Acute Measles Encephalitis in Partially Vaccinated Adults

<div><p>Background</p><p>The pathogenesis of acute measles encephalitis (AME) is poorly understood. Treatment with immune-modulators is based on theories that post-infectious autoimmune responses cause demyelination. The clinical course and immunological parameters of AME were examined during an outbreak in Vietnam.</p><p>Methods and Findings</p><p>Fifteen measles IgM-positive patients with confusion or Glasgow Coma Scale (GCS) score below 13, and thirteen with uncomplicated measles were enrolled from 2008–2010. Standardized clinical exams were performed and blood collected for lymphocyte and measles- and auto-antibody analysis. The median age of AME patients was 21 years, similar to controls. Eleven reported receiving measles vaccination when aged one year. Confusion developed a median of 4 days after rash. Six patients had GCS <8 and four required mechanical ventilation. CSF showed pleocytosis (64%) and proteinorrhachia (71%) but measles virus RNA was not detected. MRI revealed bilateral lesions in the cerebellum and brain stem in some patients. Most received dexamethasone +/− IVIG within 4 days of admission but symptoms persisted for ≥3 weeks in five. The concentration of voltage gated calcium channel-complex-reactive antibodies was 900 pM in one patient, and declined to 609 pM ∼ 3 months later. Measles-reactive IgG antibody avidity was high in AME patients born after vaccine coverage exceeded 50% (∼ 25 years earlier). AME patients had low CD4 (218/µl, p = 0.029) and CD8 (200/µl, p = 0.012) T-cell counts compared to controls.</p><p>Conclusion</p><p>Young adults presenting with AME in Vietnam reported a history of one prior measles immunization, and those aged <25 years had high measles-reactive IgG avidity indicative of prior vaccination. This suggests that one-dose measles immunization is not sufficient to prevent AME in young adults and reinforces the importance of maintaining high coverage with a two-dose measles immunization schedule. Treatment with corticosteroids and IVIG is common practice, and should be assessed in randomized clinical trials.</p></div

Presentation signs and symptoms of 15 measles acute encephalitis patients.

<p>+ and – symbols indicate present and absent, respectively.</p>§<p>Other symptoms: 006 and 008 had lymphadenopathy; 011 had papilloedema; 031 had an abnormal abdominal exam.</p>†<p>These patients developed encephalitis signs after admission and CSF was collected at that time.</p

Lymphocyte subset counts in AME patients versus controls.

<p>Results for CD8 (A), CD4 (B) and CD19 (C) counts during early illness (day 5–13) are shown for 13 controls (blue circles) and 6 AME patients (red filled circles). Results are also shown for AME patients in late illness (n = 8) and following recovery (n = 6) with lines connecting multiple time points for the same patient. Horizontal lines represent the lower +/− upper limits of the normal range.</p

Relationship between age and serum concentration and avidity of measles-reactive IgG in AME patients and controls.

<p>Results are shown for 15 AME patients (top panels) and 13 controls (bottom panels). Results are categorized as being tested before (○) or from day 7 since fever onset (•) because titers increased from day 7. Results for tests done before and after day 7 since fever for two AME patients are joined by a line. One patient tested more than 19 days after fever onset is indicated (*). Sera that were tested after administration of IVIG are also indicated (#). Vertical lines differentiate patients born before and after measles vaccine was widely available in Vietnam. Horizontal lines in panel B indicate avidity cut-offs for identifying secondary (upper) and primary (lower) type antibody responses with intermediate levels being indeterminate.</p

Timing of confusion in relation to rash and treatment with steroids and IVIG for 15 AME patients.

<p>Rash (purple); confusion (green); steroids (orange); IVIG (dark green).</p

Detection of influenza virus RNA in respiratory specimens from patients with severe versus mild influenza.

<p>Nose and throat swabs were assessed for the presence of viral RNA as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031535#s4" target="_blank">methods</a>. Red dots/lines indicate the first and last days from fever onset when viral RNA was detected, the first day being when the first sample was collected. Blue dots represent the last day that samples were tested.</p

Patient characteristics.

<p>*adapted PMEWS = adapted pandemic medical early warning score as defined in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031535#s4" target="_blank">methods</a>.</p

Activation and differentiation marker expression by CD8 T cells from patients with severe versus mild influenza.

<p>Panels a–f show the percentages of cells expressing the markers indicated on the vertical axis by time interval since onset. Each line represents an individual patient. Panel g shows the relationship between the percentages of CD8 T cells that are CD38+HLADR+ and CD27+CD28− and includes results for all time points. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031535#s2" target="_blank">Results</a> are shown for 10 patients with severe influenza (red tones symbols and lines) and 39 patients with mild influenza (blue tone symbols and lines).</p

T and NK cell counts in severe versus mild influenza.

<p>Panel's a–c show lymphocyte subset counts by time interval since onset with each line representing an individual patient. Horizontal solid lines represent the lower limit of the normal range. Panels d–f show nadir values for lymphocyte subset counts versus pandemic medical early warning score (PMEWS) with Spearman's correlation coefficients. The 2 patients that died are indicated ( ) because they were only assessed at one or two time points. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031535#s2" target="_blank">Results</a> are shown for 10 patients with severe illness (red tone symbols and lines) and 39 patients with mild illness (blue tone symbols and lines).</p

Analysis of lymphocytes and subsets.

<p>*1 severely ill patient was not assessed at enrolment.</p><p>**The day post-onset for follow-up assessments was 35 (31–47) for mild patients and 34 (31–37) for severe patients.</p