CNS F10 Note Form

8/8/2019 CNS F10 Note Form

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CENTRAL NERVOUS SYSTEM INFECTIONSAteef A. Qureshi, PhD

Professor of MicrobiologyFall 2010

Ateef QureshiDepartment of MicrobiologySt. Georges UniversitySchool of MedicinePhone [email protected]

LEARNING OBJECTIVESAt the end of this series of lectures you should be able to;1. Understand the terminology and anatomy of CNS in relation to infectious disease2. Describe the routes of entry, reservoirs and predisposing factors associated with

various infectious agents3. Compare and contrast: meningitis; encephalitis, myelitis, meningoencephalitis, brain

abscesses and empyema on the basis of symptoms and microbes involved.4. Explain mechanisms of pathogenesis and virulence factors of the infectious agents of

CNS5. Discuss immediate symptoms and complications of viral and bacterial agents in the

CNS6. Identify a syndrome and probable causative agent on the basis of CSF profiles7. Understand the differences between normal infectious agents and the prions

REFERENCES

MMuurrrraayy,, RRoosseenntthhaall&& PPffaalllleerr((22000099)) MMeeddiiccaallMMiiccrroobbiioollooggyy,, 66tthh

EEddiittiioonnChapter 21, Staphylococci, p209-210Chapter 22, Streptococci, p233-242Chapter 25, Listeria, p255-258Chapter 29, Neisseria, p296-299Chpater 30, Enterobacteriaceae, p303, 313Chapter 34, Hemophilus, p343-348Chapter 42, Spirochetes, p405-419Chapter 51, Papovaviruses, p499-502Chapter 53, Human Herpes viruses, p517-539Chapter 56, Picornaviruses, p553-560Chapter 58, Paramyxoviruses, p571-579

Chapter 60, Rhabdoviruses, Filoviruses and Bornaviruses, p593-597Chapter 62, Togaviruses and Flaviviruses, p609-620Chapter 63, Arenaviruses and Bunyaviruses, p621-625Chapter 66, Prions, p661-665Chapter 68, Pathogenesis of Fungal Diseases, p679-682, 684, 686-688


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INTRODUCTION

Given proper opportunity and environment hundreds of microorganisms are capable ofinfecting the human Central Nervous System which includes bacteria, viruses, fungi,protozoa and parasites. Depending upon the actual site of CNS involvement, specificclinical pictures emerge which are described as Meningitis, Encephalitis, meningo-

encephalitis, myelitis, abscesses and empyema. These infections are among the mostserious as they may kill the patients quickly; however, those who survive will have a lifelong impairment of one kind or the other. These range from minor discomforts, physicaldisabilities and psychological problems to behavioral changes. Modern antimicrobialtherapies have reduced the serious outcomes but they still range from 8-10%, which isunacceptably high. Prompt diagnosis and medical help is essential to maximize thepositive outcome of these infections.

The brain and the spinal cord are suspended in the cerebrospinal fluid (CSF), which aresurrounded by three layers of meninges: Pia materand the arachnoid mater(Leptomeninges) and the dura mater(pachymeninges). These structures are providedfurther protection from injury and infection, by the skull and the vertebral column.

However, this leaves very little space for any inflammation or swelling to occur.Inflammation and swelling of the brain or the spinal cord can lead to dramatic changes inthe intracranial pressure resulting in serious damage or death.

The Blood-Brain Barrierincluding the endothelial cells lining the capillaries and arecemented together by intracellular tight junctions provide a barrier for microorganismsand toxic substances. It also impedes the passage of the antibodies and antibiotics intothe CSF resulting in poor prognosis.

It is the entry and replication of the infectious agents that results in many differentoutcomes of disease syndromes. We will be studying only the very common andprominent infectious agents and their role in the diseases of the CNS. For these lectures

we will focus the organisms that are not covered in detail at other areas of this course.The list of chapters and reading references are only for your convenience to find therelated information.

