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5. HDS Neuro Psych > CNS Infections > Flashcards

CNS Infections Flashcards

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1
Q

CNS

Routes of Entry

A
  • Hematogenous (most common)
    • Invade across capillary endothelial cells
    • Arterial circulation
    • Retrograde venous spread via anastomoses with veins of the face
  • Choroid plexus
  • Direct implantation
    • Trauma
    • Congenital malformation (meningomyelocele)
  • Local extension
    • Sinuses, teeth, vertebrae
  • Peripheral nervous system
    • Spread along olfactory tracts, nerve ganglia
    • Viruses = Herpes, rabies
  • Infected leukocytes
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2
Q

Meningitis

Definition

A

Inflammatory process of the leptomeninges and CSF within the subarachnoid space, usually caused by an infection.

Types:

  • Acute pyogenic - usually bacterial
  • Aseptic - usually acute or subacute viral
  • Chronic - usually tuberculous, spirochetal, or cryptococcal
  • Chemical – due to an irritant within the subarachnoid space
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3
Q

Meningitis

Acute vs Chronic

A
  • Acute
    • Onset hours to days
    • Can be caused by bacterial or viruses
      • Ex. Neisseria, Haemophilus
  • Chronic
    • Onset over weeks
    • Usually caused by fungi, Mycobacterium
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4
Q

Aseptic Meningitis

A

Clinical term: absence of organisms by bacterial culture in a pt with manifestations of meningitis.

  • Caused by viruses, fungi, unusual bacteria (Leptospira)
    • Usually viral etiology
      • 80% of cases due to enteroviruses (Echo-, coxsackie-, polio-virus)
    • May be bacterial, rickettsial, or autoimmune in origin
  • CSF characteristics:
    • Low numbers of WBCs, mostly lymphocytes
    • ↑ Proteins
    • Normal glucose
    • Usually do not see organisms in CSF
  • If viral ⇒ usually self-limiting
    • Treat symptomatically
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5
Q

Septic Meningitis

A

“Pyogenic Meningitis”

  • Associated with bacterial infection
  • Purulent exudate in the subarachnoid space
  • May be acute (i.e. Neisseria, Haemophilus) or chronic (i.e. Mycobacterium)
  • CSF characteristics:
    • High numbers of WBCs, mostly neutrophils
    • ↑ Protein
    • ↓ Glucose
    • Organisms in CSF
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6
Q

CSF Characteristics

Comparison

A
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7
Q

Viral Mengingitis

Characteristics

A
  • Often perivascular lymphocytic cuffing
  • Microglial nodules around virally infected cells
  • Neuronophagia ⇒ microglial ingestion of infected neurons
  • Necrosis ⇒ severe viral infections
  • CSF:
    • Cells: Monocytic, moderate increased
    • Protein: Moderately increased
    • Glucose: Normal
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8
Q

Viral Menigitis

Clinical Manifestations

A
  • Fever
  • Headache
  • Stiff neck
  • N/V
  • Photphobia
  • Somnolence
  • Rash
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9
Q

Picorna Viruses

Overview

A

Family of RNA viruses which include:

  • Enteroviruses (family) ⇒ meningitis, polio, heart infections
    • Poliovirus types 1,2,3
    • Coxsackie virus A and B
    • Echovirus (Enteric cytopathic human orphan virus), types 1-34
    • Enterovirus (species), types 68-71
  • Rhinoviruses ⇒ common cold
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10
Q

Picorna Viruses
General Characteristics

A

Small, naked ss-RNA viruses (Pico-RNA-virus), with ⊕ polarity

  • It does not carry an RNA dependent RNA polymerase
  • Virus genome serves as its own mRNA as well as the source of genetic information
  • Exhibits post-translational modification of its proteins by virus encoded proteolytic cleavages
  • Naked capsid structure ⇒ resistant to environment
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11
Q

Enteroviruses

Transmission I Epidemiology

A
  • Replication in respiratory and GI tract w/ shedding
    • Shedding occurs in absence of clinical illness
  • Predominantly by fecal-oral route
    • Hand to mouth
    • Contaminated bodies of water
    • Respiratory secretions can also transmit virus
  • No animal reservoirs
    • Flies can mechanically transmit viruses (sewage and food)
  • Seasonal incidence ⇒ mainly late summer, early fall
  • Most common in young children and adolescents
  • Poor sanitation and crowded living condition promote transmission
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12
Q

Enteroviruses

Pathogenesis

A
  • Incubation usu. 7-10 days
  • Initial replication in epithelial and lymphoid cells of the pharynx (respiratory tract)
  • Seeds Peyer’s patches in the intestine
  • Can be recovered from the feces for ~ 1-2 months post-infection
  • Migrate into regional lymph nodes → bloodstream (viremia)
  • Blood → secondary or tertiary target organ(s) ⇒ presentation of classical disease syndrome
  • Cytolytic infection ⇒ replication causes direct damage to cells
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13
Q

Enteroviruses
Diagnosis

A
  • Based on clinical signs and symptoms
  • Supported by CSF finding (aseptic meningitis)
  • PCR assay for enteroviruses has good sensitivity and specificity (95%)
    • May confirm dx within 24 hrs
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14
Q

Picornaviruses

Treatment

A
  • Supportive for immunocompetent
  • Pleconoril for infants and immunodeficient (enteroviruses only)
    • ⊗ Viral attachment to host receptors
    • ⊗ Uncoating of picornaviruses
    • Must be given early
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15
Q

Enteroviruses

Infection Severity

A

Based on:

  • Infecting dose
  • Viral serotype
    • Enterovirus 71 ⇒ polio-like syndrome
    • Enteriovirus D68 ⇒ recent outbreak, polio-like
  • Pts age
    • Coxsackie in infants under 1 mo
  • Health status
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16
Q

Poliovirus

Characteristics

A
  • Type of Picorna virus (naked ⊕-sense ssRNA)
  • 3 important serotypes (types 1, 2, 3)
    • All 3 included in trivalent vaccines
  • Causes a clinical spectrum of diseases
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17
Q

Polio

Epidemiology

A
  • Americas have been disease-free since 1994
  • Worldwide Incidence:
    • 350,000 in 1988
    • 1,604 in 2009
    • ~900 in 2010
  • Worldwide vaccination
  • Persists in: Tajikistan (458), Pakistan, DR Congo, Congo, India
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18
Q

Poliovirus

Clinical Syndromes

A
  • Asymptomatic infection (90%)
    • Limited to gut, oropharynx
  • Abortive poliomyelitis (5%)
    • Flu-like symptoms, vomiting
  • Non-paralytic Polio (1-2%)
    • Aseptic meningitis
  • Paralytic Polio (0.1 to 2%)
    • Type 1 responsible for 85% of paralytic disease
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19
Q

Paralytic Polio

A
  • Infects upper and lower motor neurons
    • Become chromatolytic and eventually die ⇒ neuronophagia
    • Lymphocytic infiltration of the meninges and perivascular cuffing
    • Microglial nodules around affected cells
  • Paralysis caused by destruction of cells in spinal cord (anterior horn cells, etc.), brain stem, and motor cortex
  • Result in asymmetric flaccid paralysis with no sensory loss
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20
Q

Bulbar Polio

A

Paralysis affecting the pharynx, vocal cords and diaphragm

Results in death if ventilatory support is not provided

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21
Q

Post-polio Syndrome

A
  • Occurs 30-40 yrs after polio infection
  • 20-40% of original victims
  • Deterioation of muscles affected during initial infection
  • No virus present, no aberrant immune response
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22
Q

