Ongoing CNS Viral Replication in Latent SSPE
Yes, there is ongoing CNS viral replication during the so-called "latent" phase of SSPE—this is not true latency but rather persistent, active infection with defective measles virus that continuously replicates in neurons, driving progressive neurodegeneration.
Understanding SSPE Pathophysiology: Persistent Infection, Not Latency
The term "latent" is misleading when applied to SSPE. SSPE results from persistent mutant measles virus infection specifically in the CNS, where the virus continuously replicates in neurons despite being defective and unable to produce infectious virions 1. This is fundamentally different from true viral latency (like herpes viruses) where viral genomes remain dormant without active replication.
Evidence for Ongoing Viral Replication
- Viral RNA is continuously detectable in CNS tissues of SSPE patients, with measles virus N, M, and H gene RNA present throughout the brain, and viral burden correlating with disease progression 2
- The level of both viral RNA and viral antigen in the brain correlates with disease stage, with up to four-fold differences in viral load between patients that correspond with detection of measles virus protein 2
- Defective but replicating virus spreads trans-synaptically through the CNS, with envelope proteins accumulating mutations that allow local cell fusion and viral ribonucleoprotein spread despite massive immune responses 3
The Mechanism of Persistent Replication
The virus undergoes biased hypermutation (primarily A to G changes in the M gene) that allows it to evade immune surveillance while maintaining replication capacity 4, 3. Key features include:
- The matrix (M) gene is most heavily mutated and becomes dispensable, allowing the virus to replicate without producing budding virions 3
- Mutations arise both individually through polymerase errors and in clusters through hypermutation, presumably from RNA unwinding/modifying activity on double-stranded RNA regions 3
- The virus maintains tight interdependence between F and H fusion proteins to enable local cell fusion and spread of viral ribonucleoproteins through the CNS, even though H protein is poorly transported to the cell surface 3
Immunologic Evidence of Active Replication
The presence of persistent measles-specific IgM in both serum and CSF—often higher in CSF than serum—indicates ongoing immune stimulation from continuous CNS viral replication 1. This is pathognomonic for SSPE:
- In acute measles, IgM becomes undetectable within 30-60 days after infection 1, 5
- In SSPE, IgM remains persistently elevated for years or even decades, regardless of disease stage, reflecting continuous antigenic stimulation from replicating virus 1
- 100% of SSPE patients maintain detectable measles-specific IgM antibodies in serum, which is highly abnormal and distinguishes SSPE from resolved measles infection 1
Diagnostic Implications
Detection of intrathecal synthesis of measles-specific antibodies (CSF/serum antibody index ≥1.5) confirms local CNS production in response to ongoing viral replication 1, 5. The combination of:
- Persistent measles IgM in serum and CSF
- Elevated measles-specific IgG
- CSF/serum measles antibody index ≥1.5
Has 100% sensitivity and 93.3% specificity for SSPE diagnosis 1.
Clinical Timeline Clarification
There is confusion about the "latent period" in SSPE. The 2-10 year interval between acute measles infection and SSPE symptom onset represents the time needed for mutant virus to establish persistent CNS infection and accumulate sufficient neuronal damage—not a period of viral dormancy 1, 6.
- During acute measles, there is systemic viremia that resolves within weeks 1
- After acute infection clears, defective viral clearance allows neurovirulent strains to establish chronic CNS infection 6
- The virus continuously replicates in neurons during this entire "asymptomatic" period, with progressive accumulation of infected cells and neuronal damage 2, 4
- Clinical symptoms emerge when neuronal damage reaches a threshold, not when viral replication begins 6
Common Pitfalls to Avoid
Do not confuse SSPE with HSV encephalitis relapse, where continuing viral replication after treatment is a concern requiring extended aciclovir therapy 7. In HSV encephalitis, CSF PCR can remain positive for several days after starting treatment, and some advocate continuing treatment until CSF is PCR-negative 7. SSPE is fundamentally different—it represents years of established persistent infection, not acute infection with incomplete clearance.
Do not assume the presence of measles IgM indicates recent measles exposure or reinfection 1. In low-prevalence settings, false-positive IgM results are common, but in the context of:
- Progressive neurological deterioration
- Characteristic EEG findings (periodic complexes)
- Elevated CSF/serum measles antibody index
Persistent IgM definitively indicates SSPE with ongoing CNS viral replication 1, 5.
Treatment Implications
The lack of effective antiviral therapy reflects the unique biology of persistent SSPE virus—it replicates continuously but produces defective, non-infectious virions that cannot be targeted by conventional antivirals 6.
- Intrathecal ribavirin has been used with limited success, as the virus has already established widespread CNS infection by the time of diagnosis 8, 9
- Interferon alpha, inosine pranobex, and ribavirin show the most potential for prolonging survival beyond three years, but do not eliminate ongoing viral replication 9
- Supportive and palliative care remain the primary management strategy once SSPE is confirmed 6
The only effective intervention is prevention through measles vaccination, which substantially reduces SSPE occurrence 1, 5. The MMR vaccine does not increase SSPE risk—cases reported after vaccination represent unrecognized measles infection before vaccination 5.