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Flashcards in viral meningitis Deck (104):
1

The ?? is not a portal of entry for viral infection.

brain

Infection in the CNS is usually a secondary infection, occurring days, weeks, months, or years after the initial infection.

2

It is estimated that 30→40% of all meningitis cases are of viral etiology today only because ??

we vaccinate against mumps

(otherwise would be more)

Most are not definitively diagnosed

3

In contrast to bacterial meningitis, viral meningitis is usually ??

a benign disease with rapid resolution and little or no sequelae

4

Most common agents are the:

ECHO viruses and Coxsackie viruses (non-polio enteroviruses).
**>2 yo**

HHV-6, HHV-7.
*6 m-o-age up to 2-y-o-age.

5

Less common agents are the:

Arboviruses – if late summer and early fall seasonality.

HSV-2 – if manifesting with primary symptomatic infection (genital herpes).

LCMV – if winter seasonality and history of rodent exposure.

6

Symptoms of viral meningitis are almost the same as bacterial and include acute onset of:

*irritability
*lethargy (altered mental status)
*fever,
severe headache
nuchal rigidity
vomiting
opisthotonos
pressure on eyeball
photophobia

7

HHV-6 and HHV-7

Major cause of acute febrile illness in infants→young children.

Primary HH-6 infection in children 6→12 m-o-age accounts for many (20% of) visits to ER (with 13% of these children hospitalized).

Major cause of many (33% of all ) *first time febrile seizures (CNS infection) among children (often no long term sequelae- good!)

8

HHV-6 and HHV-7: Primary infection in immunocompetent infants/young children leads to either ??

asymptomatic infection

Exanthem Subitum/Roseola Infantum +/- S/S of aseptic meningitis

9

With either presentation (ayspmtomatic or symptomatic) HH-6 causes both ??

Latent persistent infections:
-Latent infection in T lymphocytes, monocytes occurs.
-Latent infection in CNS occurs (virus is highly neurotrophic).

chronic persistent infections:
-Life-long, active infection in salivary gland occurs

10

HH-6/7: Manifestations Exanthem Subitum/Roseola Infantum with aseptic meningits are abrupt onset of S/S that last 4 → 6 days and include:

high fever (> 38oC; 100oF).
lethargy.
irritability.
malaise.

*no rash, but then fever defervesces (breaks) (in 4 → 6 days) and rash appears (T3 hypersn rxn)

11

HH-6/7 dx

S/S of disease caused by these viruses are a common cause of presentation of infant/young children to ER and are suggestive of meningits so a spinal tap is done, but the tap is aseptic (viral etiology)

12

HH-6/7 tx

Drug sensitivity/Resistance: *Treat otherwise healthy infants supportively, no antiviral therapy* -ice bath to chill fever

if therapy is done:

resistant to these antivirals → Acyclovir, famciclovir, and valacyclovir (don't administer-"not a FAV")

sensitive to these antivirals → Ganciclovir, foscarnet and valganciclovir (use!)

13

Patient presents with genital herpes plus fever and an aseptic meningitis.

HUMAN HERPESVIRUS 2 ASEPTIC MENINGITIS

however, typically asymptomatic

14

LYMPHOCYTIC CHORIOMENINGITIS VIRUS (LCMV)
LYMPHOCYTIC CHORIOMENINGITIS

arenavirus

Resistant to drying - important for understanding for transmission of virus to

an enveloped virus with a helical nucleocasid containing an RNA genome.

15

At least 7 arenaviruses infect humans

The 2 most important are:

and one more:

LCM (most common!)
Lassa virus (causes Lassa fever) (like Ebola)

also: Whitewater Arroyo virus is passed by inhalation of infected rat urine and causes hemorrhagic fever in humans (outbreak in Ca)

16

LCMV: rare or common?

A common agent (causes about 8→10%) of viral CNS illness in the US.

17

LCMV reservoirs

Animal reservoirs have a chronic, life-long viremia – shed virus life-long in feces, urine:

Mice, especially the house mouse (Mus musculus), is the primary reservoir with a variable (3% → 40%) rates of infection.