Poliovirus

Immune Response

A
  • Neutralizing serum IgG
    • Prevents viremia
    • Major role in blocking virus from entering CNS
  • Secretory IgA
    • Prevents infection in OP and GI tract
  • CMI plays a role in resolution
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23
Q

Poliovirus

Vaccine

A

Two effective polio vaccines available today:

  • Sabin vaccine (OPV) ⇒ live attenuated organisms
    • Was used in this country for many years but discontinued
    • Still used in other countries where polio is endemic
    • Lifelong immunity
    • Induces natural immunity (i.e. IgA)
    • Herd immunity
    • Oral admin
    • Risk to immunodeficient
    • Risk of viral reversion
  • Salk vaccine (IPV) ⇒ killed virus
    • Now used in the USA
    • Need boosters
    • IgG
    • Need high community immunization levels
    • IV admin
    • Safe
    • More expensive
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24
Q

Coxsackie Viruses

A

Common cause of aseptic meningitis

Two important groups:

  • Group A
    • Hand, foot and mouth disease
    • Herpangina ⇒ herpes-like vesicles in the buccal mucosa only
  • Group B
    • Aseptic meningitis
    • Also associated with myocardial and pericardial infections
    • Usually in older children and adults
    • Very severe in newborns
      • Febrile illness that progresses to heart failure
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25
Q

Hand, Foot, and Mouth (A16)

Disease

A
  • Most common in children under 5
  • Fever, ST, oral lesions that start as papules and become blisters
  • Palms and soles involved
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26
Q

Echovirus

A

Enteric Cytopathic Human Orphan Viruses

Types 1-34

  • Leading cause of viral meningitis
  • Typically associated with a petechial rash
  • Disease is usually self-limiting
  • Severity based on viral serotype, dose, pt status and age
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27
Q

Picornavirus

Summary

A
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28
Q

Encephalitis

A
  • Inflammation of the brain parenchyma with or without meningeal irritation
    • Meningoencephalitis: Inflammation of the meninges and brain parenchyma
      • Usually has a viral etiology
  • Characterized by headache, fever, muscle aches/weakness, confusion, seizures, paralysis, LOC
  • Agents: HSV-1 and 2, Arboviruses, Naegleria, Rabies virus, Measles, Rubella
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29
Q

Herpes Simplex Encephalitis

Overview

A
  • Severe, devastating encephalomyelitis
  • Disease occurs throughout the year and in persons of all age groups
    • 50% due to primary infection
    • 50% due to recurrent infection
  • Dx w/ PCR of viral DNA from CSF
  • Acyclovir reduces morbidity and mortality
  • Histology: 3 M’s
    • Multinucleation
    • Margination of chromatin to the periphery of the nucleus
    • Molding of the nuclei together
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30
Q

HSV Encephalitis

Children and Adults

A
  • HSV-1 in children and adults
  • Virus in trigeminal ganglion → temporal lobe via neurogenic pathways
  • Temporal lobe and base of the brain
  • Necrosis and hemorrhage
  • Antiviral agents may be helpful in acute therapy
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31
Q

HSV Encephalitis

Neonates

A
  • HSV-2 in neonates
  • Transmitted in birth canal of infected mother
    • C-section reduces risk
  • CNS and systemic disease ⇒ High morbidity and mortality
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32
Q

Amoebic CNS Infection

A
  • Rare in North America
  • Rapidly fatal necrotizing encephalitis with Naegleria species (most common)
  • Chronic granulomatous meningoencephalitis with Acanthamoeba
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33
Q

Naegleria fowleri
General Characteristics

A
  • Protozoan parasite
  • 3 developmental stages: cyst, flagellate and amoeboid (trophozoite) forms
  • Cyst form occurs under unfavorable conditions
  • Other forms are free living and thrive in warm freshwater
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34
Q

Naegleria fowleri

Lifecycle

A
  • 3 developmental stages: cyst, flagellate and amoeboid (trophozoite) forms
  • Flagellate and trophozoites are free living and thrive in warm freshwater
  • Only trophozoites are infectious
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35
Q

Naegleria fowleri
Transmission and Epidemiology

A
  • Lives in very warm freshwater lakes mostly in southern states, hot springs and thermally polluted waters (powerplant runoff)
  • Found in sediment & disturbed by water activity
  • CNS entry through nose → cribriform plate and emissary veins
  • Travels along the olfactory nerve to the brain
  • Infections occur during the summer months
  • 33 documented infections since 1996 with only 3 survivors
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36
Q

Naegleria fowleri
Clinical Manifestations

A
  • Early sx may include nasal congestion and loss of sense of smell
  • Symptoms of severe hemorrhagic, destructive meningo-panencephalitis occur 1 - 14 days after contact
    • Includes headache, fever, nausea, vomiting and stiff neck
    • Progress to seizures, loss of motor control and cognitive function
  • Infection is fulminant and progresses to death within 3-6 days
    • 95% mortality
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37
Q

Naegleria fowleri
Diagnosis

A
  • ID organisms in brain on autopsy
  • A few cases have been dx early by the ID of trophozoites in CSF
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38
Q

Naegleria fowleri
Treatment and Prevention

A
  • Treatment:
    • Only a few cases successfully treated with Amphotericin B
  • Prevention:
    • Adequate chlorination of swimming water
    • Avoid water related activities during period of high temp
    • Hold the nose shut during water related activities in high-risk areas
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39
Q

Cysticercosis

A
  • Caused by Taenia solium (pork tapeworm)
  • Common in developing world
  • Man is the intermediate host for T. solium
  • Transmission and Pathogenesis:
    • Fecal contamination of drinking water with eggs
    • Larvae hatch and penetrate gut
    • Disseminate in blood
    • Cysts (cysticerci) develop in any organ
    • Prefer brain, muscles, skin and heart
    • In CNS become small, gliotic foci
  • Usually not lethal, but often neurologically symptomatic and can cause ↑ ICP
  • Seizure is common presentation
  • Treatable with anti-helminthics
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40
Q

Leptospira

Morphology and General Characteristics

A
  • Gram ⊖, obligate aerobe spirochete
  • Long and thin with hooks at one or both ends
  • Has periplasmic flagella ⇒ highly motile
  • Classified on the basis of specific antigens into 150 different strains called serovars
  • Easiest spirochete to grow ⇒ cultured on serum enriched media
  • Leptospirosis is usually a mild infection in both man and other animals
  • Common in Hawaii
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41
Q

Leptospira

Transmission & Pathogenesis

A
  • Contact with water, food or soil contaminated with urine of infected animals
  • Entry usually via ingestion or abrasions
  • Blood → kidney → urinary excretion
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42
Q

Leptospirosis

Clinical Manifestations

A
  • Disease ranges from subclinical to mild flu-like symptoms, meningitis or severe systemic disease
    • Severity related to serovar of infecting strain
  • About 10% of individuals develop a highly fatal form known as Weil’s disease
    • Characterized by jaundice, liver and kidney failure, vasculitis and myocarditis
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43
Q

