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INFECTIONS OF THE INFECTIONS OF THE CENTRAL NERVOUS CENTRAL NERVOUS

SYSTEMSYSTEM

Maciej Przybylski Dept. of Medical MicrobiologyMedical University of Warsaw

Pathways of CNS infections

• Haematogenous spread• Spread of pathogens from adjacent tissues

• Traumas (skull fracture)

• Cranial surgery or invasive procedures (implacement of shunts)

• Congenital anatomical defects

• Neural (axonal transport)

• Olfactory route

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Risk factors for CNS infections• Infections

– bacteremia– endocarditis– recurrent or chronic infections of paranasal sinuses– otitis media– infections of mastoid process– stomatological infections– respiratory tract infections

• Trauma– cranial bones fractures– craniotomy

• Abnormalities in CSF circulation– anatomical or aquired defects of ventricular system– shunts implacement– liquorrhea

• Congenital anomalies of the nervous system• Immunosuppression• Splenectomy• Animal bites

– arthropods– rabid mammals

• Vaccinations with atenuated vaccines (poliomyelitis, varicella-zoster)

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Pathways of spread to the central nervous system

• hematogenous– H. influenzae– S. pneumoniae– N. meningitidis– L. monocytogenes– Mycobacterium tuberculosis

complex– enteroviruses– VZV– LCM (arenavirus)– paramyxoviruses

• mumps• measles

– fungi (cryptococcus, coccidoides, candida)

– rickettsiae

• neural– rabies virus

– HSV-1, HSV-2, VZV• olfactory

– HSV-1, HSV-2, VZV– simian herpesvirus (B virus)

• direct– Staphylococcus aureus

(craniotomy, skull fracture, from adjacent tissues, via surgical shunt)

– Staphylococcus epidermidis (surgical shunt)

– Listeria monocytogenes (traumas, surgeries in immunodeficient patients)

– Enterobacteriaceae (trauma, direct spread from tissues)

Immune system

•antibodiesin the normal CNS - derived from the serum

•levels ofIgG and IgA - 0.2 to 0.4 %of the serum levels

•trauma or inflammation disrupts the blood-brain barrier -

antibodies leak into the CNS with other serum proteins

•B cells generate immunoglobulins locally (IgM! )

•polymorphonuclear cells are the dominant inflammatory

cells in acutebacterial infections of the CNS

•mononuclearcells are the dominant inflammatory cells in

viral infections and in subacute or chronic infections

(tuberculosis and fungal infections)

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CNS infections• Meningitis -bacterial, viraland (rare) fungal

– acute, subacute, chronic

• Encephalitis -viral, bacterial, fungal– acute, chronic, postinfectious (late), after vaccinations

– worldwide or endemic

– endogenous, exogenous, vector-borne

• Brain abscess -bacterialand (rare) fungal– localization

• Other: meningoencephalitis, leukoencephalopathies

Meningitisan inflammation of the pia-arachnoid meninges

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Etiology of bacterial meningitis

• Streptococcus pneumoniae• Neisseria menigitidis• Haemophilus influenzae• E. coli• K. pneumoniae• S. agalactiae• S. pyogenes• Pseudomonas spp.• Proteus spp.• S. aureus• S. epidermidis• Listeria monocytogenes

Newborns:• E. coli capsular type K1• S. agalactiae• other Enterobacteriaceae• Listeria monocytogenes

„Aseptic” bacterial meningitis:• Mycobacterium tuberculosis• Leptospira spp.• Brucella spp.• Borrelia burgdorferi sensu lato

Big Bacterial Three

• Streptococcus pneumoniae

• Neisseria meningitidis

• Haemophilus influenzae capsular type b

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Streptococcus pneumoniae

Indian ink (capsule) stain

Gram-stained slide from culture

Gram stained smear of CSF deposit

Cell appearance (TEM)

Gram stain from culture plate

Neisseria menigitidis

Purpuric rash

Gram stained smear of CSF deposit

Diplococcal appearance (SEM)

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Haemophilus influenzae

Gram-stained slide from culture

Gram stained smear of CSF deposit

Cell appearance (SEM) Satellite growth on blood agar plate

Bacterial meningitis

• Bacterial meningitis develops quickly (12-24 hrs)