Why do we want to study the whole system instead of individual infectious agents?The Organ System approach in Medical Microbiology provides a framework andprospective for the clinical syndromes. To study each causative agent individually ismostly repetition and loses focus from the patient and his/her symptoms.There are three organ systems in the body which are closed systems (no directconnection to the outside environment)

1. Bone and Joints,2. Vascular system

3. Central Nervous System.

These systems are normally sterile and have no normal flora which resides there.Therefore, introduction of any organism into these body organ systems, is going to havea high morbidity and mortality.


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Central Nervous System (CNS) InfectionsThe CNS has the following special features which play an important role in the diseaseoutcome;

1. There is no direct communication with the external environment. It is protected bythe Blood Brain Barrier.

2. Pathogens reach CNS either by direct extension from a contiguous structure or

by hematogenous dissemination from a distant site.3. In order to institute appropriate empiric therapy, it is critical to know the normal

flora and most common pathogens associated with each of these distant sitesfrom where the infectious agent is coming.

Fenestrated

endothelium

B-CSF-B

Thin Basement

Membrane

B-B-B B-CSF-B

Blood Vessel

ICAM

Junctions

Thick

Basement

Membrane

Brain-CSF-B

Choroid plexus

epithelium

A.Qureshi, S10

Comparison of

Blood-Brain, Blood-CSF and Brain-CSF Barriers

*Low antibody, little/no phagocytes and complement

B-B-B

CSF*Brain

Gap Junctions

TerminologyBefore we embark upon any discussion of CNS infections we should familiarizeourselves with the proper terminology of the syndromes associated with these infections.

1. Meningitis- infection of the CNS coverings (meninges)2. Encephalitis- infection of brain parenchyma3. Myelitis- infection of spinal cord4. Meningoencephalomyelitis- infection of many areas of brain5. Abscess- localized pockets of infection in spinal cord or brain6. Empyema- epidural or sub epidural abscess

CNS SyndromesMeningitis

Meningitis is divided into two categories depending upon the length of the diseasesyndrome

Acute Meningitis- Describes the severity of symptoms, and is usually caused bya variety ofviral or bacterialagents which have a short life cycle. Bacterial


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meningitis is more severe and death usually follows within hours of developmentof symptoms. Viral meningitis is milder and death occurs rarely.

Chronic Meningitis- The severity of symptom here is not the issue because boththe fungi and tubercle bacillihave a long life cycle; therefore, control of theinfection is comparatively easier.

Encephalitis- Infection of brain parenchyma usually by a viralagent. Depending uponthe specific virus the outcome of the disease varies, ranging from a mild disease tosevere brain damage leading to paralysis and death.

Myelitis- Infection of the spinal cord by a variety ofviralagents. Here again the diseaseoutcome ranges from mild to severe depending upon the virus involved.

Abscesses (including Empyema)Abscesses are also divided into two categories according to the causative agentsgeneration time. Fast growing agents like bacteria cause acute abscesses and slowgrowing agents such as tubercle bacilli, fungi and protozoa cause chronic abscesses.

Acute Brain Abscess- generallypoly microbial

Chronic Brain Abscess- tubercle bacilli, fungi and protozoa

Entry, Replication and SpreadSince the CNS is supposed to be sterile the infections have to gain entrance through;Hematogenous (Blood)

Meningococcicomethrough respiratory epithelium into the meninges West Nile virus spreads through mosquito bites Rubella virus infects through Transplacental transmission

Neural Route

Rabies virus spreads through peripheral nerves to nerve axons to ganglia and

spinal cord and finally to brain Human Herpes viruses 1-3 travels through nerves

Direct inoculation through trauma or injury. Infectious agents many be introduceddue to any kind of trauma and injury resulting in compromising the blood-brain barrier.

Epidemiologic ConsiderationsFor a disease syndrome to occur there are many epidemiologic factors which may effectthe final out come of the disease.

1. Patient demographics- age, immune status2. Disease pattern- acute or chronic3. Exposure history- exposure, bites etc

4. Epidemiology- geographic location, season, outbreaks5. Etiology of infection- bacterial, viral, fungal or protozoanThis table is an example of such an effect.