Hamsters.

Other rodents.

18

LCMV Spread from rodents to humans via:

direct contact with infected (i.e., infected pet)

inhalation of aerosols or dusts containing virus in:
urine
feces
tissues

ingestion of contaminated food

19

LCMV: Peak incidence of disease is in the ??

winter

(when infected mice come into houses) and humans inhale aerosols or dusts contaminated with the virus in rodent urine, feces, tissues

20

LCMV may cause ?? in immunocompromised patients

systemic disease and death

21

LCMV is an often undetected cause of ??

sporadic and epidemic congenital infection

22

LCMV pathogenesis

CNS infection results in a prolonged inflammation, with a dense, perivascular infiltration of the meninges and all parts of the brain with macrophages and lymphocytes (T cells attack infected nerve cells).

A lymphocytic pleocytosis

23

LCMV is a significant and undiagnosed human ??

teratogen!

24

LCMV Clinical forms are recognized (?? day incubation period); a biphasic course:

10-14 day

25

"Grippe"

a flu-like illness of variable duration, short to persists for a long time (a few days→ weeks → months), is the most common manifestation of LCMV disease.

i.e. fever, sore throat, etc.

26

After defervescence (the flu-like illness is resolving), the pateint may progress to CNS disease (~ 25% of all persons infected with LCMV develop CNS infection):

a Subacute meningitis (persists for several months) with classic triad of symptoms:

fever
headache
nuchal rigidity

a transient paralysis may also occur

27

Other CNS syndromes rarely occur in LCMV and include:

Encephalitis (diffuse)
transverse myelitis
Guillain-Barré’ syndrome

28

Prenatal LCMV infection (in utero) especially in first and second trimester can be teratogenic and/or result in:

spontaneous abortion
chorioretinitis
microcephaly
macrocephaly
hydrocephalus

*Most (@75%) children that survive have serious neurological sequelae

29

LCMV ddx

STORCH
enteroviruses
HBV-B19

30

LCMV dx

*history of rodent contact.

*CSF specimen + fluorescent antibody test.

acute and convalescent sera.

Virus recovery by animal inoculation can be done BUT is a laboratory hazard

NOT Cx

31

LCMV tx

supportive, prolonged recovery (may take as long as 3 months)

32

LCMV prevention

rodent control – especially avoid careless handling/disposal of dead rodents

33

NON-POLIO ENTEROVIRUSES

picomavirus (review)
non-polio enteroviruses

34

non-polio enteroviruses

Little cross neutralization between serogroups–many (>70) serotypes:

ECHOvirus (enteric cytopathic human orphan virus – many [31] serotypes).

Coxsackie viruses (A and B - many [30] serotypes).

Enteroviruses 68→71.

Human Parechoviruses: HpeV-1→3

35

NPE: rare or important?
causes what??

One of the most common and important viral pathogens in humans (5 → 10M symptomatic cases/y in US)

causes a nonspecific febrile illness with or without rash

36

NPE is responsible for ??

½ of all febrile illness in infants and young children during the summer and early fall months. (>50%! w/ fever)

Major reason why blood culture and/or spinal taps are done on infants and young children in the US.

37

NPE: Most common known cause of ??

aseptic meningitis (80 → 90% of all cases) in countries which immunize against mumps

important known causes of morbidity in both children and adults

38

NPE transmission

fecal-oral route (water is most common vehicle) -- mainly among small children and adults changing the diapers of an infected infant.

inhalation of aerosols via the RT

direct contact with respiratory secretions (e.g., saliva, sputum, or nasal mucus).

hand→eye, rarely,

in utero; true for some strains of ECHOvirus and Coxsackie viruses

39

NPE reservoir

Humans are sole host

Environment and humans can be reservoir.

40

NPE gender

Males and females are equally infected, but males more commonly manifest with disease

41

NPE age

incidence and severity vary inversely with patient age

Highest attack rate is in children

Severe disease is more common in adults.?

