions
Age: 18-50 - S. pneumo, N. mening >50 - S. pneumo, N. mening + Listeria Trauma/Surgery: – S. aureus, coag neg staph, P. acnes, gram neg bacilli CSF Leak: H. influenza Immunocompromised : • ↓Immunoglobulins - S. pneumo • Splenectomy: S. pneumo, H.influenza • Steroids- nocardia, cryptococcus • Neutropenic –gram neg bacilli, molds • AIDS – Cryptococcus, histo, TB • Alcoholic: S. pneumo, H.influenza, Listeria
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Meningitis - At birth to 3 months
• 20,000 cases of bacterial meningitis in US yearly. • 70% of these in children 50% meningitis deaths. • Infants suffer more common from Haemophilus influenzae meningitis
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• In babies - diagnosis of life threatening infs is
difficult
• They do not display clinical signs
• Symptoms - failure to thrive, off their feeds, fever, diarrhea.
• Group B Streptococci in female genital tract, infects babies during passage through birth canal. • Penicillin + Gentamicin
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• Meningitis in postnatal period is common but now very rare due to capsular polysaccharide protein -Conjugate vaccine during infancy. • A vaccine has been developed to protect infants---Hib – children from 2 months of age. Non vaccinated children: Permanent neurological damage-risk hearing loss, delayed language development, mental retardation, seizures. 3rd generation cephalosporin or chloramphenicol . close contacts- rifampicin prophylaxis
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• • • • •
Encapsulated GNB- pathogens of RT. Spread from RT via blood to brain. Infants 3-4months protected by maternal abs, By age 3-4 yrs will have their own abs. Window of opportunity between these ages.
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• Listeria – GPB found in high
• • • • numbers in cheese. Consumption of these foods during pregnancy is discouraged They might cause fetal infections. In immunocompromised – renal transplant & cancer too Newborn babies also at risk- healthy carriers not uncommon 1st week of life- septicemia ---> meningitis
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•
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Meningitis in children & young adults
N meningitidis- most common
• S pneumoniae cause bacterial meningitis at any age • 80% -N meningitidis, S pneumoniae, H influenzae. • N meningitidis – epidemic disease • All others are sporadic.
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Meningococcal meningitis
• GN diplococcus found within PMN. • 20% population carry in oropharynx • Carriage rate higher in crowded areasmilitary barracks, boarding school dormitories. • Spread by inhalation of infected droplets. • Serotypes in developed countries- B,C,Y • Less developed areas-A,C ,Y and W-135
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• UK –first to introduce-conjugate C vaccine • Part of routine childhood immunization since November 1999. • Incub period 1-3 days, sore throat, head ache, fever, neck stiffness, photophobia • In 80% cases, petechial rash-evidence of septicemia. • In 35% , disseminated intravascular coagulation (DIC), endotoxiemia, shock, renal failure • Severe cases, bleeding in brain and adrenal glands
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Severe toxic symptoms of N meningitidis
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• Untreated-mortality 100%- 10% even if treated, • Hearing loss in some survivors. • Penicillin or 3rd generation cephalosporin
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Differential diagnosis of fever, altered
sensorium and petechial rash
• • • • Meningococcal disease Rickettesial infection (RMSF etc.) S. aureus endocarditis S. pneumoniae, H. influenzae (especially with Splenectomy) Septic shock Viral meningitis Viral hemorrhagic fevers HUS, vasculitis, etc.
• • • •
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Streptococcus pneumoniae meningitis:
• Capsulated GP Diplococcus • Children less than two yrs and elderly. • Sickle cell anemia, alcoholics, splenectomized patients, head trauma- more at risk. • Abs to capsular ags opsonises the bacteria and promotes phagocytosis but protection is type specific-there are more than 85 capsular types. • High mortality (20-30%)even when treated • In 15-20% permanent neurological damage. • CDC-heptavalent protein conjugate vaccine • For children from 2-23 months of age
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• Older children from 24-59 months are at high risk (sickle cell disease, HIV inf, chronic illness etc) • Penicillin - in some countries strains are resistant to penicillin.
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Mycobacterium tuberculosis meningitis:
(Tubercular meningitis)
• Rare-difficult to diagnose and so delay in treatment • Patients here have a focus of My. tuberculosis elsewhere in the body. • In > than 50% cases, meningitis is associated with acute miliary tuberculosis • In high prevalent TB areas, meningitis seen from 0-4 yrs of age• less prevalent areas –meningitis seen in adults.
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•
• • • • • •
Gradual onset over a few weeks.
Malaise, apathy, anorexia within few weeks to photophobia. Neck stiffness and impairment of consciousness. Delay in diagnosis, treatment – serious neurological damage. Spinal TB found only in developing countries The bacteria in the vertebrae destroy intervertebral disks to form epidural abscesses. They compress spinal cord and cause paraplegia.
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• Treatment- isoniazid and rifampicin both cross blood-brain barrier. • Conventional culture of samples take 8 weeks.
• PCR based identification is done in a day.