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Encephalites of Viral Etiology

WinterChildren &ImmunocompromisedAllVaricella-ZosterVirus

SummerInfants & childrenAllEnteroviruses

Summer-FallOlder childrenMidwest & NE US;

S. Canada

California

Encephalitis Virus

Summer-FallInfants & Older adultsWestern US &

Canada

WEE Virus

Summer-FallChildrenAtlantic & Gulf

Coast and Great

Lakes

EEE Virus

Summer-FallOlder adultsAllWest Nile Virus

NoneAllAllHerpes Virus 1&2

Predominant

Season

Age GroupGeographic

Distribution

Virus

Modified from Table 61-3, page 593, Schaecters Mechanisms of Microbial Diseases, 4th. Edition,2007 A. Qureshi, S2010 Meningitis and Meningism

Meningitis; Infection of the membranes and fluid surrounding the brain and spinal cord(spinal meningitis) causing inflammation of the meningesMeningism; It is the Group of Symptoms and signs associated with the inflammation;

Headache Nuchal rigidity Nausea and vomiting Photophobia

Tests for MeningismDemonstrate inabilityto flex the neck and touch the chin to the chestDemonstrate inabilityto oppose the nose with the kneesTripod sign- inabilityto sit without making a tripod with handsKernigs sign- patients leg can not be straightened because of hamstring spasmBrudzinskisneck sign- patient retracts the legs when neck is lifted

Warning Signs of Meningism in ChildrenBulging fontanelleVomitingStrange high-pitched cry

ConvulsionsOpisthotonus

MeningitisIt is the inflammation of the meninges due to viral or bacterialinfections.

Aseptic

Over 50% of the cases are due to a variety of viruses


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All of the other cases are due to bacteria with special growth requirements or theyare slow growers.

Causes ofAsepticMeningitis

Mycobacterium tuberculosis

Leptospira sp*

Micoplasma pneumoniae

Mumps

HHV-5 (CMV)

HHV-6

HIV

Uncommon

Borrelia burgdorferi*

Inadequately treated bacterialmeningitis

Enteroviruses

Arboviruses*

HHV-2

Common

BacteriaViruses

* *Incidence varies with the region

Modified from :Neurol. Clin. 2008, 26:635

Septic

Caused by bacteria only Associated withhigh Mortalityand Severity Etiology isAGEdependent

Causes ofSepticMeningitis

L. monocytogenes

Other Gram negatives

(including P. aeroginosa)

Any age

(immunosuppressed)

Staphylococcus aureusAny age (cranialsurgery)

Neisseria meningitidis

L. monocytogenes

Other Gram negative

organisms

Streptococcus

pneumoniae

> 60 months


H. influenzae type b

Streptococcus

pneumoniae

3 to 60 months

Escherichia coli

L. monocytogenes

Streptococcus agalactiaeBirth to 3 months

OthersMost commonAGE


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Symptoms associated with MeningitisDepend upon age, microorganism and the route to meningesEarly symptoms (nonspecific)

Fever*MalaiseAches and pains

NauseaVomitingHeadache*

More specific to meningitisPhotophobiaNuchal rigidity*DrowsinessConvulsions, fitsInconsolable crying (infants/toddlers)

* HALLMARKS of Meningitis

EncephalitisDefined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms

HeadacheFeverAltered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures

EtiologyViral

Herpes viruses, enteroviruses, arboviruses, rabies virus, HIV, HTLV-1,

Paramyxoviruses (mumps, rubeola virus and arenaviruses)Bacterial (RARE)

Exceptions:Legionella pneumoniae, Borrelia burgdorferi, Treponema pallidumFungal

Cryptococcus neoformansParasitic

Plasmodium falciparum, Trypanosomes

MyelitisAcute inflammation of the spinal cordDepending upon virus, this can lead to flaccid paralysisSymptoms

HeadacheFeverIrritation followed by

Weakness of one or more extremitiesEtiology

Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000


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Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properly

Abscess- Fixed boundariesEmpyema - Lack of definable shape or size

SymptomsUsually are rapid and associated with their location

HeadacheChanges in mental status- drowsiness to comaGeneralized seizure

Fungal brain abscessDisseminated hematogenously from remote site usually from the lungs or oropharynxand create multiple areas of infection within brain. Meningoencephalitis occurs earlyby vascular invasion

EtiologyAspergillus, Cryptococcus and Candida spp. are usually involved.