42

NPE seasonality

In the temperate climates, peak incidence is during the summer and fall months

but sporadic cases occur year round, with the prevalent serotype(s) varying annually

43

NPE Risk Factors:
Patients at greatest risk for enteroviral encephalitis and/or sequelae from CNS enteroviral disease include:


neonates
the immunocompromised (humoral or CMI)

44

Other: Neonatal sepsis:

Usually an ECHOvirus.

May be acquired by any route but usually by vertical transmission.

POE to CNS is via a viremia.

Predisposing factors:
male.
prematurity.
maternal infection 2 weeks before delivery

45

Pathogenesis and Clinical Manifestations of non-polio enteroviruses:
incubation period?
manifestations?

3 → 7 days

In children and adults, the abrupt onset of a nonspecific illness:

fever
headache
malaise, fatigue
+/- vomiting, diarrhea
+/- maculopapular rash



46

this febrile, nonspecific disease (NPE) described above sometimes develops into:

Classic common syndromes:

fever + rash (mostly maculopapular, can be petechial, vesicular)
HFMD
herpangina
pleurodynia
pharyngitis
conjunctivitis

Severe diseases:

aseptic meningitis
neonatal viremia + meningitis or encephalitis
encephalitis
myocarditis
hepatitis

47

Aseptic meningitis NPE:
undifferentiated febrile illness sometimes progresses to acute onset aseptic meningitis in:

Person is infectious about 3 days post-infection until about 10 days post onset of – s/s
Symptoms last from 7 → 10 d

young child (fever, irritability)

older child (fever, headache, nuchal rigidity)

adult (fever, nuchal rigidity; and a headache so severe that narcotics are required to manage the pain)

48

NPE Encephalitis (generally a diffuse, but increasing recognition of focal encephalitis)

Much less common than aseptic meningitis, but with a much higher mortality rate.

49

?? causes regional & world-wide epidemics of undifferentiated febrile illness that sometimes progress to encephalitis

Enterovirus 71

50

Enterovirus 71 produces 3 different encephalitis syndromes based on geographic location:

A transient or persistent acute flaccid paralysis (AFP) + encephalitis which mimics polio (US, Europe, South America).

HFMD cases→meningoencephalitis but few case fatalities (China, Japan).

HFMD cases→encephalitis with brain-stem involvement + pulmonary edema, hemorrhage. Deaths due to pulmonary edema and cardiac dysfunction caused by brain-stem infection not heart-lung infection (Taiwan-1998; Malaysia-1999).

51

NPE: Neonatal sepsis (a viremia, not bacteremia, which may → to encephalitis/disseminated disease):

occurs when the child acquires infection (usually an ECHOvirus) by any route (usually vertical transmission).

Predisposing factors:
male
prematurity
maternal infection in 2 weeks before delivery.

Syndromes by agent:
encephalomyocarditis (characteristic of group B coxsackieviruses).
hemorrhage-hepatitis syndrome (typical of echovirus 11)

52

NPE neonatal sepsis: Infection is systemic with corresponding signs and symptoms which occur within the first 2 weeks of life are:

fever/chills/temperature instability
rash
anorexia/poor feeding,
jaundice (liver)
GIT (vomiting) distress,
RT distress
Cardiac (tachycardia) distress,
neurologic findings,.
bulging anterior fontanelle (indicates pressure on the brain)

53

NPE neonatal sepsis: death is due to:

hepatic failure (ECHO virus)
myocarditis (Coxsackie virus)
hemorrhagic infarcts of major organs

54

NPE dx

CSF specimen:

*PCR for enteroviral agents.

Tissue culture is gold standard, rarely done.

PMNs predominate early, then a shift to lymphocytosis

55

NPE tx

symptomatic, supportive

Pleconaril (which binds to capsid→blocking viral uncoating) on compassionate use/release basis.

56

NPE prevention

NONE

57

Human Parechovirus and Human Parechovirus 3:
The Most Common Viral Cause of ???

Meningoencephalitis in Young Infants?

58

HPeV etiology

Formally echovirus 22 and echovirus 23 within the EV genus.

