A retrospective cohort study of 21 children in the California Encephalitis Project (CEP) with confirmed herpes simplex encephalitis (HSE) from 1998 to 2011 was performed. This study represents one of the largest series of pediatric HSE patients and highlights important clinical and laboratory features as well as critical differences in presentation compared with adult HSE.
MATERIALS AND METHODS
The CEP was initiated in June 1998 as a collaboration between the California Department of Public Health’s Viral and Rickettsial Disease Laboratory and the Centers for Disease Control and Prevention’s Emerging Infections Program. The CEP ended in 2011.
The CEP included both pediatric and adult patients with suspected encephalitis referred by physicians throughout the state of California. All patients in our study cohort met the following CEP case definition for encephalitis: hospitalization with encephalopathy (depressed or altered level of consciousness lasting ≥24 hours, lethargy or personality changes) with ≥1 of the following characteristics: fever, seizure, focal neurological findings, pleocytosis [white blood cell (WBC) count >5 cells/mm3] or electroencephalography or neuroimaging findings consistent with encephalitis.
For this pediatric HSE study, all patients >6 months to 18 years of age who had a positive cerebrospinal fluid (CSF) polymerase chain reaction (PCR) test for herpes simplex virus (HSV) type 1 from 1998 to 2011 were included. Age, gender, race/ethnicity, clinical signs and symptoms at admission, neuroimaging and electroencephalogram (EEG) findings, laboratory test results [CSF WBC counts, red blood cell (RBC) counts, protein levels] and patient status at discharge were obtained from CEP case history forms and patient medical records. Statistical analyses were performed using Stata13 (StataCorp LP: College Station, TX).
During a 12-year period, 21 of 1748 encephalitis cases in the CEP between the ages of 6 months to 18 years had confirmed HSE (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/B926). There were 10 (48%) male patients; more than half (n = 11, 52%) were <4 years of age. Nine (43%) patients were Hispanic, 5 (24%) White and 5 (19%) Asian/Pacific Islander. The median length of stay for all cases was 15 days (range: 6–48).
Complete CSF profiles (WBC, RBC and protein) were obtained for 20 of 21 patients, 1 of which had a traumatic tap. Of the remaining 19, most had pleocytosis (n = 18, 95%) in their initial LP, less than half had elevated CSF protein level (n = 9, 47%), and 1 (5%) had an RBC count >500 cells/mm3. Of the 21 patients, 6 (29%) had a negative PCR result in the first CSF sample. Initial CSF findings for these 6 patients demonstrated median WBC, RBC and protein counts of 47 cells/mm3 (range 1–90), 3 cells/mm3 (range 2–260) and 29 mg/dL (range 22–48), respectively. A subsequent positive PCR test was obtained on follow-up CSF samples collected a median of 3 days after the initial negative (range 2–4) and a median of 6 days after symptom onset (range 5–7).
Neuroimaging [computed tomography (CT) scan and magnetic resonance imaging (MRI)] was abnormal in many patients: 21 (95%) for MRI and 14 (70%) for CT scans (Table 1). The MRI findings showed 7 patients had isolated temporal lobe involvement, 8 had temporal and extratemporal lobe involvement and 5 had exclusively extratemporal lobe involvement. Overall, neuroimaging identified 13 (59%) patients with extratemporal lobe involvement (including those with simultaneous temporal and extratemporal abnormalities). A hemorrhagic component was seen in 5 (23%) patients. For the 15 patients with EEG testing, 13 (87%) were abnormal. Eight (53%) of these 15 patients had diffuse or multifocal slowing in their EEG, 2 (13%) had periodic lateralized epileptiform discharges and 2 (13%) had temporal epileptiform activity.
Of the 21 patients, 4 (18%) died during their hospitalization despite receiving acyclovir treatment at time of admission. These patients ranged from 13 to 17 years of age. Their initial CSF findings had a higher median WBC than survivors (475 vs. 47 cells/mm3), higher median RBC (214 vs. 4 cells/mm3) and higher protein count (68 vs. 38 mg/dL); however, these differences were not statistically significant. All 4 patients who died presented with fever and headache and 3 had emesis at time of admission; none had seizures at presentation but 1 patient later developed seizures. Temporal lobe involvement was seen on neuroimaging in all (1 also had frontal lobe involvement); 3 also had hemorrhagic component or edema. Temporal epileptiform activity was detected by EEG for 1 patient; the other 3 patients did not have EEG performed.
This review describes 21 children from the CEP with confirmed HSE during a 12-year period and offers insights in terms of differences in presentation by age groups and mortality. It also supports the growing body of literature that the clinical manifestations of HSE in children can be different in than adults.
Large clinical studies of both adults and children with HSE illustrate a bimodal distribution of age that peaks in the pediatric population and in those >50 years of age.1 Some studies have found HSE predominantly in patients >3 years of age, whereas other studies have not identified any age predilection within the pediatric age group.2–4 Our study identified over half of HSE in the younger age group (6 months to 4 years) and another peak in the adolescent years (10–18 years). Interestingly, all deaths in the CEP data were among children 13 years of age or older.