Leptospirosis

Diagnosis

A

Serology, by microscopic agglutination

Cultures of blood, spinal fluid and urine

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44
Q

Leptospirosis
Immunity / Prevention

A

Due to bactericidal antibody and is serovar specific

Avoid exposure to contaminated water/animals

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45
Q

Arboviruses

Overview

A

Arthropod-borne virus ⇒ any virus transmitted by arthropod vectors

  • Infects vertebrates and invertebrates
  • Transmitted via bite of infected arthropod (mosquito)
  • Initiate persistent productive infection in salivary glands of small mammals, birds, and/or arthropods
  • Humans are usually dead-end hosts
  • Spring, Summer, early Fall
  • Aseptic meningitis to severe encephalitis that can cause serious morbidity and high mortality
  • CSF:
    • Few lymphocytes
    • ↑ Protein
    • Normal glucose
  • Neuronal necrosis ⇒ neuronophagia
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46
Q

Arboviruses

Categories & Characteristics

A
  • Togaviruses (Alphaviruses): enveloped, ⊕-sense ssRNA
  • Flaviviruses: enveloped, ⊕-sense ssRNA, smaller than alphaviruses
  • Bunyaviruses: Enveloped, helical nucleocapsid, 3 segments of ⊖-sense ssRNA
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47
Q

Arboviruses

Transmission

A
  • Disease during summer months and rainy seasons
  • Viruses multiply in vertebrate and blood sucking insect hosts
    • Extrinsic incubation period ⇒ time needed for virus to multiply in arthropod and achieve a concentration sufficient to infect and cause disease in humans
    • Some insects maintain the virus in nature by transovarial transmission
  • Humans usu. dead-end host ⇒ insufficient viremia
    • Exceptions include urban yellow fever and dengue
      • Humans can serve as reservoirs
      • Longer persistence of virus in blood and/or sequestration in the organs (West Nile infections)
      • Implications for blood banking and organ transplantation
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48
Q

Arboviruses

Pathogenesis

A
  • Replicates in endothelial cells, monocytes, and MΦ
  • Good inducers of Type I Interferons
    • Flu-like sx initially
  • Spread to CNS via viremia
    • IgG may block
    • Delayed Ab response results in CNS disease
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49
Q

Arboviruses

Clinical Syndromes

A

Range of diseases:

  • Many infections are asymptomatic
  • Flu-like syndrome
    • Fever with myalgias, arthralgias, and non-hemorrhagic rash
  • Encephalitis
    • Fever, HA, AMS, seizures, coma
  • Hemorrhagic Fever ⇒ Dengue
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50
Q

Comparison of Selected Arboviruses

A
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51
Q

West Nile Virus

Overview

A
  • Flavivirus
  • Originated in Eastern Africa, Middle East
  • Reservoir: Wild birds
  • Vector: Mosquito
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52
Q

West Nile Virus

Clinical Disease

A
  • Asymptomatic (80%)
  • West Nile Fever (20%)
    • Flu-like syndrome
  • West Nile meningitis or encephalitis (0.5%)
    • Neuro-invasive
    • May include muscle weakness and/or paralysis
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53
Q

West Nile Virus

Epidemiology

A
  • First seen in US in 1999
  • Highest incidence in AZ, NY, TX
  • Outbreaks usu. preceded by infection in the bird population
  • Risk factors:
    • Immunocompromise
    • Age – very old or very young
    • Pregnancy
  • Median age
    • Symptomatic disease 47 y/o
    • Neuro-invasive disease > 75 y/o
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54
Q

West Nile Virus

Transmission

A
  • Mosquito bites
  • Transfusion and transplanted organ
    • Seen in early 2,000s
    • Red cross started screening blood in 2003
  • Intra-uterine / breastfeeding

Suggests longer viremia than other encephalitis viruses and/or sequestration in tissues of healthy individuals

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55
Q

West Nile Virus

Prevention

A
  • Spraying when mosquitos breed
  • Eliminating breeding sites (stagnant water)
  • Caution susceptible individuals to wear protective clothing or stay indoors during mosquito feeding times
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56
Q

Dengue Virus

Characteristics

A
  • Flavivirus family
    • Enveloped, ⊕-sense ssRNA, smaller than alphaviruses
    • Replicates in the cytoplasm
    • Genome serves as mRNA
    • Translation is the first step in replication
  • Reservoirs: monkeys and humans
  • Vector: urban mosquito (Aedes aegypti)
  • Four serotypes
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57
Q

Dengue Virus

Epidemiology

A
  • Tropical and subtropical areas
  • High density viremic population for transmission
    • May be asymptomatic
    • > 50% of world’s population at risk of infection
    • 50-100 million cases of dengue fever each year
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58
Q

Dengue Fever

A

“Breakbone fever”

1° infection w/ Dengue virus

  • Clinical manifestations:
    • High fever, chills, malaise
    • Headache, retro-orbital pain
    • Severe lumbosacral back and bone pain, myalgias
    • Rash is frequently present
  • Runs its course in 5-7 days
  • Usually resolves without complications
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59
Q

Dengue Virus

Primary Infection Pathogenesis

A
  • Replicates 1° in vascular endothelium and monocytes or MΦ
  • Induces release of large quantities of cytokines
  • Viremia ⇒ systemic spread ⇒ viral amplification
  • Neutralizing Ab ⇒ resolution of infection
  • Subsequent infection w/ different serotype can lead to Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS)
    • DSS or DHF may occur even if 1st dengue infection asymptomatic
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60
Q

Dengue Virus

Secondary Infection Pathogenesis

A
  • 1° infection w/ any serotype ⇒ virus specific Ab ⇒ life-long immunity to that serotype
  • Ab acts as “enhancing antibody” to other serotypes
  • Infection w/ a different serotype ⇒ Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS)
    • Formation of immune complexes (virus-Ab) ⇒ internalized via Fc receptors into MΦ
      • More efficient infection
      • Greater replication of the virus
      • ↑ production of MΦ cytokines
    • MΦ processed virus interacts with T-cells ⇒ hypersensitivity rxn @ endothelial surface
    • Circulating immune complexes ⇒ ± complement activation ⇒ release of vasoactive amines
      • ↑ vascular permeability, perivascular edema, and mononuclear infiltration ⇒ effusions in the pleura and other cavities
      • ↓ Platelet production ⇒ ↓ clotting factors ⇒ ± hemorrhage from respiratory & GI tracts
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61
Q

Dengue Virus

Prevention & Control

A
  • No vaccine
    • Attenuated tetravalent vaccine in clinical trials
  • Mosquitos feed all day w/ peak in early morning and late afternoon
  • Use protective clothing and insect repellant
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62
Q

Non-Arbo

Hemorrhagic Viruses

Overview

A
  • Includes:
    • Arenaviruses
      • Lassa virus
      • Machupo virus
      • Junin virus
    • Filovirus
      • Marburg virus
      • Ebola virus
    • Hantavirus
      • Hantaan virus
      • Sin Nombre virus
  • All enveloped RNA viruses
  • Animal or insect reservoir
    • Monkeys, rodents, bats
  • Humans are not the natural host
    • Except for Dengue
  • Geographically restricted to where reservoir lives
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63
Q

Hemorrhagic Viruses

Transmission

A
  • Initial transmission
    • Occurs when activities of reservoir, host, or vector overlap
    • Transmission mech. to humans unknown
    • Ex. contact w/ bush meat – Marburg
  • Ongoing transmission
    • Once infection occurs in humans, highly transmissible by body fluids to others
    • Occurs in outbreak form
    • Ex. Ebola, Marburg, Lassa
64
Q

Hemorrhagic Viruses

Pathogenesis and Clinical Disease

A
  • Initial Syndrome
    • Abrupt onset of flu-like illness
    • Fever, fatigue, malaise, headache, joint and muscle aches
    • Progresses to either conditions below
  • Pulmonary shock-like syndrome
    • Pulmonary edema
    • Respiratory failure
    • Death
  • Hemorrhagic syndrome
    • Coagulopathy
    • Petechial hemorrhage
    • Bleeding from gums, eyes, ears, and GI tract
    • DIC, organ failure, death
65
Q