There are 16 to 17 HPeV genotypes

HPeV1 and HPeV3 being the most prevalent strains.
-HPeV1’s wide genetic variability led to further division into 2 clades: HPeV1A and HPeV1B.
-found worldwide

59

Disease caused by HPeV, particularly HPeV3, occurs mostly in ??

young infants

HPeV3 was detected mostly in infants less than the age of 3 months, whereas HPeV1B was detected in children up to 3 years of age

60

HPeV3 has been the most frequent single viral agent causing ?? in what season?? since 2005.

neonatal sepsis/meningitis

summer-autumn seasons
(outbreaks mostly every other year)

61

in addition to pediatric community outbreaks, HPeVs have been associated with ??

nosocomial outbreaks in pediatric and neonatal units

62

HPeV clinical manifestations

sepsis-like illness, meningitis, or a nonspecific febrile illness

Presentations in which HPeV3 should be suspected include neonatal seizure and neonatal sepsis

63

HPeV dx

HPeV3 confirmation is by reverse transcription polymerase chain reaction (RT-PCR) of cerebrospinal fluid (CSF) or, less often, serum.

RT-PCR–positive CSF usually lacks pleocytosis

Peripheral leukopenia/lymphopenia and modestly increased C-reactive protein levels are common.

liver dysfunction or other laboratory abnormalities are uncommon

Mortality/sequelae are rare, but if they occur, they follow difficult–to-control seizures

64

VIRAL ENCEPHALITIS

Viral replication in brain parenchyma → severe CNS dysfunction which causes manifestations.

Few survive, and those who do have serious emotional disorders and learning deficits

65

The most frequent etiologic agents of viral encephalitis are:

Arboviruses
Herpes simplex virus-1 (HSV-1).

66

Key to viral encephalitis is whether signs and symptoms are focal or diffuse:
diffuse agents ??
focal agents ??

The etiologic agents of diffuse encephalitis besides Arbovirus:
Herpes simplex virus-1 (HSV-1)??
Non-polio enterovirus

The etiologic agents of focal encephalitis besides HSV-1:
Arbovirus??
Non-polio enterovirus
rarely polio virus or rabies


67

If one of these etiologic agents produces an asymptomatic infection in a human, the infection does NOT ??

spread to the CNS

68

ARBOVIRUSES

DIFFUSE VIRAL ENCEPHALITIS

Arthropod-borne viruses
(400→ 500)

association with chronic infection in the reservoir host.
humans are generally the dead end host.
disease in the reservoir, if it occurs, is similar to human disease if POE is same.

69

Togaviridae group: Comprise most arthropod-borne viruses, also Rubella (German Measles).

Alphavirus

Flavivirus
flavi = Latin for yellow, includes yellow fever, dengue, hepatitis C agents, also Japanese encephalitis virus, Nipah virus are an important disease agents in Asia

70

Alphavirus:

Eastern equine encephalitis (EEE)
Western equine encephalitis (WEE)
Venezuelan equine encephalitis (VEE)

Hep C (not an arbovirus)

71

Flavivirus:

St. Louis encephalitis (SLE)
West Nile Encephalitis (WNE)
Powassan encephalitis (POW)

72

Bunyaviridae - bunyavirus includes:

Hantavirus

California encephalitis serogroup: Includes:
California virus
Jamestown canyon virus
La Cross viruses (LAC) virus.

Highest incidence occurs in:
California,
Midwest,
Southeastern US.

73

Reoviridae (respiratory, enteric orphans): important agents include:

the rotaviruses.

Coltiviruses: Colorado tick fever is caused by CTFVirus
Rare (300 case/y) in US, likely greatly under-reported.

74

Arboviruses cause two primary syndromes in humans, either:

hemorrhagic fever.
encephalitis or meningitis.

75

Epidemiology of Arthropod-borne viruses (arboviruses):

Incidence of each agent varies annually, depending on host, vector, climate.

are the primary cause of epidemic encephalitis.

are agents of benign, aseptic meningitis in summer months when reservoir (birds), vector (mosquitoes), humans are outdoors.

