Chronic CNS viral disease: PML and SSPE

Question 1

chronic diseases of CNS caused by viruses

Answer 1

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

Question 2

PML

Answer 2

Progressive Multifocal Leukoencephalopathy:

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

Question 3

PML Etiologic agent

Answer 3

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

Question 4

polyomaviruses: 3 human agents

Answer 4

JC virus
BK virus – Polyomavirus hominis type 1
SV40.

(Human papillomaviruses are also members of the papovavirus family)

Question 5

PML in immunocompetent:

Answer 5

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

Question 6

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

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

Answer 6

BK viruses

urine

Question 7

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

and ?? (JC).

Answer 7

kidney

B lymphocytes

Question 8

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

Answer 8

immune system

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

Question 9

BKV causes:

Answer 9

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.

Question 10

JCV causes:

Answer 10

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

Question 11

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

pathogenesis:

Answer 11

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.

Question 12

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

Answer 12

pediatric brain tumors.

Question 13

JCV:

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

Answer 13

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

Question 14

JCV clinical/neuro manifestations

Answer 14

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

Question 15

PML ddx

Answer 15

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

Question 16

PML dx

Answer 16

*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.

Question 17

PML px

Answer 17

80% of those reactivation disease die within 9 months.

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

Question 18

PML tx and tx px

Answer 18

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

Question 19

Natalizumab

Answer 19

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

Question 20

SSPE

Answer 20

Subacute Sclerosing Panencephalitis:

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

Question 21

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

Answer 21

children and young adults

defective measles virus infection

Question 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 ??

Answer 22

(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

Question 23

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

Answer 23

immigrants and internationally adopted children

Question 24

SSPE pathogenesis:

Answer 24

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.

Question 25

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

Answer 25

infected brain biopsies

Question 26

SSPE pathological features:

Answer 26

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.

Question 27

SSPE: Clinical and neuropathological characteristics:

onset–>decline

Answer 27

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.

Question 28

px of SSPE

Answer 28

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

Question 29

SSPE ddx FYI

Answer 29

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

Question 30

SSPE CSF parameters:

serum:

what indicates intrathecal synthesis of measles-specific IgG??

Answer 30

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)

Question 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?

Answer 31

“Burst-suppression”

correlates with myoclonic jerks

MRI

Question 32

SSPE tx

Answer 32

NONE

Question 33

SSPE prevention

Answer 33

no vaccination yet