Hemorrhagic Viruses
Treatment

A

Supportive therapy only

High mortality rates

66
Q

Hantaviruses

Overview

A
  • Hantaan virus
    • Causes hemorrhagic fever or pulmonary shock syndrome
    • Outbreaks common in US national parks
    • Hikers, campers, seasonal cabin dwellers, occupational risks
    • Transmission via contact w/ aerosolized mouse feces, urine
  • Sin Nombre Virus
    • Causes pulmonary shock syndrome
    • Outbreak in Four Corners region in 1993
    • Endemic in Eastern Asia (China, Russia, and Korea)
    • Deer mouse vector
    • Transmission by breathing aerosols containing virus from contaminated urine
    • Outbreaks coincide with high rainfall, increased food and rodent population
67
Q

Hantavirus

Clinical Syndromes

A
  • Hantavirus Pulmonary Syndrome (HPS)
    • Flu-like syndrome for 2-3 days
      • Dry cough, malaise, HA, N/V, SOB
    • Progresses to ARDS, kidney failure
    • Mortality 35%
  • Hemorrhagic Fever with Renal Syndrome (HFRS)
    • Eastern Asia (China, Russia, and Korea)
    • Intense HA, nausea, fever, chills, back and abd pain
    • Low BP, acute shock, vascular leakage
    • AKI ⇒ severe fluid overload
    • Mortality up to 15% depending on strain
68
Q

Hantavirus

Diagnosis and Treatment

A
  • Diagnosis:
    • Serology, immunohistochemistry, PCR
  • Treatment:
    • Largely supportive
    • Intubation and oxygen therapy for HPS
    • IV ribavirin for HFRS (early)
69
Q

Arenavirus

A
  • Hemorrhagic virus
  • Endemic in Africa and parts of South America
  • Enveloped, ambisense RNA
  • Includes Lassa, Machupo, Junin
  • Reservoir: persistent infection in rodents
  • Shedding of virus in saliva, urine, and feces
70
Q

Filovirus

A
  • Hemorrhagic virus
  • Endemic in Africa and parts of South America
  • Enveloped ⊖-sense RNA
  • Includes Marburg and Ebola (50-90% mortality)
  • Reservoir: monkeys, bats
71
Q

Rabies Virus

Overview

A

Severe encephalitis of midbrain and medulla

  • Bite of infected animal: racoons, dogs, bats
  • Neurotrophic transmission
  • Negri bodies are pathognomonic
  • Extraordinary CNS excitability (sensory & motor)
  • Pharyngeal muscle contraction ⇒ hydrophobia (do not drink water)
  • Flaccid paralysis, mania/stupor, coma
  • Pre and post-exposure vaccination is effective
72
Q

Rabies Virus

Characteristics and Morphology

A
  • Rhabdoviridae family of RNA viruses
  • Infect many mammals including humans
  • Bullet shaped w/ glycoprotein coat surrounding matrix protein
  • Helical ribonucleoprotein core
  • Unsegmented ⊖-sense ssRNA
  • Contains an RNA dependent RNA polymerase
  • Replicates entirely in the cytoplasm
  • Excess nucleocapsid material accumulates in cytoplasm of infected cells ⇒ forms characteristic inclusions known as Negri bodies
73
Q

Rabies Virus

Pathogenesis and Clinical Disease

A
  • Incubation: 4 weeks to > 1 year
    • Duration depends on bite site (shorter w/ bites of face and head), age, concentration of virus, and host immune status
    • Enters muscle @ bite site & replicates
    • No sx during incubation period
  • Virus infects the peripheral nerves ⇒ prodromal phase
    • Fever, nausea, vomiting, headache, lethargy
    • Retrograde axonal transport → DRG of spinal cord
  • Travels up the CNS to the brain ⇒ neurological phase
    • Affects hippocampus, brainstem, and cerebellum
    • CNS manifestations including depression, anxiety, hallucinations, hydrophobia, paralysis, delirium and seizures
      • Gross brain: may see mild congestion w/ perivascular infiltration or cuffing, no tissue necrosis
    • From CNS, disseminates to the body including skin, salivary glands, cornea, adrenals, and kidneys
      • Replication takes place in the brain and probably also in salivary glands
    • Stage progresses to coma and death within 1 to 3 weeks
      • Death usually occurs from pulmonary or cardiac complications
74
Q

Rabies Virus

Diagnosis

A
  • Antemortem diagnosis
    • Fluorescent microscopy of skin biopsy of the nape of the neck
    • Isolation of virus from saliva
    • Ab in CSF or serum
  • Postmortem diagnosis
    • Negri bodies in the brain (70-90%)
75
Q

Rabies Virus
Treatment

A

Treatment consists of three phases:

  1. Local wound management
    • Thorough flushing and disinfection of wound essential
    • Assess need for tetanus prophylaxis
  2. Passive immunization
    • Given rabies immune globulin (RIG) within 24 hours
    • Goal to prevent virus from entering neural tissue
    • Little value once sx begin
  3. Vaccination
    • 3 commercially available inactivated virus vaccines
    • 5 doses given IM within 1 month
    • 1st dose of vaccine @ the same time as passive therapy but at separate sites
76
Q

Rabies Virus

Prevention

A
  • Pre-exposure vaccination
    • For individuals in high-risk groups
    • Veterinarians, animal handlers, rabies virus lab workers and spelunkers
    • Boosters may be advised for those with continuing risk
  • Key prevention strategies include:
    • Vaccination of domestic dogs, cats and ferrets
    • Avoid contact with wildlife and strays
    • Seal chimneys and opening into houses to prevent den building
    • Wear gloves or use a shovel to dispose of a bat once you think you’ve killed it
77
Q

Acute Bacterial Meningitis

Clinical Manifestations

A
  • Some combination of:
    • Headache
    • Fever
    • Nuchal rigidity (stiffness of the neck on passive forward flexion)
    • Nausea
    • Lethargy
    • Reduced consciousness
    • Seizures (particularly in children)
  • Paralysis and motor deficits more associated with encephalitis
  • Many of the signs and sx of encephalitis overlap with those of meningitis
78
Q

Acute Pyogenic Meningitis

Etiology Age Stratification

A

Vary with patient’s age:

  • Neonates: E. coli and group B Streptococci
  • Infants: S. pneumoniae
    • Immunization (1987) marked decrease in H. influenzae
  • Adolescents and young adults: Neisseria meningitidis
  • Adults: S. pneumoniae
  • Older Adults / Immunocompromised: Listeria monocytogenes
79
Q

Neonatal Meningitis & Sepsis

Pathogens

A
  • Group B Streptococci
  • Escherichia coli
  • Listeria monocytogenes
80
Q

Group B Streptococci (GBS)

Overview

A

Streptococcus agalactiae

  • Causes 10% of meningitis cases overall
  • # 1 cause of neonatal sepsis and meningitis
  • ~10k cases/year of GBS, ~300 deaths/year in the USA, 1-3 cases/1k births
  • Important in neonates but increasing in > 50 y/o
  • High mortality: up to 30% of cases die even w/ treatment
81
Q

Group B Streptococci (GBS)

Characteristics

A
  • Gram ⊕ cocci in chains
  • β-hemolytic
  • Bacitracin resistant
  • CAMP test ⊕