76

Arbovirus transmission

vectors are principally mosquitoes and ticks.

Colorado tick fever and Powassan fever virus are spread by ticks

The rest of the arboviruses are spread by mosquitoes (Culex spp., Ades spp.)

77

Arbovirus Reservoir:

Wide variety of animal reservoirs, however, birds and small mammals serve as principal reservoirs in the U.S.

78

Arbovirus General cycle of infection:

Survival of virus by alternating between vertebrate host (reservoir) and arthropod host (vector). Humans are usually infected tangentially.

79

Arbovirus Age and gender and seasonality:

Some arboviruses primarily cause disease in children; others in the elderly

Gender: NA

Sporadic epidemic occur in summer/early fall months when reservoir, vector, humans are outdoors.


80

Arbovirus Risk factors:

for individuals:
summer and exposure to mosquitoes and ticks.
age.

creation of epidemics are dependent upon the specific virus, its vector, reservoir host:
-A large susceptible reservoir host population (small mammals and birds).
-Large vector population (mosquitoes).
-Favorable climate that supports mosquito vector and reservoir host.

81

Arbovirus Pathogenesis
incubation period?

Primary virus replication (viremia) occurs with each arbovirus having specific target cells, such as ??

3 → 7 days

endothelial cells of the capillaries, macrophages, monocytes, erythrocytes, and the reticuloendothelial system (liver, spleen, lymph nodes) → either no or mild symptoms (typically asymmptomatic! w. seroconversion)

82

arbovirus path 2:
A second round of replication in ?? can occur immediately after the primary round, producing a second viremia, which may yield sufficient virus to attack ?? depending upon the specific virus → ??

reticuloendothelial cells

brain, liver, skin, vasculature, kidney

severe symptoms

*In humans, during the first and second rounds of replication, the viremia is usually low, resulting in mostly asymptomatic infections and humans being incidental hosts

83

Arbovirus Clinical manifestations:

Asymptomatic infection (most common result – [4 of 5 persons infected]).

Disease: Abrupt onset of symptoms which last for a few days → 2w and vary

84

if arbovirus disease occurs, can result in Mild, self-limiting flu-like illness (1 of 5 persons infected) lasting about 1w:

URT symptoms (coryza).
fever.
chills.
sore throat
headache.
nausea, vomiting.
muscle weakness and/or myalgias.
arthralgias.
maculopapular rash.

nonspecific: similar to enterovirus, adenovirus, etc.

85

if arbovirus disease occurs, can result in CNS disease (1 of 150 persons infected):

Mild, self-limiting aseptic meningitis.

acute, fulminant, diffuse, encephalitis (can be focal) and death.

+/- acute flaccid paralysis

86

If a person w/ arbovirus progresses to CNS disease:
onset/duration ??

Onset of CNS disease is usually 1→4 days → 1 week after onset of constitutional signs.

Encephalitis lasts about 1 week.

87

If a person w/ arbovirus progresses to CNS disease:
Manifestations include signs of meningoencephalitis

lethargy
irritability
drowsiness
acute flaccid paralysis
seizures

may evolve into coma, then death due to immunopathology (brain edema) and/or myocarditis

88

diffuse viral encephalitis ddx

Arboviruses
enteroviruses
herpes viruses.
rabies virus (dumb rabies).

89

arbovirus dx

CSF specimen – protein and glucose levels as per viral infection and (PMNs-->monos) mononuclear pleocytosis.

Serologic diagnosis using specific antibody tests performed on CSF or serum specimens.

Isolation of virus from mosquito tissue culture inoculated with a brain biopsy specimen of dead patient is rarely done.

EEG (FYI diffuse, background slowing/diffuse, generalized slowing with occasional delta waves).

CT scan appears normal or generalized, diffuse edema without focal abnormalities.

MRI of brain is more sensitive, reveals areas of infection/inflammation

90

arbovirus tx

supportive

91

arbovirus prevention

Eradication of vector is impossible; goal is limiting the vector population.

Education/behavioral changes:
Avoidance of exposure (late afternoon and evening hours).
Application of DEET-containing insect repellant to skin and clothes.