The spectrum of clinical manifestations observed in this study was varied, with the most common manifestations being lethargy, fever, confusion and seizures. In fact, seizures were observed in 92% of children aged 6 months to 4 years compared with only 40% of children aged 10 years or greater, a difference that is statistically significant and also highlighted in the literature.2 It is possible that the lower incidence of seizures in adolescents contributed to a delay in seeking medical care, ultimately leading to a higher mortality.
Although elevated CSF WBC counts and protein levels are associated with HSE, several studies show that normal CSF values are not unusual in children with HSE and can correspond to false-negative HSV PCRs.2,5,6 In addition, HSV PCR can be negative even in children with abnormal CSF. The initial negative HSV PCR test in CSF may be explained by viral clearance because of host antibody responses, presence of polymerase inhibitors that interfere with the PCR or a low viral load in the specimen.7 In the cases reported here, the initial negative PCR results were unlikely to be because of host antibody in our cases because they later became positive. They were also not likely to have been the result of inhibitors, because the Elongase DNA polymerase (Gibco BRL) used by our laboratory is less affected by hemoglobin than is Taq DNA polymerase. Therefore, the initial false negative results in patients were likely because of low viral load.
Not surprisingly, in this study MRI had a higher sensitivity than CT scans, particularly early in the illness. Of the 9 patients with normal CT scans, 8 had abnormal MRI whereas 3 individuals had an abnormal follow-up CT scan. Schleede et al5 found that 6 (25%) non-neonatal patients in their study population exhibited normal MRI findings even 1 week after disease onset.5 Diffusion-weight sequences may be the most sensitive early in the disease, but MRIs can be normal in HSE.5 While temporal lobe abnormalities were commonly found in HSE patients, children differ from adults in the incidence of extratemporal lobe involvement.2,8,9 Neuroimaging results from this study underline the high frequency of isolated extratemporal lobe involvement. In such cases, abnormalities commonly appeared in the frontal and parietal lobes, with other brain areas less commonly represented.
There are a number of limitations to this study. This selected referral population in CEP might be more diagnostically challenging because of less typical presentations (ie, regarding demographics, clinical manifestations and CSF and neuroimaging findings) and might have caused an inflated false-negative HSV PCR rate. Additionally, outcome data are limited to what was available in discharge summaries.
Overall, the findings in this study strengthen the recommendations made by the Infectious Diseases Society of America, which caution clinicians not to dismiss HSE as a possible diagnosis based on negative HSV PCR results from a single CSF sample and/or lack of temporal lobe involvement on neuroimaging.10 Rather, it is essential that clinicians maintain a high index of suspicion for HSE among patients, particularly children, who may not fit the typical clinical picture. Further studies to address the relationship between mortality and age in pediatric patients as well as differences in clinical presentations between age groups will help elucidate the factors contributing to HSE mortality.
1. Whitley RJ, Soong SJ, Linneman C Jr, et al. Herpes simplex encephalitis
. Clinical Assessment. JAMA. 1982;247:317–320
2. De Tiège X, Héron B, Lebon P, et al. Limits of early diagnosis of herpes simplex encephalitis
in children: a retrospective study of 38 cases. Clin Infect Dis. 2003;36:1335–1339
3. Puchhammer-Stöckl E, Presterl E, Croÿ C, et al. Screening for possible failure of herpes simplex virus PCR in cerebrospinal fluid for the diagnosis of herpes simplex encephalitis
. J Med Virol. 2001;64:531–536
4. Elbers JM, Bitnun A, Richardson SE, et al. A 12-year prospective study of childhood herpes simplex encephalitis
: is there a broader spectrum of disease? Pediatrics. 2007;119:e399–e407
5. Schleede L, Bueter W, Baumgartner-Sigl S, et al. Pediatric herpes simplex virus encephalitis: a retrospective multicenter experience. J Child Neurol. 2013;28:321–331
6. Gkrania-Klotsas E, Lever AM. Herpes simplex I encephalitis presenting as a brain haemorrhage with normal cerebrospinal fluid analysis: a case report. J Med Case Rep. 2008;2:387
7. Tyler KL. Update on herpes simplex encephalitis
. Rev Neurol Dis. 2004;1:169–178
8. Wasay M, Mekan SF, Khelaeni B, et al. Extra temporal involvement in herpes simplex encephalitis
. Eur J Neurol. 2005;12:475–479
9. Arita JH, Lin J, Peruchi MM, et al. Herpes simplex type 1 encephalitis restricted to the brainstem in a pediatric patient. Case Rep Med. 2010;2010:606584
10. Tunkel AR, Glaser CA, Bloch KC, et al.Infectious Diseases Society of America. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47:303–327