Differentiated from Group A β-hemolytic strep ⇒ Bacitracin sensitive & CAMP ⊖

82
Q

Group B Strep

Transmission

A
  • Normal intestinal flora and normal vaginal flora (10-30% of women)
    • Neonates acquire during passage through birth canal
    • Direct contact after birth
  • Entry through respiratory system, skin, GI tract
  • Risk factors for disseminated GBS infection:
    • Lack of response to polysacc Ag
    • Underdeveloped neonatal immune system
83
Q

Group B Strep

Risk Factors

A
  • 60% of infants born to colonized women become colonized
  • Premature delivery
  • Prolonged membrane rupture (>18 hrs)
  • Intrapartum fever of mom (38°C)
  • Previous neonate w/ GBS
  • Detection of GBS in urine
84
Q

Group B Strep

Colonization

A

High risk groups:

  • African Americans
  • Diabetics
  • Sexually active
  • Multiple partners
85
Q

Group B Strep

Virulence

A
  • Polysaccharide capsule
    • 11 serotypes
    • Ia, III, and V most often ass. w/ disease
      • Rich in sialic acid
86
Q

Group B Strep

Pathogenesis

A

Presents w/ fever, lethargy, difficulty feeding, irritability, respiratory distress, hypotension, cyanosis.

  • Entry through respiratory system, skin, GI tract
  • Normal sequence of events: Pneumonia → Bacteremia → Meningitis
    • Starts w/ mucosal infection (PNA)
    • Encapsulated organisms can easily move from blood into CNS
  • Mortality ~ 5%
    • Depends on birthweight: > 1500 g = 14% mortality, < 1500 g = 65% mortality (1 kg = 2.2 lbs)
  • Neurologic sequalae in 15-30% of survivors
87
Q

Group B Strep

Infection Classifications

A
  • Early-onset infections
    • Serotypes I, II, III
    • Sx during first 5 days of life
    • Infection acquired during birth
    • ↑ Risk w/ premature delivery & prolonged rupture of membranes > 12 hrs
  • Late-onset infection
    • Serotype III
    • Seen in full term infants
    • Presents at 7 days - 3 months old
    • Direct contact transmission: nursery, mother
    • ↑ survival, ↔︎ neurologic sequalae
88
Q

Group B Strep

Diagnosis, Treatment, Prevention

A
  • Diagnosis:
    • Cultures of blood or CSF
  • Treatment:
    • Penicillin or Ampicillin IV
    • Sometimes in combo w/ aminoglycosides
  • Prevention:
    • Screen of pregnant women @ 35-36 weeks gestation
      • Intrapartum prophylaxis of culture ⊕ women ↓ transmission
    • Colonized or high risk women
      • IV Abx during labor
    • High risk newborns
      • IV Abx for 48 hrs after birth
89
Q

Escherichia coli

A
  • #2 cause of neonatal sepsis (40%) and meningitis (75%)
    • Enterobacter, Proteus and Klebsiella can also cause neonatal sepsis
  • Neonates (< 1 m/o) acquire E. coli during passage through birth canal
    • Transmission from nursery personnel also seen
  • Virulence ⇒ anti-phagocytic K1 capsular polysaccharide
    • Rich in sialic acid
    • Neurotropic and assists in adherence to meninges
    • Very resistant to phagocytosis
90
Q

Listeria monocytogenes

A
  • Uncommon cause meningitis & sepsis (10% overall)
  • Gram ⊕ rods
  • Elderly and pts with impaired T-cell immunity
  • Transmission
    • Fetus via placenta
    • Neonate via birth canal
    • Ingestion ⇒ outbreaks
      • Young children
      • Elderly
      • Immunocompromised of all ages
91
Q

Acute Bacterial Meningitis

(Young child, adolescent, adult)

Pathogens

A
  • Streptococcus pneumoniae
  • Haemophilus influenzae Type B
  • Neisseria meningiditis
92
Q

Pneumococcal Meningitis

Overview

A

Streptococcus pneumoniae

  • Causes 50% of septic meningitis cases
  • #1 cause of meningitis in children < 6 y/o after neonatal period and > 20 y/o
    • Can cause meningitis in all age groups
  • Children
    • Nasopharyngitis and otitis media with hematogenous spread
  • Elderly (very old)
    • PNA with hematogenous spread
  • Conjugate vaccine has reduced incidence
  • 20% mortality
  • Frequent cause of severe neurologic sequalae including cortical deficits and deafness (25-50%)
93
Q

S. pneumoniae

Epidemiology & Transmission

A
  • Transmission:
    • Usually endogenous
    • Exogenous via respiratory secretions
    • Accompanied by pre-disposing factors
  • Epidemiology:
    • Infects humans, no reservoir
    • ​20-40% are carriers in NP
    • Incidence greatest < 6 y/o and > 60 y/o
    • 1 mil deaths worldwide
94
Q

S. pneumoniae

Morphology & Characteristics

A

> 80 serotypes based on capsular polysaccaride

95
Q

S. pneumoniae

Virulence Factors

A
  • Polysaccharide capsule ⇒ major factor
    • Anti-phagocytic
    • Strains w/ large capsules more virulent
    • Loss ⇒ avirulent
  • IgA protease
    • Aids establishment of infection
  • Pneumolysin
    • Toxin w/ pore-forming action
    • Injures cilia and endothelial cells ⇒ aids spread
96
Q

Pneumococcal Meningitis

Pathogenesis

A
  • Starts w/ mucosal infection (PNA, otitis media)
  • Spreads via blood to CNS
  • Massive inflammatory response, mostly PMNs
  • Edema and accumulation of pus
97
Q

S. pneumoniae

Diagnosis

A
  • Smear ⇒ gram ⊕ cocci
  • Culture ⇒ blood agar or blood culture
  • Optochin sensitive
  • Detection of capsular Ag
    • Latex agglutination test
    • Quellung reaction
      • Ab to organisms in pure culture or clinical material
      • Causes capsule to swell
      • Can be used for typing
98
Q

S. pneumoniae

Treatment

A

50% are PCN resistant

Fluoroquinolones or Vancomycin for serious disease.

99
Q

S. pneumoniae

Prevention

A
  • 1st gen vaccine (Pneumovax 23)
    • Capsular polysacc. from 23 most common serotypes
    • Rec. for high risk pts
  • Conjugate vaccine (Prevnar 13)
    • 13 invasive serotypes polysacc. + CRM proteins
    • Given to infants as part of routine vaccinations
100
Q

Haemophilus influenzae (HiB)

Overview

A
  • Causes < 10% of meningitis cases overall
  • Formerly important pathogen in children
  • Nasopharyngeal infections with hematogenous spread
  • Less common since immunization (HIb)
101
Q

H. influenzae Type B (HiB)

Meningitis

A
  • Meningitis only caused by HiB
    • Usually follows URT infection
  • Vaccine preventable
  • Unimmunized child < 2 y/o high risk
  • 3-6% mortality
  • Sequalae frequent ⇒ 20% w/ permanent hearing loss
102
Q

H. influenzae Type B

Characteristics

A
  • Small, gram ⊖ rods (cocco-bacillus)
  • Complex nutritional requirements
    • X factor ⇒ hematin
    • V factor ⇒ NAD or NADP
  • Grows well on chocolate agar
  • Small satellite colonies grow around colonies of S. aureus or other factor V excreting organisms ⇒ satellite phenomenon
  • Most invasive strain ⇒ causes 90% of all H. influenzae infections
  • Virulence due to unique polyribose-ribitol phosphate (PRP) capsule
103
Q