• causative agent is hard to assess on the basis of clinical symptoms

• can cause brain damage or death

• endogenous or contagious

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Clinical manifestations

Meningitis

• headache, fever, neckstiffness

• Brudzinski’s sign

• Kernig’s sign

• reduced consciousness

• Accompanying signs:

• seizures (small children)

• cranial nerve palsies

• hydrocephalus

• vasculitis

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Meningitis: laboratory diagnosis(CSF andblood)

• CSF examination– CSF parameters: cytosis (lymphocytes/polymorphonuclears), glucose,

sodium, lactate and protein level– Direct Gram-stained slide (CSF deposit)– Cultures of bacteria/fungi from CSF– Detection of bacterial/fungal antigens (H. influenzae, S. pneumoniae, N.

meningitidis, C. neoformans)– Detection of viruses: molecular methods (nucleic acid amplification) or

culture in cell line (rarely)

• Blood examination– Blood culture– Detection of bacterial/fungal antigens– Detection of viral nucleic acids

• Urine examination– Detection of bacterial/fungal antigens (only newborns)

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Complications of meningitis

• communicating hydrocephalus

• loculated CSF collections

• subdural effusion/empyema

• cerebral infarction

• cerebral abscess

• dural sinus trombophlebitis

Treatment - ASAP

•bacterial and fungal meningitis

appropriate antimicrobial agents

supportive care

•viral meningitis

symptomatic treatment

or antiviral agents if possible

Meningitis

•the prime managementproblem is to identify bacterial illness and rule out acute viral meningitis

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Bacterial meningitis - prophylaxis

• Vaccines against– Streptococcus pneumoniae

(polysaccharide or conjugated),– Neisseria meningitidis A&C (or A,

C, W-135, Y, B)– Haemophilus influenzae type b

• Identification ofN. meningitidiscarriage in small children carepersonnel and pediatric medicalpersonnel

• eradication ofN. meningitidiscarriage

Viral meningitis• Human enterovirus A-D (echoviruses, Coxsackie viruses);

Picornaviridae• Tick-borne encephalitis virus; Flaviviridae• Herpes simplex virus 1 and 2 (Herpesviridae)• Varicella-Zoster virus (Herpesviridae)

• Also:– lymphocytic choriomengitidis virus (LCM); Arenaviridae– paramyxoviruses (mumps virus, measles virus)– flaviviruses (West-Nile virus, Saint-Louis encephalitis virus,

Japanese encephalitis virus, Dengue virus)– Colorado tick fever virus (Reoviridae)– poliovirus, parechovirus (Picornaviridae)– togaviruses („alphaviruses”: Venezuelan, Eastern and Western

encephalitis viruses)

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Infection of the Brain Parenchyma

ABSCESSa focus of purulent infection

usually due to bacteria

Source of microrganisms:• contiguous focus of infection • hematogenousspread

AbscessEtiology

•streptococci and enterococci

•Staphylococcus aureus

•Enterobacteriaceae

•Haemophilus

•Bacteroides spp., Fusobacterium spp.

•fungi (uncommon)

•mixed infections of aerobic and

anaerobic bacteria

Bacteroides fragilis

S. aureus

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Sources/predisposing factors for cerebral abscess

• severe localised infection – septicemia –endocarditis

• sinus and mastoid infections

• immunocompromised patient

• diabetic patient

• congenital heart disease

• trauma, surgery

Abscess

Clinical manifestations

•headache, focal signs, seizures

•no fever

•CSF is usually sterile

•bacteriological diagnosis - by culturing an aspirate of the

abscess cavity

Treatment

• multiple antibiotics

• surgery (encapsulation - the abscess should be drained)

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Epidural abscesses•local pain, tenderness•focal signs

Spinal epidural abscesses•rapid course•segmental pain along nerve roots•paresis•irreversible paraplegia

Subdural abscesses (subdural empyema)•spread rapidly•septic thrombosis of bridging veins•hemiplegia and seizures

Spinal epidural, subdural and cerebral and abscesses aresurgical emergencies

Encephalitisinflammation of the brain

Etiology

mild forms of encephalitis

•enteroviruses, mumps, measles

•life-threatening viral encephalitis

•herpes simplex viruses and

arboviruses (TBE)

uniformly fatal infection

•rabies virus

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Endemic areas of TBE in Europe

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EncephalitisPathogenesisHerpes simplex viruses

•in neonates - HSV-2(newborn HSE)