Entry into CNSEntry is most likely through Choroid plexus as it is highly vascularized, inflammation may

increase entry into CNS. Again, remember the modes of entry;Direct extension

Infections of teeth, middle ear or mastoids or sinuses may spread into the system.Etiology (Most common)

Aerobic and anaerobic streptococci,BacteroidesEnterobacteriaceaePsudomadsFusibacterium

Peptococcus

Hematogenous (important for abscesses)Etiology depends upon location of the source of infection

Mouth- mixed floraLungs- Streptococci, Fusibaterium, Corynebacterium, and Peptococcus sp.Heart- Strep. viridans, Staph. aureusUrinary tract- Enterobacteriaceae, PseudomonasWounds- Staph. aureus

Penetrating head trauma and surgeryEtiology

Most common- Staph. aureus Immunodeficient patients and/or HIV infections- Nocardia, Aspergillus, Candida


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Diagnosis of CNS infectionsCerebrospinal Fluid

Chemical and cellular analysisCulturePCR

Neuroimaging

Helpful in partial differentiation of viral encephalitisJapanese B virus: grey matter involvementNipah virus: multiple, small, white matter lesionsHuman herpes virus-1: hemorrhagesAbscesses and Empyema differentiation

Features of CSF

50-10040-80


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CSF findings

Glucose normal Protein- moderately high WBC count- increased, predominantly lymphocytes

Gram stain- NO BACTERIA

From this point on, each virus family or individual virus will be discussed. Pleasemake a special note of the virus family and the individual virus.

Picornaviridea

EnterovirusesEnteroviruses belong to family Picornaviridea. They are naked, small (25-30 nm),

icoshedral viruses resistant to pH 3-9, detergents and heat. They contain single-stranded positive polarity RNA (Transfecting viruses) belonging to BaltimoreClass Iva. As is common to all RNA containing viruses, RNA replication is in thecytoplasm. Most viruses are Cytolytic.

Over 63 serotypes involved in meningitis.

More than 90% ofmeningitis cases are due to Enteroviruses. In addition to meningitis,Othersyndromes caused by this family of virus may include;

Hand-foot and mouth disease Herpangina Myocarditis Pleurodynia Acute hemorrhagic conjunctivitis

These clinical syndromes are determined by;

Virus class and serotype Tissue tropism Infectious dose Portal of entry Patient: age, sex, Immune competence

Epidemiology

Worldwide distribution Humans are the only reservoir Asymptomatic infections are common Show seasonality;

In Temperate climates- summer to Fall, wateris the main source of infection. In Tropical climates- year-roundinfections which are invariably fecal-oralin

nature. Infants and children are MOST susceptiblePlease refer to Murray et al (6th.Ed); Box 56-4 p 556

PoliovirusesPolio virus is a member of the family Picornaviridae and has only 3 serotypes and may

cause meningitis to myelitis. Because there are only three serotypes, use of oral


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vaccine against all 3 serotypes has successfully eradicated polio from the WesternHemisphere.

The virus possesses the same characters as that of Enteroviruses, spreads throughfecal-oral route by consuming contaminated food and water, or through direct contactwith infected stool or throat secretions.

Symptoms common as those of meningeal irritation, headache, fever, nuchal rigidity,followed by weakness in one or more extremities

Clinical syndrome:Acute Flaccid Paralysis, due to infection of anterior horn of grey matter

PathogenesisThe virus infects enterocytes of the GI tract, transverses intestinal wall throughbasement membrane and then moves into gut-associated lymphoid tissue, e.g.Peyers patches (site of primary replication). The resulting viremia seeds peripheraltissue, from there the virus enters into the neurons of the peripheral nervous systemthat innervates the peripheral tissues, and finally, the virus traffics to the CNS using

retrograde axonal transport (Lancaster and Pfeiffer, 2010).

