Age: 4.0
Sex: F
Vaccine: VARCEL
Symptoms: Autopsy, Biopsy brain abnormal, Blood calcium decreased, Blood culture negative, Blood electrolytes normal
Clinical narrative: Varicella-zoster virus (VZV) causes varicella as primary infection; virus remains latent and can reactivate to cause herpes zoster. Neurologic complications associated with both illnesses, albeit rare, have been reported among both healthy and immunocompromised patients. The patient was admitted to the hospital in February 2011, after complaining of sudden severe headache and right eye pain. During the 10 days before admission, she had experienced frequent and intermittent episodes of vomiting, headaches, seizures, lethargy, low-grade fever, mental status changes, poor interaction, and poor appetite. She did not have cough, abdominal pain, diarrhea, or rash. No history of recent travel, or known sick contacts at home or the child care center she attended were noted. She had received 1 dose of varicella vaccine at age 13 months and had no history of varicella disease. Her medical history was remarkable for nasal septum perforation with subsequent recurrent sinusitis requiring prolonged courses of antibiotic therapy. Additionally, she had hypocalcemia-related seizures at age 1 year secondary to partial hypoparathyroidism; a DiGeorge syndrome workup including a fluorescence in situ hybridization test for 22q11 chromosomal deletion was negative. No documentation of T & B cell subsets being performed was found. She received calcium supplements and had no more seizures. The patient had no history of chronic medical conditions or immunosuppressive medications, was born full-term without reported complications, had reached appropriate developmental milestones, and had performed adequately at preschool. On physical examination, the patient was drowsy, drooling, lethargic, and increasingly unresponsive to verbal stimuli. Her vital signs were normal. Neck was supple. Pupillary reflexes and fundoscopy were normal. She had a right gaze preference and probable left hemianopia with some tremors in her extremities. No rash or dysmorphic features were noted. Her general and neurologic examinations were otherwise unremarkable. Laboratory data revealed a white blood cell count of 10x109/L (neutrophils 85%, lymphocytes 7%, monocytes 8%); platelet count was 287x109/L. Total calcium was 8.6 mg/dL and ionized calcium was 1.07mmol/L. The patient's electrolyte panel, glucose, liver enzymes, and renal function tests were within normal limits. Blood cultures were negative. Lumbar puncture and cerebrospinal fluid (CSF) tests were not performed. No extensive laboratory evaluation of immunocompetence was performed. A computed tomography (CT) brain scan showed a discrete enhancing lesion measuring 3x3 cm without ring enhancement in the right posterior parietal lobe with surrounding vasogenic edema, indicating an infectious or inflammatory process. A well-defined abscess was not clearly identified and an underlying mass lesion could not be excluded. Follow-up magnetic resonance imaging was consistent with a primary glial neoplasm with local mass effect. A head CT scan in 2008 after her hypocalcemic seizure indicated no brain abnormalities. A facial computed tomography (CT) scan in February 2011, approximately 2 weeks before her hospital admission, demonstrated a perforated nasal septum, paranasal sinus opacification, and an enhancing mass suggestive of redundant nasal mucosa, enlarged vomeronasal organ, or nasal glioma. Recommended nasal endoscopy and biopsy were not performed. The patient was given a preliminary diagnosis of primary brain tumor, with mild local mass effect, and treated with supportive measures. No antibiotics or antivirals were administered. The patient's condition worsened, and during hospital day 4 she developed symptoms of increased intracranial pressure. An electroencephalogram (EEG) revealed strong epileptiform activity in the area of the suspected tumor and subclinical seizures on video electroencephalogram (EEG) monitoring. A head computed tomography (CT) scan indicated no changes. During hospital day 5, the patient's symptoms worsened, and she had no pupillary light reflex. An emergent head CT scan indicated an obstruction of the fourth ventricle and evidence of herniation. She underwent emergent external ventricular device placement. Intraventricular pressure monitoring beginning at that time revealed extremely elevated pressures. On hospital day 6, the day the patient died, a cerebral perfusion study indicated no intracerebral blood flow, consistent with brain death. A postmortem examination was performed. The brain appeared swollen with tissue softening and hemorrhages. No discrete brain lesion was grossly visible. A biopsy of the right side of the brain was performed. Microscopic examination revealed necrosis with inflammation, including clusters of microglia, consistent with encephalitis. No