Chronic CNS viral disease: PML and SSPE Flashcards Preview

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Flashcards in Chronic CNS viral disease: PML and SSPE Deck (33):
1

chronic diseases of CNS caused by viruses

Long period of latency- months to several years

Protracted course after clinical signs appear, leading to serious illness and death

Infection limited to one organ or tissue system

2

PML

Progressive Multifocal Leukoencephalopathy:

An uncommon, subacute, progressive demyelinating disease of the CNS.

3

PML Etiologic agent

papovaviruses; belonging to the Papovaviridae: naked dsDNA viruses with icosahedral symmetry

4

polyomaviruses: 3 human agents

JC virus
BK virus -- Polyomavirus hominis type 1
SV40.

(Human papillomaviruses are also members of the papovavirus family)


5

PML in immunocompetent:

causes a common, asymptomatic infection (acquired by respiratory route during childhood).

6

Worldwide, 60→90% of the adult population is seropositive for ??

At any time, ~10% of the human population is shedding said virus in ??

BK viruses

urine

7

Each virus persist lifelong in the ?? (BK and JC)
and ?? (JC).

kidney

B lymphocytes

8

PML: A fatal disease is most often associated with some underlying disorder of the ??.
JC and BK viruses are reactivated by ??

immune system

immunosuppression (any disease and/or treatment which causes profound T cell depression)

9

BKV causes:

a fatal opportunistic kidney (nephropathy) reactivation disease in some (~8% of) renal transplant patients with a loss of graft function occurring in 50% of cases.

a severe urinary tract disease in advanced HIV/AIDS patients.

10

JCV causes:

a rare (2→4%) opportunistic CNS reactivation disease in advanced HIV/AIDS patients older adults, & persons on Natalizumab

11

JCV: First human demyelinating disease shown to be caused by a virus

pathogenesis:

invades brain and infects oligodendrocytes

-->replicates in oligodendrocyte nuclei (intranuc. inclusions), causes cell dysfunction and death (lytic infection)

-->Virus shed from infected oligodendrocytes spreads to contiguous cells, thus extension of infection occurs along myelin tracts

-->Also infects and causes an abortive infection in astrocytes, in which morphologic features resembling neoplasia (glioblastomas) are present.

12

JC viral genes are present in many (>70% of all) ??

pediatric brain tumors.

13

JCV:
??? is most affected with multiple foci of myelin destruction

Subcortical white matter

absence of oligodendrocytes
abnormal (bizarre-shaped) astrocytes
sparing of neurons and their axons
enlarged oligodendrocytes with intranuclear inclusion are present at the periphery of demyelination

*Inflammatory cells are sparse or absent

14

JCV clinical/neuro manifestations

Rapid evolution (3→6 months from initiation of disease to death)

Diverse signs and symptoms:
Muscle weakness
Ataxia
Cognitive and speech Visual loss and other sensory abnormalities

15

PML ddx

HAD
Primary brain tumor – EBV-associated primary CNS lymphoma Toxoplasmosis encephalitis
PML
Cryptococcal meningoencephalitis
CMV polyradiculopathy, encephalitis, myelopathy, etc.

16

PML dx

*Clinical signs and symptoms
*PCR of CSF is sensitive in about 82% of the cases,
*Neuroimaging - MRI detects demyelinating lesions, esp. in the white matter,
Characteristic EEG
*Characteristic pathology observed in brain biopsy.

17

PML px

80% of those reactivation disease die within 9 months.

Mean survival for advanced HIV/AIDS patient is 3→5 months

18

PML tx and tx px

Cidofovir appears effective

HAART has had a (+) effect on incidence, severity of PML in AIDS pt.

If CD4 count is 100 cells/μL, prognosis is good if HAART is initiated

19

Natalizumab

monoclonal antibody directed against the α 4 chain of VLA-4

tx for highly active, relapsing–remitting multiple sclerosis; later withdrawn by the manufacturer in February 2005 after 3 patients developed PML during clinical trials

back on market for Crohn's in 2008

20

SSPE

Subacute Sclerosing Panencephalitis:

A rare, slowly progressive, inflammatory, demyelinating disease of the CNS

21

SSPE occurs primarily in ??caused by a ?? of the CNS.

children and young adults

defective measles virus infection

22

SSPE manifests years ?? after wild-type measles virus (MV) infection
does not occur with ??

Risk of SSPE is much (16X) greater if MV infection occurred ?? vs ??

(6→15 y; range 1→35 y)

attenuated strains such as that used in vaccine

before 2-y-o-age
MV infection after 5-y-o-age

23

Common incidence: 7 → 11 cases/100,000 cases of measles, so ?? are at higher risk.

immigrants and internationally adopted children

24

SSPE pathogenesis:

UNKNOWN
Active, persistent defective/(mutant?) measles virus infection of CNS, resulting in a continuous immune-mediated inflammatory response
Both neurons and glial cells are infected.

25

Intact, infectious virion (measles) is never recovered from ??.

infected brain biopsies

26

SSPE pathological features:

Involvement of both white and gray matter with changes predominantly in the posterior cerebral

Perivascular cuffing (lymphocytes, plasma cells) of cerebral vessels.

*Varying degrees of demyelination observed*
*Intense inflammation* (gliosis and microglial reaction are striking).

*NOT an autoimmune disease.

27

SSPE: Clinical and neuropathological characteristics:
onset-->decline

Insidious onset, behavioral changes/problems, lowered school performance.

Followed by obvious intellectual decline, disturbed motor functions (awkwardness, stumbling, myoclonic jerks – AKA drop attacks), seizures, blindness (retinopathy).

Next a stuporous rigid state.
Then loss of cortical function, mutism, flexed posture.

28

px of SSPE

Death occurs slowly in 1→2 y after onset of symptoms.

no therapy

RARELY (in ~ 5% of all cases) there is long-term remission (5 → 20 years) yet CSF measles virus titers remain elevated

29

SSPE ddx FYI

SSPE,
Creutzfeldt-Jacob Disease,
Huntington’s chorea,
Wilson’s Disease,
Progressive myoclonic epilepsy,
mitochondrial disease,
adult-type neuronal ceroid lipofuscinosis

30

SSPE CSF parameters:

serum:

what indicates intrathecal synthesis of measles-specific IgG??

Normal except hyperglobulinorrachia (highly elevated measles-specific antibody titers)

Elevated serum measles IgG titer

→ CSF:serum measles IgG index (*indicates intrathecal synthesis of measles-specific IgG*)

31

?? pattern in EEG of non-comatose pt early in SSPE (other cases where this occurs is with sporadic Creutzfeldt-Jacob Disease patient)

correlates with ??
other dx modality?

“Burst-suppression”

correlates with myoclonic jerks



MRI

32

SSPE tx

NONE

33

SSPE prevention

no vaccination yet

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