Outcomes of infectiona. Unapparent infections

About 95% of infections are asymptomatic, the virus can be found in the RES.Diagnosis is by virus isolation from feces and oropharynx, and by specific serumantibodies.

b. Abortive polio is a minor illness with flu like symptoms which are similar to any othersystemic viral infection.

c. Polio encephalitis- RAREd. Non-paralytic polio (aseptic meningitis)

Similar to other enteroviral meningitis

e. Paralytic polio (


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Viral Encephalitis

Arboviruses

Arthropod-borne viral infections are transmitted by mosquitoes and ticks and distributedworldwide. These viruses are the most common cause of sporadic and epidemic viralencephalitis. Seizures are generally the complications in children.All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a

transfectingRNA. There are two major families of arboviruses involved;Togaviridae

Belongs to Baltimore Class IVbEarly and late proteins are madeVirus buds at the plasma membrane

FlaviviridaeBelongs to Baltimore class IVaA Polyprotein is translated first which cleaves into many individual active proteins

Virus buds into the cytoplasmic vesicles from where the virus is released throughthe process of exocytosis.

Togaviridae (Alphavirus)

Venezuelan Equine Encephalitis (VEE)Epidemiology

The virus spreads through Culex and Aedes species of mosquitoes.Symptoms

During the prodromal period- fever, chills, weakness, headache, myalgia (due to viralreplication) are the major symptoms.The symptoms progress rapidly to nuchal rigidity, confusion, somnolence, seizure in

50% of cases and coma (due to spread through microvascular permeability of brain,from there it progresses through cell-to-cell which occurs via axon and dendritites)

NO DEATHS in humans, 80% mortality in horses

Eastern Equine Encephalitis (EEE)Epidemiology

The virus is common in North America and spreads throughAedes and Culiseta sppof mosquitoes.Aedes spp. may spread the virus from horse to human which is thedead-end host.

Clinical symptoms are similar to that of VEE. The disease has a HIGH MORTALITYin humans.

Western Equine Encephalitis (WEE)Epidemiology

The virus spreads through Culex and Culiseta spp of mosquitoes. It is common inrural areas of US in the summer months. Fatality rate ranges about 3-4%, deathusually occurs in 1-2 days. Children have a 30% chance of CNS sequelae.

Pathophysiology of Equine EncephalitidesIt is characterized as defuse CNS infection. Neutrophils and macrophages infiltrate brain

parenchyma causing focal necrosis and spotty demyelination. Vascular inflammation


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with endothelial proliferation and small vessel thrombosis may also occur.Pathogenesis for EEE and WEE differs which is as described below;

EEE: Large number ofactive virus entering in brain parenchyma effecting theperikaryon and dendrites of neurons with minimal glial cell infiltration.

WEE: Damage mediated by large number ofimmunologically active cells that enterbrain. Cell death is by apoptosis primarily in the glial and inflammatory cells.

FlaviviridaeSt. Louis Encephalitis virus (SLE)Epidemiology

The virus is transmitted by culexmosquitoes. Overt infection depends upon at leastthree important factors such as; efficiency of replication of the virus at extra neuralsites, the degree of viremia in the host and the age of the host.

PathophysiologyVirus enters into the brain through BBB (astrocyte complex) or crosses fenestrated

endothelium in the choroid plexus.Symptoms

Mortality (2-20%) is higher in the elderly. Generally a mild disease with malaiseand fever. Only 20% develop CNS sequelae consisting of irritability, memory loss,movement disorders, and motor deficits. Seizures and coma are COMMON for thosewho develop the sequelae and the disease never develops into a chronic illness.

Japanese B Encephalitis virus (JBE)Epidemiology

This virus is also spread through Culexmosquitoes. Incubation period ranges from 4-14 days and the disease is common in the rural areas of Asia.