H. influenzae

Diagnosis

A
  • Fastidious
  • Specimen from NP swab, pus, blood, or CSF for smears and culture
  • Grows on chocolate agar or BAP with X factor (hematin/hemin) and V factor (NAD)
  • PRP capsular Ag of HiB released into body fluids
    • Antigen detection methods ⇒ latex agglutination
104
Q

H. influenzae

Immunity

A
  • Passive protection by maternal Ab
    • No episodes until after 6 m/o
  • Opsonizing anti-capsular Ab
    • Capsule-type specific
    • Enhance phagocytosis by PMNs
    • Bacteriolytic in presence of complement
  • Active acquired Ab gradually increases up to ~ 10 y/o
105
Q

H. influenzae

Treatment

A
  • Ampicillin for 5-10 days
  • Some are beta-lactamase producers
    • ~ 25% of HiB
  • Newer cephalosporins are drugs of choice
    • Ceftriaxone, cefotaxime
106
Q

Neisseria meningitidis (Meningococcus)

Overview

A
  • Causes 25% of meningitis cases overall
    • Children < 5 y/o, adolescents and young adults
    • Most common cause of epidemic meningitis
  • Airborne transmission
  • Vaccination available (military and most colleges require it)
  • Pyogenic gram-⊖diplococci
  • 13 serogroups based on capsular carbohydrate composition
107
Q

N. meningitidis

Epidemiology & Transmission

A
  • Respiratory droplet transmission
    • Prolonged close contact ↑ risk
  • Humans are the only natural host
    • Common in children (6 mo – 2 yrs) and adolescents
    • Transient colonization of nasopharynx (1-40%)
    • 5% of population chronic carriers (up to 35% of military recruits)
  • Epidemic outbreaks
    • USA ⇒ Group B
    • Rest of the world ⇒ Group C
    • Usually seen in Winter and Spring
  • Bimodal distribution
    • Maternal Ab gives protection (6-9 m/o)
    • Disease peak in children (< 1 y/o)
    • 2nd peak in adolescents and young adults (15-25 y/o)
108
Q

N. meningitidis

Risk Factors

A
  • Age
  • Winter / dry season
  • Overcrowding
  • Certain social behaviors
    • Passive exposure to cigarette smoke
109
Q

N. meningitidis

Virulence Factors

A
  • Polysaccharide capsule ⇒ resists phagocytosis
    • Linked to bacterial protection and invasion
    • Polymers of sialic acid
  • Most strains have pili (outer membrane proteins)
    • Attach to CD46
    • Facilitates invasion into mucosal epithelial cells
    • Non-piliated mutants less pathogenic
  • Endotoxin/LOS (lipo-oligosaccharide) ⇒ same activity as LPS
    • Proinflammatory mediators
    • Fever, shock, alternate complement pathway activation
  • IgA protease
110
Q

N. meningitidis

Clinical Syndromes

A
  • Nasopharyngitis
    • Most infections mild or inapparent
    • Frequently transmitted by droplets, coughing and sneezing
  • Meningococcemia
    • Septicemia occurs w/ or w/o meningitis
    • Thrombosis of small blood vessels
    • Produces metastatic lesions → skin, joints, eyes, lungs, etc.
    • Skin involvement ⇒ petechial rash, may become confluent and produce purpura
    • 40% mortality
  • Meningitis
    • Inflammation and pyogenic infection of meninges
    • Abrupt onset HA, fever, stiff neck, ± N/V
    • ± Petechial rash and metastatic lesions in other organs
    • Does not develop following every case of nasopharyngitis or meningococcemia
    • 9-12% mortality w/ abx
  • Fulminating meningitis
    • Severe meningitis w/ sudden onset of sx
    • Characterized by presence of a large number of organisms in the blood stream and meninges
  • ± DIC and gram-⊖shock
  • “Waterhouse-Friderichsen syndrome”
    • Commonly associated w/ meningococci
    • Adrenal gland bleeding and destruction
111
Q

Waterhouse–Friderichsen

Syndrome

A
  • Most commonly caused by N. meningitidis
  • Overwhelming meningococcemia leads to massive hemorrhage in the adrenal glands
  • Characterized by low BP, shock, DIC, widespread purpura, and rapidly developing adrenocortical insufficiency
112
Q

N. meningitidis

Immunity

A
  • Need Ab response to the capsule
  • Carriers develop protective response (anti-capsulate Ab) over time
  • Complement deficiency of terminal components (C5-C8) predisposes to disseminated disease
113
Q

N. meningitidis

Diagnosis

A
  • Gram stain ⇒ presumptive dx
    • Grow on chocolate agar, Thayer Martin Agar
  • Latex agglutination
    • Direct detection of capsular polysaccharides
    • Low sensitivity for serogroup B ⇒ helpful if ⊕, does not r/o if ⊖
  • PCR of CSF
    • If abx have been used and to type strains
  • Biochemical tests
    • All Neisseria are Oxidase ⊕
    • N. gonorrhoeae is Glucose ⊕ only
    • N. meningitidis is Glucose ⊕, Maltose ⊕
114
Q

N. meningitidis

Treatment and Prevention

A
  • Treatment
    • Penicillin G (no known PCN resistance)
    • Ceftriaxone or chloramphenicol if febrile
      • Ceftriaxone will also cover other causes of bacterial meningitis (e.g. GBS)
  • Prophylaxis for close contacts (e.g. family members)
    • Oral Rifampin ⇒ reaches high concentrations in oral secretions
  • Prevention
    • Vaccines available for less prevalent serogroups
      • Serogroups A, C, Y, W-135 ⇒ ↓ carrier rate
      • Conjugate licensed for US adolescents
    • New Group B vaccine
      • Poorly immunogenic capsule
      • For 16-23 y/o, high risk, or outbreak control
115
Q

Acute Pyogenic Meningitis

CSF Gram Stain Comparison

A
116
Q

Brain Abscess

A
  • Organisms: Streptococci or Staphylococci
  • Sources:
    • Direct implantation
    • Local extension (mastoiditis, sinusitis)
    • Hematogenous (heart, lungs, bone, teeth)
  • Predisposition:
    • Infective endocarditis
    • Right to left cardiac shunts (bypasses lungs)
    • Chronic pulmonary sepsis (bronchiectasis)
  • Location: Frontal lobe > parietal lobe > cerebellum
  • Clinical:
    • Progressive focal deficits
    • ↑ ICP, WBCs and protein
    • Normal glucose
  • Causes death by:
    • ↑ ICP ⇒ herniation
    • Abscess rupture ⇒ ventriculitis, meningitis, venous sinus thrombosis
117
Q

Cerebral Edema & Brain Herniation

A
118
Q

Chronic Meningoencephalitis

Etiologies

A
  • Tuberculosis
  • Neurosyphilis
  • Neuroborreliosis
119
Q

Tuberculous Meningoencephalitis

A

Chronic Meningoencephalitis

  • Part of diffuse active disease vs “isolated” seeding from undiagnosed infection (often PNA)
  • Most common pattern is diffuse meningoencephalitis
  • May spread via CSF to the choroid plexus and ependymal surface
  • Clinical manifestations: headache, malaise, mental confusion, and vomiting
  • Gross:
    • Subarachnoid space w/ gelatinous or fibrinous exudate
    • Characteristically involves the base of the brain, effacing the cisterns and encasing cranial nerves
  • Micro:
    • Mixed inflammatory infiltrates
    • Well-formed granulomas with caseous necrosis and giant cells
    • Organisms can be seen with acid-fast stains
  • CSF:
    • Moderately increased cellularity (lymphocytes, PMNs)
    • Protein elevated, often markedly
    • Glucose moderately reduced or normal
    • Bacteria may be cultured from the CSF but typically not seen in cytology specimens
120
Q