Immunity is type specific and life-long.

Immunization: Vaccines exist but are not for general use.
There are 2 vaccines for horses
US military has human vaccines for:
Eastern Equine Encephalitis. (EEE)
Western Equine Encephalitis.(WEE)

92

Eastern Equine Encephalitis (EEE):

East Coast, risk highest in wooded areas near swamps and marshes.
(uncommon)

Mosquito vectors.

Children, adolescents and older adults constitute most cases.

*worst mortality rate*; survivors are more likely to manifest with *serious neurological sequelae!*

EEEV is unique in that infection often (not always) results in EEE. **Asymptomatic infection is NOT the norm!!**

93

Western Equine Encephalitis (WEE):

Infections west of Mississippi River predominate; Rural residence highest risk factor.

Mosquitoes is the vector

Most (50% of) cases occur in children

*Most benign form of encephalitis*

94

St. Louis Encephalitis (SEE):

Midwestern US (both urban and rural)

Mosquitoes are the vector.

Age susceptibility varies due to difference in herd immunity between these populations (increased morbidity in very young and very old).
-Children, adolescents in Western US
-Elderly in Eastern USA

*Leading cause of epidemic arboviral encephalitis in US before West Nile Virus epidemic in 2002*

95

West Nile Encephalitis (WNE):

Closely related to St. Louis encephalitis (cross-reacts serologically with SLE). Like SLE, causes more severe disease in elderly (>50 y-o-age) persons.

Geographic distribution:
Africa
Europe
Middle East
West Asia
Australia.
North America.

96

In fall of 1999, West Nile virus (WNV) was detected in ??

the metropolitan NYC area where it caused a micro-epidemic. More recently (2003 → present), the range is the entire eastern ½ of US, California, and part of Canada. 232 people in the US died in 2002.

*Most common arbovirus infection in the US today*.

97

WNV Transmission

Primarily, mosquitoes are the vector.

besides mosquitoes:
Transfusions (4 cases).

1 in utero (6 other women with WNE gave birth to uninfected children)

1 case of a women with WNE passed infection to child via breast milk.

Organ transplants.

98

WNV s/s:
*West Nile Fever*:


flu-like symptoms (moderate to high fever or chills, anorexia, malaise, muscle aches, joint pain, respiratory symptoms).

nausea, vomiting, diarrhea
maculopapular rash spreading from the trunk to head and limbs
frontal headaches of >7days duration.
eye pain.

(typically do not progress on)

99

West Nile Encephalitis is West Nile fever with S/S of one or more of the following:

meningitis.
encephalitis.
parkinsonism – tremors (obviously not in limb(s) with flaccid paralysis)

Focal symptoms of muscle weakness/ascending, asymmetrical diffuse flaccid paralysis:

-diminished deep-tendon reflexes/areflexic leg weakness,

-EMG/nerve conduction velocity studies demonstrate axonal-type polyneuropathy affecting anterior horn cells or their axons vs. demyelination.

-No muscle or sensory pain or sensory loss is noted.

100

Note that ?? are not common manifestations in diffuse encephalitis causeds by other arbovirus agents.

focal symptoms

101

WNV: Regarding neurologic sequelae: Risk of disease is associated with:

advanced age (elderly)
immunosuppression via therapies or hematologic malignancies

102

WNV dx

WNV tx

plasma cells in the CSF

Ribavirin is efficacious in vitro (in cell culture) studies

103

California (CAL) Encephalitis Serogroup:

California and east of the Mississippi River – suburban and rural (forests/sylvatic)

Mosquito vector.

Age susceptibility – Nearly all cases occur in children and adolescents, but usually they manifest with a mild disease.

Seizures may occur during illness, some patients who recover from illness will experience seizures as sequelae

104

?? is the most important cause of arboviral pediatric encephalitis in the USA.

other CALs

La Cross (LAC; Midwestern, Southeastern US)
(CAL Encephalitis Serogroup)

Jamestown canyon and other CAL groups rarely cause disease in humans.

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