Symptoms

During the prodromal period the symptoms are almost the same as that of SLE;however, fever starts by the 2nd week of disease. Encephalitis syndrome remainswith tremors only and NOT seizures are observed. Patients with low CSF IgG/IgMratio do tend to have a higher death rate.

West Nile Encephalitis virus (WNV)Epidemiology

Wild birds are the reservoir of the virus and spreads throughAedes mosquitoes.About 3-15% of the cases are fatal. Person to person transmission is very RARE.

SymptomsViral prodrome is characterized with a maculopapular rash on trunk and extremities

with headache, HIGH fever, nuchal rigidity, stupor, tremor and seizures and

paralysis.


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BunyaviridaeAt leas 200 different viruses which infect humans are included in this family.Bunyaviridae are enveloped viruses containing single-stranded negative polarity,segmented(3) RNA. These viruses spread through mosquitoes, ticks and flies. Two ofthe virus species are important for North America which are;

California Encephalitis virus La Crosse virus

RhabdoviridaeLyssavirus: Rabies virusThe virus is Bullet shaped makes identification easy under the electron microscope. Itcontains a Single-stranded, negative polarity RNA enclosed in a Helical nucleocapsidcovered by an envelope. The virus codes for 5 proteins- N, P, M, G and L. Protein G isvery important for virus attachment. Surface glycoprotein (G) attaches to cell receptorsincluding Acetylcholine receptor at neuromuscular junctions. The virus enters into thecell via endocytosis. Virus has a preference for nerve and salivary gland cells (travelsvia axons to CNS). It spreads from brain to salivary glands, kidneys and conjunctival

cells. Virus is detected in tears.EpidemiologyThere are estimated 35000-50,000 cases reported worldwide with highest numberreported in Asia (~90% cases). It is characteristically Endozoonotic: meaning that allwarm blooded animals are susceptible. The animals are divided into two types; in theUrban areas the dogs and cats are important and in the rural and jungle areas ( Sylvatic)the wildlife including fox, squirrels, coyotes, skunks and mongoose are susceptible.SymptomsIncubation period ranges from 20-90 days, may extend to a year depending upon thedistance from the brain and the degree of tissue damage. The disease is divided intothree distinct categories;

Nonspecific general malaise, fever, headache (tingling pain and weakness at the

bit site) Progressive- neurologic symptoms including insomnia, confusion, slight or partialparalysis, agitation, hyper salivation, dysphagia (hydrophobia)

Paralyticdisorientation, stupor Death within days after symptoms (~7 days)

DiagnosisSaliva- virus isolation, RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies, Babes nodules consisting of glial cells

TreatmentPrevention

Wash all wounds with soap and water

1 dose of immune globulin and 4 doses of vaccine on days; 0, 3, 7 &14, days + 2boosters on days 0 and 3*

* New recommendations by CDC published on Mar 18, 2010


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Rabies postexposure prophylaxis (PEP) schedule - US, 2010(MMWR Vol.59/RR2; Mar 18, 2010)

Not previously vaccinated

Human diploid cell vaccine (HDCV) or purified chick

embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid but

neverin the gluteal region), 1 each on days 0, 3, 7 and

14.

(For immunocompromised; 5 shots)

Vaccine

Administer 20 IU/kg body weight. If anatomically

feasible, the full dose should be infiltrated around and

into the wound(s), and any remaining volume should

be administered at an anatomical site (intramuscular

[IM]) distant from vaccine administration.

Human rabies

immune globulin

(HRIG)

All PEP should begin with immediate thorough

cleansing of all wounds with soap and water. If

available, a virucidal agent (e.g., povidine-iodine

solution) should be used to irrigate the wounds.

Wound cleansing

Regimen*

(for ALL age groups including children)

Intervention

Rabies postexposure prophylaxis (PEP) schedule - US, 2010(MMWR Vol.59/RR2; Mar 18, 2010)

Previously vaccinated

HDCV or PCECV 1.0 mL, IM (deltoid but neverin the

gluteal area), 1 each on days 0 and 3.

For persons with immunosuppression, rabies PEP

should be administered using all 5 doses of vaccine on

days 0, 3, 7, 14, and 28.

