Chronic CNS viral disease: PML and SSPE Flashcards
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
PML
Progressive Multifocal Leukoencephalopathy:
An uncommon, subacute, progressive demyelinating disease of the CNS.
PML Etiologic agent
papovaviruses; belonging to the Papovaviridae: naked dsDNA viruses with icosahedral symmetry
polyomaviruses: 3 human agents
JC virus
BK virus – Polyomavirus hominis type 1
SV40.
(Human papillomaviruses are also members of the papovavirus family)
PML in immunocompetent:
causes a common, asymptomatic infection (acquired by respiratory route during childhood).
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
Each virus persist lifelong in the ?? (BK and JC)
and ?? (JC).
kidney
B lymphocytes
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)
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.
JCV causes:
a rare (2→4%) opportunistic CNS reactivation disease in advanced HIV/AIDS patients older adults, & persons on Natalizumab
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.
JC viral genes are present in many (>70% of all) ??
pediatric brain tumors.
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
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
PML ddx
HAD
Primary brain tumor – EBV-associated primary CNS lymphoma Toxoplasmosis encephalitis
PML
Cryptococcal meningoencephalitis
CMV polyradiculopathy, encephalitis, myelopathy, etc.
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.
PML px
80% of those reactivation disease die within 9 months.
Mean survival for advanced HIV/AIDS patient is 3→5 months
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
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
SSPE
Subacute Sclerosing Panencephalitis:
A rare, slowly progressive, inflammatory, demyelinating disease of the CNS
SSPE occurs primarily in ??caused by a ?? of the CNS.
children and young adults
defective measles virus infection
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
Common incidence: 7 → 11 cases/100,000 cases of measles, so ?? are at higher risk.
immigrants and internationally adopted children
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.
Intact, infectious virion (measles) is never recovered from ??.
infected brain biopsies
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.
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.
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
SSPE ddx FYI
SSPE, Creutzfeldt-Jacob Disease, Huntington’s chorea, Wilson’s Disease, Progressive myoclonic epilepsy, mitochondrial disease, adult-type neuronal ceroid lipofuscinosis
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)
?? 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
SSPE tx
NONE
SSPE prevention
no vaccination yet