Chronic TB Infection

Complications

A
  • Arachnoid fibrosis ⇒ hydrocephalus
  • Obliterative endarteritis (Heubner’s Arteritis) ⇒ arterial occlusion and infarction of underlying brain
  • Tuberculoma
  • Pott Disease
121
Q

Obliterative Endarteritis

“Heubner Arteritis”

A
  • Severe proliferating endarteritis (inflammation of the intima or inner lining of an artery)
  • Results in occlusion of artery lumen
  • Seen in both TB and Syphilis
122
Q

Tuberculoma

A
  • Inflammation may become localized and form a mass-like lesion
  • Causes mass effect
  • Caseating granulomas
  • May be calcified
123
Q

Pott Disease

A

“Vertebral Tuberculosis”

  • Rare
  • Neurologic complications from collapse of vertebral bodies ⇒ spinal cord compression
  • May form soft tissue abscesses adjacent to involved vertebrae
124
Q

Syphilis

Overview

A
  • Caused by Treponema palladium (gram ⊖ spirochete)
  • CNS involvement in ~10% of untreated cases
    • Usually 3-10 years after primary infection
  • Patterns of CNS involvement:
    • Meningovascular Neurosyphilis
    • Paretic Neurosyphilis
    • Tabes dorsalis
  • Transmission: sexual contact, congenital (crosses the placenta), contact with a primary lesion
125
Q

Neurosyphilis

Clinical Characteristics

A
  • Typically involves base of brain, convexities, spinal cord
  • Microscopic:
    • Dense lymphoplasmacytic inflammation
  • CSF:
    • WBC: variable lymphocytes and plasma cells
    • ↑ Protein
    • Glucose normal to low
  • Organisms generally not seen in cytology specimens
  • VDRL (Venereal Disease Research Laboratory): ⊕
126
Q

Meningovascular Syphilis

A

Chronic meningitis due to T. palladium

  • Typically involves the base of the brain and more variably the cerebral convexities and spinal leptomeninges
  • Complications:
    • Obliterative endarteritis (Heubner arteritis)
      • Accompanied by distinctive perivascular inflammatory reaction rich in plasma cells and lymphocytes
    • Cerebral Gummas
      • ± Plasma cell-rich mass lesions in meninges → parenchyma
      • Typically seen in bone and skin
127
Q

Paretic Neurosyphilis

A

Invasion of the brain by T. pallidum

  • Clinically insidious but progressive cognitive impairment
    • Mood alterations (including delusions of grandeur)
    • Terminate in severe dementia (general paresis of the insane)
  • Parenchymal damage of the cerebral cortex most common in frontal lobe but also other areas
  • Micro:
    • Loss of neurons
    • Proliferation of microglia (rod cells)
    • Gliosis
    • Iron deposits
  • Spirochetes may be demonstrated in tissue sections
128
Q

Tabes Dorsalis

A

Damage to sensory axons in the dorsal roots by T. pallidum

  • Clinical manifestations:
    • Impaired joint position sense and ataxia (locomotor ataxia)
    • Loss of pain sensation ⇒ joint damage (Charcot joints)
    • Characteristic “lightning pains”
    • Absence of DTRs
    • Other sensory disturbances
  • Microscopic:
    • Loss of axons and myelin in dorsal roots
    • Pallor and atrophy in the dorsal columns
129
Q

Neuroborreliosis

A
  • Lyme Disease sequelae
  • Caused by Borrelia burgdorferi (gram ⊖ spirochete)
  • Transmitted by Ixodes tick
  • Symptoms variable:
    • Facial nerve palsies
    • Other polyneuropathies
    • Encephalopathy
130
Q

CNS

Fungal Infections

A
  • Primarily in immunocompromised individuals
  • CNS typically involved following widespread hematogenous dissemination
    • Can be local extension (DM, Neutropenia)
  • Most frequent pathogens:
    • Candida albicans
    • Mucor species
    • Aspergillus fumigatus
    • Cryptococcus neoformans
  • In endemic areas - Histoplasma, Coccidioides, and Blastomyces
  • Three main forms of injury:
    • Chronic meningitis
    • Vasculitis – (Aspergillus & Mucor—sometimes others)
    • Parenchymal invasion
131
Q

Cryptococcal Meningitis

A
  • Common opportunistic infection in AIDS
  • May be fulminant and fatal in as little as 2 weeks or indolent, evolving over months or years
  • Clinical: Few meningeal symptoms
  • CSF may contain few cells but usually has a high concentration of protein
  • Polysaccharide capsule (usually)
  • Examination of the brain shows gelatinous material within the subarachnoid space and small cysts within the parenchyma (“soap bubbles”)
  • Diagnosis in CSF:
    • Cryptococcal antigen
    • Cytology
      • India ink stain [Historical]
  • Treatable with antifungal drugs
132
Q

Toxoplasma gondii

Overview

A

Protozoal CNS Infection

  • Opportunistic infection ⇒ HIV
  • Subacute, evolving during a 1- or 2-week period
  • May be both focal and diffuse
  • Microscopic: free tachyzoites and encysted bradyzoites at the periphery of the necrotic foci
  • Vessels near lesions may show marked intimal proliferation or vasculitis with fibrinoid necrosis and thrombosis
133
Q

Toxoplasma gondii

Adult Disease

A
  • Reactivation due to immune suppression
  • Common cause of neurological symptoms in AIDS patients
  • Multiple small abscesses in deep grey matter
134
Q

Toxoplasma gondii

Congenital (Fetal) Disease

A
  • Blood-borne from maternal infection causing necrotizing CNS lesions in the fetus that may calcify
  • Pregnant women shouldn’t clean the cat litter box
  • Multifocal, calcific, necrotizing lesions results in severe brain damage
135
Q

Chronic Degenerative Diseases

A
  • Slow infections
  • Long incubation periods that can last decades
  • Caused by conventional viruses (JC virus and measles) or unconventional agents (prions)
  • Once sx manifest, death is inevitable within 1 to 2 years
136
Q

Subacute Sclerosing Pan Encephalitis (SSPE)
Overview

A
  • Persistent, chronic measles infection
  • Rare (7 in 1 mil cases) ⇒ ↓ since intro of live measles vaccine
  • Vaccination w/ attenuated virus protects against SSPE
  • Children or young adults
  • Manifests 5-8 years after initial measles virus infection
  • Results in death within 2 years of onset
137
Q

Subacute Sclerosing Pan Encephalitis (SSPE)

Pathogenesis

A
  • Variant or altered measles virus ⇒ ∆ M protein (involved in virus assembly)
    • ∆ Budding ⇒ ⊗ release of progeny virus ⇒ accumulation of defective virus in neurons
  • Very high levels of anti-measles Ab found in CSF and serum
  • Lack of Ab to M protein
138
Q

Subacute Sclerosing Pan Encephalitis (SSPE)

Clinical Disease

A
  • Slowly progressive degenerative neurological disorder
  • Characterized by demyelination in multiple brain regions
  • Spasticity, loss of motor skills, seizures, progressive dementia
  • Microscopic:
    • Brain atrophy and gliosis
    • Inclusions in oligodendrocytes and neurons
    • EM: defective measles virus ⇒ nucleocapsids
139
Q

