When does continuous central nervous system (CNS) viral replication start in latent subacute sclerosing panencephalitis (SSPE)?

Continuous CNS Viral Replication in SSPE: Timing and Pathophysiology

Continuous CNS viral replication in SSPE does not start during a "latent" period—it begins immediately after the initial measles infection establishes persistent infection in the CNS, though clinical symptoms emerge years later after a silent incubation period. 1

Understanding the Terminology: "Latency" vs. Persistent Replication

The term "latent SSPE" is misleading because SSPE involves continuous active viral replication from the outset, not true viral latency:

• SSPE results from persistent mutant measles virus infection specifically in the CNS that begins after the initial measles infection, with the virus establishing continuous replication in neurons from early on 1
• The virus spreads trans-synaptically between neurons with ongoing replication, accumulating mutations in envelope proteins (particularly the M gene with characteristic A to G hypermutations) throughout this period 1, 2, 3
• The presence of persistent measles-specific IgM in both serum and CSF indicates ongoing immune stimulation from continuous CNS viral replication, and this IgM remains elevated for years or even decades regardless of disease stage 1

The Clinical Timeline: Silent Replication, Not Latency

The disease progression involves continuous viral activity during what appears clinically silent:

Phase 1: Initial Measles Infection with CNS Seeding

• Acute measles infection occurs with systemic viremia during the acute illness 1
• The virus establishes persistent infection in CNS neurons during or shortly after this acute phase 1, 4

Phase 2: "Silent" Incubation Period (Not True Latency)

• Typically lasts 2-10 years but can be as short as 4 months, with most cases presenting 6-8 years after initial measles infection 1, 5, 6
• During this period, there is no systemic viremia but continuous CNS viral replication is occurring 1
• The virus replicates continuously in neurons, spreading trans-synaptically, while accumulating biased hypermutations 1, 2, 3
• Persistent measles-specific IgM remains detectable throughout this period, reflecting ongoing immune stimulation from active CNS replication 1

Phase 3: Clinical SSPE Emergence

• Insidious onset of neurological symptoms with progressive deterioration 1, 7
• Symptoms typically begin between ages 5-15 years 5

Diagnostic Evidence of Continuous Replication

Multiple diagnostic markers confirm ongoing viral activity throughout the pre-symptomatic period:

• 100% of SSPE patients maintain detectable measles-specific IgM antibodies in serum, which is highly abnormal since IgM typically disappears 30-60 days after acute measles 1
• Persistent IgM in both serum and CSF, often higher in CSF than serum, indicates ongoing immune stimulation from continuous CNS viral replication 1
• CSF/serum measles antibody index ≥1.5 confirms intrathecal synthesis, demonstrating local CNS antibody production in response to active infection 1, 7
• The combination of persistent measles IgM, elevated IgG, and elevated CSF/serum measles antibody index has 100% sensitivity and 93.3% specificity for SSPE diagnosis 1

Critical Clinical Pitfall to Avoid

Do not confuse the asymptomatic incubation period with viral latency—the virus is actively replicating throughout:

• Unlike true latent infections (e.g., herpes simplex), where viral replication ceases between reactivations, measles virus in SSPE maintains continuous low-level replication in neurons from the time of CNS infection 1, 4, 2
• The persistent presence of IgM years after initial infection is pathognomonic for ongoing viral activity, not reactivation of latent virus 1
• Recent reports show progressively decreasing latency periods, with cases occurring as early as 4 months after measles infection, suggesting that continuous replication can lead to clinical disease much sooner than historically observed 6

Molecular Mechanisms Supporting Continuous Replication

Research demonstrates that viral replication is ongoing throughout the pre-symptomatic period:

• Biased hypermutations (A to G changes) accumulate in the MV M gene over time, indicating continuous viral replication and evolution within the CNS 2, 3
• The virus establishes defective, non-replicating forms that are recoverable by co-cultivation, but replication continues at low levels in neurons 2
• Neural cells do not express typical measles receptors (SLAM, CD46), yet the virus maintains infection through receptor-independent mechanisms that support continuous spread 4

Prevention: The Only Effective Strategy

Since continuous replication begins with initial CNS infection:

• Measles vaccination is the only effective prevention strategy for SSPE, substantially reducing disease occurrence 1, 5
• The MMR vaccine does not increase SSPE risk, even in previously infected individuals 1, 5
• All children should receive two doses of MMR vaccine (first at 12-15 months, second at 4-6 years) to prevent the initial measles infection that leads to SSPE 5