evidence of a tumor was observed. Brain specimens were sent to the Centers for Disease Control and Prevention for additional testing. Multifocal encephalitis with viral-like inclusions were seen by hematoxylin-eosin stain. Extensive multifocal immunohistochemical staining of varicella zoster virus (VZV) antigens was seen in association with tissue damage; no evidence of herpes simplex virus or bacterial infection was observed. Polymerase chain reaction (PCR) testing of DNA extracted from specimens was positive for wild-type varicella zoster virus (VZV). VZV encephalitis was determined to be the cause of death. In June 2011, a pediatrician notified the local Department of Health that a four year-old female patient died of varicella zoster virus (VZV) encephalitis. To the reporters knowledge, this is the first reported fatal case of VZV encephalitis in a child who had received 1 dose of varicella vaccine. Additionally, the child did not have rash. Two major pathologic mechanisms have been proposed as contributing to the development of VZV encephalitis: direct viral invasion of the brain and an autoimmune process. The findings in this case, including acute presentation, localization of viral antigens in encephalitic lesions, and detection of VZV DNA from brain tissue, suggest direct viral invasion. Among children who have received varicella vaccine, nonfatal neurologic complications have been reported rarely following varicella or herpes zoster; a few of these were confirmed to be a result of vaccine-strain VZV. Among unvaccinated persons, wild-type VZV is known to cause fatal neurologic complications. Because the patient described in this report had received 1 dose of varicella vaccine and had no recognized evidence of an immunocompromising condition, her clinical presentation raises questions about why the illness was fatal, and we found no conclusive answers. Although, VZV-associated illness generally manifests with rash, encephalitis related to primary VZV infection without a rash in an unvaccinated immunocompetent child was described in one report. Cases of neurologic complications associated with reactivated VZV but without rash (zoster sine herpete) in unvaccinated immunocompetent children have also been reported. Detection of wild-type VZV, and the absence of varicella rash history, indicate this patient had unrecognized varicella, either previously or at the time of this fatal illness. We were unable to determine whether the patient's encephalitis was because of breakthrough infection or herpes zoster. In healthy vaccinees, breakthrough varicella is usually mild. However, in this patient, we cannot exclude the possibility of an underlying immunocompromising condition, given some features in her medical history that could have led to severe breakthrough. If the patient's illness was breakthrough, its severity might also be attributable to lack of response to vaccination. Serologic studies have reported that 15%-24% of healthy children lack adequate antibody response after 1 dose of varicella vaccine, and clinical studies have revealed that approximately one-quarter of breakthrough cases have clinical characteristics similar to varicella among unvaccinated persons. Waning of vaccine-induced immunity was suggested by one study but not confirmed by others. In this patient, the reporter also could not exclude the possibility of herpes zoster. Past breakthrough disease, although not reported, could have been missed considering that the presentation is usually mild or atypical. The differential diagnosis between varicella and herpes zoster could be made clinically in most situations by assessing rash, but this patient did not have rash at presentation. No laboratory tests exist to differentiate between the 2 illnesses. Children with acute otherwise unexplained neurologic symptoms may warrant an investigation for encephalitis, and that VZV should be considered as a possible cause of encephalitis, even if rash is not present and varicella vaccine has been received. Available tests include PCR to detect the viral genome in CSF and assays to detect intrathecal immunoglobulin G. Biopsy can also be considered in individual cases and may aid with diagnosis. Early diagnosis improves the chance of successful treatment. For this patient, past varicella vaccination, absence of rash, and atypical neuroimaging did not raise suspicion of VZV encephalitis. To provide protection among children who do not respond adequately to the first dose of varicella vaccine and to further reduce the disease burden of varicella, a second dose of varicella vaccine is recommended for children aged 4-6 years. The fact that this child was appropriately vaccinated for age may prompt consideration of earlier administration of the second dose. A copy of the published article will be provided as further documentation of the patient's experience. Additional information has been requested.