Polyoma Viruses

A

JC Virus and BK Virus

  • Belongs to the papovavirus family
    • Naked circular dsDNA genome
    • Replicates and assembled in the nucleus
  • Most individuals acquire asymptomatic infection during childhood
    • ~ 65% infected by age of 14
  • Latency → immunosuppression → reactivation
    • Immunocompetent adults reactivate and shed virus periodically
    • 40% of immunocompromised secrete JC or BK in urine
140
Q

BK Virus

A
  • Latent polyoma virus
  • Causes renal disease in immunosuppressed hosts
  • Causes nephropathy in ~ 5% of kidney recipients
    • May result in loss of a transplanted kidney
  • Viremia in 50% of bone marrow transplant recipients
    • Ureteral stenosis, hemorrhagic cystitis
141
Q

Progressive Multifocal Leukoencephalopathy (PML)

A

Reactivation of latent polyoma virus (JC virus)

  • Asymptomatic infection during childhood (65%)
  • Virus remains latent in the kidney
  • Immunosuppression ⇒ viral replication ⇒ dissemination to CNS ⇒ progressive disease
    • Complication of AIDS (5-10%)
  • Lytic infection destroys oligodendrocytes ⇒ widespread demyelination
    • Severe neurologic disability
      • Speech, vision, paralysis → death
  • No Ab produced
  • Median survival of 6 months
142
Q

Prion Disease

Overview

A

Transmissible Spongiform Encephalopathies

  • Infectious agent composed of a misfolded protein (prion)
  • No nucleic acid has been found ⇒ do not replicate
  • May be sporadic, familial or transmissible (infectious)
  • All known prion diseases ∆ structure of the brain or other neural tissue
  • All are currently untreatable and universally fatal
143
Q

Prions

A

Proteinaceous Infectious Particle

  • Normal prion protein (PrPC) encoded by a cellular gene (PRNP)
    • Highest level of expression in the CNS
    • Unknown function but normally found on cell surface
    • Normal 3D configuration (helical) ⇒ susceptible to digestion by proteases
  • Abnormal prion form (PrPSC) ⇒ identical AA sequence but 3D folding differs (β sheet) ⇒ resistant to protease digestion
    • Found within vacuoles instead of cell membrane
144
Q

Prion Transmission

A
  • Ingestion of infected food
  • Improperly sterilized surgical equipment (neurosurgery)
  • Infected blood products
    • American Red Cross Deferral for Donors:
      • Persons who have spent long periods of time in countries where “mad cow disease” is found (UK) are not eligible to donate
      • Related to concerns about variant Creutzfeldt Jacob Disease (vCJD)
145
Q

Prion Disease
Pathogenesis

A

When a prion enters a healthy organism ⇒ induces existing, properly folded proteins to convert into disease-associated, prion form

  • PrPSC can form dimers with PrPC and ‘teach’ it to form the abnormal configuration
  • ↑ formation of PrPC ⇒ converted into PrPSC
  • T½ of days instead of hours like normal cellular form
  • Found inside cytoplasmic vesicles within cells and is secreted
  • Accumulation of non-degradable PrP proteins in the brain ⇒ neurological degeneration
  • No immune activation or inflammation is detected
146
Q

Prion Disease

Histology

A

Spongiform change

  • Vacuolation of neurons
  • Diffuse astrocytosis and cellular loss
  • Formation of eosinophilic amyloid plaques and fibrils comprised of aggregated PrPSC
147
Q

Prion Disease

Types

A
148
Q

Familial Prion Diseases

A
  • Caused by a specific mutation in the PRNP gene
  • Mutation causes asparagine → aspartate at residue 178 of PrPC
  • Results in FFI when it occurs in a PRNP allele encoding methionine at codon 129
  • Results in CJD when present in tandem with a valine at this position
  • How these amino acids influence disease phenotype is not understood
149
Q

Scrapie

A
  • Found in sheep and goats
  • Clinically recognized for more than 250 years
  • Intense itching ⇒ scrape body against fixed objects
  • Progressive behavioral changes, tremors, ataxia and paralysis
  • Spinal cord pathology
150
Q

Kuru

A
  • Fore tribe in New Guinea
  • Similar presentation to CJD (with intense itching) except for the absence of dementia
    • Shaking, difficulty walking, and difficulty swallowing
  • Incubation period 4-20 years
  • Death in ~ 1 year
  • Transmissible agent passed during food preparation for cannibalism
    • Cannibalism abolished ⇒ ↓ cases
  • Women and children primarily affected
151
Q

Creutzfeld-Jakob Disease (CJD)

A

Subacute dementing illness with myoclonic jerks

Sx include radial loss of muscle control and speech, tremors, shivering and dementia

  • Sporadic CJD (90%)
    • Mutation in one neuron
    • Arises in pts with no known risk factors
    • Most common type
    • Onset > 70 y/o
  • Hereditary CJD (10%)
    • Mutation in germline
    • ⊕ Fhx and/or ⊕ for genetic mutation associated with CJD
    • Onset < 60 y/o but wide range
  • Acquired CJD (< 1%)
    • Transmitted by contact with brain or nervous system tissue
      • Usually iatrogenic ⇒ injection, corneal transplant, transfer of pituitary material, contaminated neurological equipment
      • No evidence of transmission via casual contact with a CJD patient
    • Incubation period 2-30 years
152
Q

Variant Creutzfeldt Jakob Disease (vCJD)

Overview

A

Bovine Spongiform Encephalitis (BSE)

“Mad Cow Disease”

  • Developed when infected feed was fed to cows that entered the human food chain
  • Most prevalent in the UK
  • American Red Cross Deferral for Donors:
    • Persons who have spent long periods of time in countries where “mad cow disease” is found (UK) are not eligible to donate.
    • This requirement is related to concerns about variant Creutzfeld Jacob Disease (vCJD)
153
Q

Variant Creutzfeldt Jakob Disease (vCJD)

Pathogenesis

A
  • Ingested prions accumulate in gut secondary lymphoid tissue
  • Travel lymphatogenously
  • Access neurons and travel up neurons to the brain/CNS
  • There may be genetic susceptibility to ingested/acquired prion diseases
    • Polymorphisms in certain codons of the PrP protein may confer susceptibility
    • Homozygosity at codon 129 is present in 95% of CJD cases and 100% of nCJV
154
Q

Creutzfeldt Jakob Disease (CJD)

Diagnosis

A
  • Clinical diagnosis initially
  • Confirmed by immunohistochemistry of the brain on autopsy (CJ and vCJ)
  • vCJD can be dx by immunoblot of PrP using tonsil biopsy tissue
  • Elevated CSF protein 14-3-3 (marker of brain cell death) may have potential dx value
155
Q

CJD vs vCJD

A
156
Q

Gerstmann-Sträussler-Scheinker syndrome (GSS)

A
  • Progressive cerebellar ataxia
  • Autosomal dominant
  • Onset earlier ~ 50 y/o
  • Longer duration
157
Q

Fatal Familial Insomnia (FFI)

A
  • Intractable and progressive insomnia, ataxia, autonomic disturbances, stupor, and finally coma
  • Caused by a specific mutation in the PRNP gene
  • Mid-life onset
  • Disease course typically less than 3 years
  • A non-inherited form of the disorder (fatal sporadic insomnia) has also been described

5. HDS Neuro Psych (46 decks)

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