•the acutegeneralizednecrotizing encephalitis is

accompanied by evidence of systemic infection of the

liver, adrenals and other organs, generalized rash is

often seen

•in children and adults - HSV-1 (usually localized)

•entry of a new virus, across the olfactory mucosa

•reactivation of latent virus in the trigeminal ganglia

•infection is usually localized in theorbital frontal and

medial temporal lobes

Encephalitis

Pathogenesis

Arboviruses (togaviruses, flaviviruses, and bunyaviruses)

•spread to the brain from the blood

•systemic infection is asymptomatic or is accompanied

with nonspecific symptoms

•between 1 in 20 and 1 in 1000 infections are complicated

by CNS infection

•the encephalitis isdiffuse, but is localized largely to

neurons

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Encephalitis

PathogenesisRabies•acquired through thebite of a rabid animal•axonal transport (from the inoculated skin or muscle to the corresponding dorsal root ganglion or anterior horn cells and then to populations of neurons throughout the CNS)•typical behavioral changes of clinical rabies

EncephalitisClinical manifestationsHerpes simplex virus-1

•focal temporal lobe signs

•headache, fever, hallucinations and bizarre behavior

•focal seizures, hemiparesis

•aphasia

Arbovirus infections

•a more diffuse and acute disease

•rapid depression of consciousness, greater frequency of

generalized seizures and multifocal signs

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Encephalitis

•cultures - usually negative•viral nucleic acids amplification (qPCR)

•EEG, computerized tomography, nuclear magneticresonance•brain biopsy: arbovirus infections•IgM - in serum•IgM in CSF (VZV meningitis)

Encephalitis

Treatment

herpes simplex virus encephalitis

•acyclovir

other forms of viral encephalitis

•supportive care

arboviral encephalitis

•prevented by vaccines

•reduced by mosquito control

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Viral infections of CNS

Slow and chronic infections of central nervous system: spirochetes

• Treponema pallidum• Borrelia burgdorferi sensu lato

(B. burgdorferi/afzelii/garinii)– Lyme disease (secondary/tertiary):

neuroborreliosis

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Spirochetes

•neurologic diseases over the lifetime of the untreated patient•secondary syphilis mild meningitis later complications

•acute meningovascular inflammatory disease leading tostroke (meningovascular syphilis)•progressive dementia (general paresis) •chronic arachnoiditis involving primarily the posterior roots of the spinal cord (tabes dorsalis)

Syphilis (Treponema pallidum)

Spirochetes

Lyme diseaseBorrelia burgdorferi sensu lato:

•Borrelia burgdorferi•Borrelia afzelii•Borrelia garinii

early neurologic involvement

•mild meningitis and facial palsy

late neurologic involvement(15 % of untreated patients)

•subacute or recurrent meningitis, encephalitis, cranial

nerve palsies and peripheral neuropathies

•chronic meningoencephalitis

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• HIV-1– encephalopathy– vacuolar myelopathy– neuropathy

• HTLV-1– tropical spastic paraparesis

• Measles virus– subacute sclerosing panencephalitis (SSPE)

• JC poliomavirus– progressive multifocal leukoencephalopathy (PML)

• Rubella virus– congenital encephalitis, panenecephalitis

Slow and chronic infections of central nervous system (viruses)

Retroviruses

HIV •infects the CNS soon after systemic infection in most

patients

•acute meningitis

•acute demyelinating polyneuritis

•dementia, myelopathy and a painful sensory neuropathy

HTLV-I (human T-cell lymphotropic virus type 1) •slowly progressive myelopathy (tropical spastic paraparesis

or HTLV-associated myelopathy)

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In chronic spirochetaland retroviral infections theCSFhas amild mononuclear cell inflammatory response,mild elevation of protein levels, and elevated IgGin an oligoclonal pattern

• Kuru agent• Creutzfeldt-Jakob disease (CJD)• new variant of CJD (vCJD)• Gerstmann–Sträussler–Scheinker syndrome• Sporadic fatal insomnia• Familial fatal insomnia – inherited prion disease

• presenile dementiawith histopathologic abnormalities limited to the CNS

• the brain shows vacuolization of neurons and glia, but no inflammatory response

• rapidly progressive cognitive deficits with myoclonic movements

Slow and chronic infections of central nervous system (prions)

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Spongiform encephalopathy

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