Vaccine

HRIG should not be administered.HRIG

All PEP should begin with immediate thorough

cleansing of all wounds with soap and water. Ifavailable, a virucidal agent such as povidine-iodine

solution should be used to irrigate the wounds.

Wound cleansing

Regimen*

(for ALL age groups including children)

Intervention


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Other virus infections of the CNSArenaviridae- Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae- Human Herpes virus 1-8Retroviridae- HIV-1Papovaviridae- Polyoma virus (JC virus)-PML (Progressive Multifocal

Leukoencephalopathy)Viral DNA is detected in majority of healthy humans.Multifocal signs include; hemiparesis, visual loss, seizures, dementia, personalitychanges and gait problems. Characteristic white matter lesions are commonly detectedin posterior occipital area of the brain.Paramyxoviridae- Mumps virus and Rubeola virus are in this family. SubacuteSclerosing Pan Encephalitis (SSPE) is a complication of Rubeola virus infection.

It is a slow fatal condition after more than 10 years of measles. Reported Worldwide,generally the disease is more common in boys (3:1) than girls. First signs includeBehavior changes in school age children. Death occurs in 10% of cases in 3 monthsduring the Fulminantcourse and in 4-10 years during the chroniccourse.

Bacterial Infections of CNSThere are over 25 bacterial infectious agents are involved in serious life threatening

infections requiring prompt diagnosis and treatment. Except for the Mycobacteriumspp, all of the bacterial infections of the meninges, cause Septic meningitis (Bacterialmeningitis). Only the very common bacteria involved in Meningitis will be discussedhere. This is by no means the COMPLETE list of bacterial meningitis.

Bacterial invasion into CNSThe invasion may take place either from a nearby site such as Middle ear or chronicsinusitis or spreads from a distant site which may be a hematogenous invasion or fromdirectintroduction which may be RARE, sometimes the source can not be identified.

Bacterial Meningitis(Reported by Dr. Jungkind)

Neonates- Strep agalactiae, Coliforms and Listeria monocytogenes Infants- Streptococcus pneumoniae,Neisseria meningitidis and H. influenzae Children- Strep pneumoniae, N. meningitidis and Listeria monocytogenes Streptococcus pneumoniae is most common except in the neonates >75% of infections are caused by N. meningitidis, Strep. pneumoniae and H.

influenzae


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Causes ofSepticMeningitis

L. monocytogenes

Other Gram negatives

(including P. aeroginosa)

Any age

(immunosuppressed)

Staphylococcus aureusAny age (cranial

surgery)


L. monocytogenes

Other Gram negative

organisms

Streptococcus

pneumoniae

> 60 months


H. influenzae type b

Streptococcus

pneumoniae

3 to 60 months

Escherichia coliL. monocytogenes

Streptococcus agalactiaeBirth to 3 months

OthersMost commonAGE

(Modified from: Table 61-2, page 592, Schaechters Mechanisms of Microbial Disease, 4

thEdition)

Bacterial Virulence FactorsNeisseria meningitidis

Capsule, IgA protease, pili, endotoxinHaemophilus influenzae

Capsule, IgA protease, pili, endotoxinStreptococcus pneumoniae

Capsule, IgA protease only


Coffee bean-shaped intracellular (PMNs) Gram negative bacteria which are exclusivelyhuman pathogens. Many members of the genus are commensals of upper respiratorytract. About 30% of the population may transiently carry N. meningitidis. It is responsiblefor more than 75% cases ofseptic meningitis. Transmission is via droplet inhalationand more than 1/3 of the cases occur in the first five years of age. High rates ofmorbidity and mortality, ~50% survivors have neurologic or other sequelae.

Diagnosis

Clinical signs include rash, sepsis, fever and nuchal rigidity.CSFtap is the most important sample to checkprotein, glucose and WBC countCulture- fastidious organism requires 5-10% CO2; therefore, samples for culturemust be sent in slight anaerobic conditions;

Blood or CSF samples are plated on chocolate agar.Nasopharyngeal swabs are plated on to Modified Martin-Thayer agar, whichcontains antibiotics to inhibit normal flora of the nasopharyngeal region.