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HOST RESPONSES TO INVASION • • • • • • Normal CSF: water clear 90% consciousness 80% Meningismus 85% Focal neurosigns 25% Ocular palsies – 10%
Vomiting – 30%
Seizures – 30% Petechiae/purpura 50% (meningo.)
Hemiparesis
Myalgias 20% Papilledema 1%
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Pictorial depiction of symptoms of meningitis
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Approach to suspicious patient • History • Clinical Exam • LP • Empirical Treatment • Does H& PE help in determining when to perform an LP?
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Signs of meningeal irritation:
• Brudzinski’s sign: resistance to passive neck flexion. • Kernig’s sign: inability to extend leg when thigh is flexed at 90º with the trunk.
Subacute/chronic: TB/Fungal infections
increased cranial pressure (papilledema, nausea, vomiting), disorientation, confusion, personality change.
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Complications of meningitis in infants and children
- Hearing loss is the most encountered sequelae; it occurs * in 30% cases of S. pneumoniae meningitis, * in 20% of H. influenzae meningitis, * in 10% of N. meningitidis meningitis - Mental retardation, seizures, delay in language acquisition, visual impairment, behavioural problems and hydrocephalus.
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• Blood stained CSF- bad take or subarachnoid haemorrhage. • TB meningitis- spider’s web clot-high protein content Biochemical tests on CSF: • Viral, Mycobacterium, Cryptococcus meningitis-- glucose normal or just subnormal, protein slightly raised • Bacterial--– glucose very low due to metabolism, protein significantly raised
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LABORATORY DIAGNOSIS:
SAMPLE: • CSF IN A STERILE CONTAINER • DIVIDED INTO THREE PARTS 1. STAINING— gram staining, AFB 2. CULTURE- selective medium 3. OTHER REACTIONS & TESTS
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Laboratory methods of diagnosis
* CSF Gram staining * CSF biochemistry -(protein, glucose, chlore) and culture which may take 24 to 48 hours, * Latex agglutination test detects antigens of common pathogens (H. influenzae type b, S. pneumoniae, N. meningitidis, E. coli K1 and group B Streptococcus) results are available within 20 – 30 minutes, but the sensitivity ranges from 50 to 90% and specificity can be variable.
* Blood culture is of great help.
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Are CSF cytokine/chemokines concentrations useful in the differential diagnosis of meningitis?
Higher in bacterial IL-1 TNF IL-8 (81% sens. 92% spec)
Higher in viral IP-10 Mig I-TAC MIP-1a
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ANTIBIOTIC RECOMMENDATIONS BASED ON GRAM STAINING
FINDING
GRAM POSITIVE COCCI
ANTIBIOTIC
VANCOMYCIN + BROAD SPECTRUM CEPHALOSPORIN
GRAM POSITIVE RODS
AMPICILLIN+/- AMINOGLYCOCIDE
GRAM NEGATIVE RODS
ANTIPEUDOMONAL CEPAHLOSPORIN + AMINOGLYCOSIDE BROAD SPECTRUM CEPHALOSPORINS
GRAM NEGATIVE DIPLOCOCCI
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Acute therapy for acute bacterial meningitis
Organism
Step. pneumoniae
Treatment
Vancomycin + 3rd cephalosporin
N.meningitidis
L.Monocytogenes Grp B streptococci H.Influenzae Enterobacteriaceae Pseudomonas aeruginosa
Ceftriaxone
Ampicillin + gentamicin Penicillin G Ceftriaxone 3rd cephalosporin + aminoglycoside Cephalosporin + aminoglycoside
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Empiric Rx for purulent meningitis
Predisposing Factor Age 18-50 years Age > 50 years Immunocompromised Basilar skull fx Head trauma/ neurosurgery CSF fluid shunt
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Antimicrobial Therapy Vanco + Ceftriaxone Ceftriaxone + Amp Vanco + Amp + Cefepime Vanco + Ceftriaxone Vanco + Cefepime Vanco + Cefepime
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Specific antibiotic treatment
N. meningitidis Antibiotic Penicillin Ceftriaxone Ampicillin Ceftriaxone Penicillin Ceftriaxone Vanco +Ceftriaxone + Rifampin Alternative Chloramphenicol Bactrim or Chloramphenicol Vanco Vanco Vanco and Rifampin
H. influenzae B lactamase neg
B lactamase pos S. pneumoniae PCN MIC2.0
Duration of antibiotic
Based on tradition more than scientific evidence Pneumococcal 10-14 days Meningococcal 7 days H influenza 7-10days Listeria 3 weeks
• • • •
Many of life's failures are men who did not realize how close they were to success when they CSF: • Microscopy & culture ofgave up.
Microscopy: cell types - Thomas PMN • acute bacterial meningitis—excess of Edison • Viral,Cryptococcal,TB meningitis-excess of lymphocytes. • India-ink for C neoformans –capsule • Gram stain , Ziehl-Neelsen stain-rapid provisional diagnosis • Culture difficult- antibiotics • Ag detection kits –before culture results. • Blood culture & CSF samples for isolation
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