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EnterobacteriaceaeEscherichia coli K1These are Gram negative, lactose fermentingfacultative anaerobes. During pregnancythere is an increased vaginal colonization of K1 strain ofE.coliwith an approximately 8%mortality. The bacteria spread from nasopharynx to the meninges.Symptoms


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SymptomsDegenerative changes in CNS result in mental changes. Patients may develop frankpsychosis and/or a shuffling gait tabes dorsalis

DiagnosisSpinal fluid may be helpful by observing elevated WBCs and protein.VDRL positive.

Leptospira interogansAnimals are reservoirs. The bacteria spread through animal urine contaminatedwater and food (the bacteria can survive for weeks in water). No body of water in theUS is free from it (approximately 100 cases/year are reported in US). Bacteria areSensitive to Acid pH, drying and soap.Sewer workers, miners, veterinarians and meat packers are at risk.

SymptomsIncubation is from 7-13 days (range 5 days - 4 weeks)Bacteremic phase-influenza like symptoms and fever (bacteria NOW enter theCNS)2ndPhase- ~3+weeks

Headache with aseptic meningitisSometimes hemodynamic collapse is also observed.

DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages

Borrelia burgdorferiThese are large spirochetes- 0.2x10-30 m carried by ticks. Nearly 15% of thepatients show neurologic abnormalities. The disease is rarely fatal.

SymptomsClassic bulls eye rash, fever, joint pain, meningeal irritation

2nd

Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis

DiagnosisLoose irregular spirals, Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA

Fungal Infections of CNS

Disseminate hematogenously from a remote site of infection usually in the oropharynx orlung. Create multiple areas (cause abscesses ) of infection within brain and other organsMeningoencephalitis occurs early by vascular invasion of the fungus.

Secondary thrombosis, cerebral infarction and hemorrhages may also b e observed.Common fungi

Candida albicans Cryptococcus neoformans Histoplasma capsulatum Aspergillus fumigatus


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DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction. Yeast forms seen with silver stainCryptococcus-fungi appear like encapsulated spheres. Capsules can be seen bymucicarmine stain

Histoplasma- CT scanAspergillus- branching hyphae; classical appearance

Please revisit your notes on Respiratory fungal infections by Dr. Lennon

Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70% alcohol,X-rays and UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestPrion can be inherited in about 15% of cases.

PathogenesisNormal PrPc- glycoprotein with secondary structures dominated byAlpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleatsWhen PrPSc molecules comes in contact with the normal PrPc molecule, the normalPrPc changes into the abnormal PrPSc

Modified protein aggregates in neurons as myeloid plaquesSpongy appearance of cerebrum is due to the formation of vacuoles in the cortexand cerebellum

Spread of PrionsSporadic- no apparent causeInherited- through autosomal dominant traitIngestion- infected food, cannibalism

Kuru- incubation period is about 20 years. Symptoms include progressive trunchalshaking and unsteady gait. Death occurs within 3-24 months. Medical events- can alsospread the disease (Iatrogenic) through surgery, organs etc

Creutzfeld Jekob Disease (CJD)Most common prion human disease with a peak incidence at 55-65 years, but can affectteenagers also.No treatmentSymptomsSymptoms include insidious mental deterioration with early cerebellar and visualproblems followed by severe dementia within 6 months involving brain and lower motorneurons.Cases of CJD have been due to;Use of infected corneal transplants,


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Using nonsterilized surgical equipment.Pituitary hormone injections derived from cadavers.Accidental cuts suffered during autopsies or surgeries.

Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient

death. It is normally a bovine infection but crossed to humans as Mad Cow Disease.DiagnosisBiopsy of Brain to look for Spongiform encephalopathy and accumulation of abnormallyfolded protein.It is a sporadic disease.CSF- no cells are found in the CSF.

This was by no means a complete inventory of infectious agents involvedThere are many more; however, we discussed ONLY the very common andfrequent infections.

Documents

CNS F10 Note Form