HERPES SIMPLEX VIRUS REACTIVATION AFTER SUBTOTAL HEMISPHERECTOMY IN A PEDIATRIC PATIENT

Abstract

We report herpes simplex encephalitis (HSE) in a toddler after a subtotal hemispherectomy for seizures related to HSE 16 months earlier. Herpes simplex virus reactivation in the cerebrospinal fluid shortly after treatment of HSE has been described, but is extremely rare in other situations. HSE reactivation is a potential complication of epilepsy surgery after HSE in children.

Herpes simplex encephalitis (HSE) is the most common cause of sporadic fatal encephalitis worldwide.^1–3 Beyond the newborn period, the development of HSE is believed to be the result of reactivation of the virus from neural ganglia, but is on occasion coincident with primary infection. Recurrences have been described after short courses or with lower doses of acyclovir therapy, usually soon after stopping treatment.³ We report the case of a 23-month-old boy with a remote history of HSE and postoperative herpes simplex virus (HSV) reactivation in the cerebrospinal fluid (CSF) after a subtotal hemispherectomy for seizure control. Review of the literature revealed 1 previously reported case of HSE reactivation after neurosurgery in a child with a history of HSE in infancy, and 10 cases of HSE after neurosurgery without a prior history of HSE.

CASE REPORT

A 23-month-old immunocompetent boy, with a history of HSE associated with a right middle cerebral artery infarction and medically intractable seizures, developed fevers after a right subtotal hemispherectomy for seizure management. At 7 months of age, he had presented with fever, irritability, staring spells, and muscle rigidity. Maternal history of herpes infection was denied as was a history of neonatal herpes infection. HSV polymerase chain reaction (PCR) from CSF was positive and he completed 21 days of intravenous acyclovir therapy. Dosing of acyclovir and typing of HSV were not available for review. A right middle cerebral artery infarction was noted by magnetic resonance imaging at the time of diagnosis and subsequent left-sided hemiparesis and visual field defects. Seizures continued during and after acyclovir therapy. His refractory epilepsy was nonresponsive to multiple antiseizure medications, including phenytoin, phenobarbital, levetiracetam, and clonazepam. Topiramate led to some reduction in daily seizure frequency. Inpatient video electroencephalography revealed right hemispheric epilepsy with left arm tonic seizures and asymmetric spasms, left greater than right. Presurgical evaluation included an 18 fluorodeoxyglucose positron emission tomography, which demonstrated marked reduction of tracer in the right centrotemporal areas corresponding to an extensive area of encephalomalacia in the middle cerebral artery territory, consistent with a prior middle cerebral artery infarction. Epilepsy surgery was recommended and a right functional hemispherectomy was performed approximately 14 months after treatment of HSE. Surgery was uncomplicated and included extraventricular device (EVD) placement. Dexamethasone was started at 0.1 mg/kg/dose every 12 hours, as is routine for this surgery as well as acyclovir 20 mg/kg/dose every 8 hours. On postoperative day 1, he was febrile to 38.2°C. Daily EVD CSF Gram stain, bacterial culture, cell count, glucose, and protein were sent until removal of EVD on postoperative day 3 (Table 1). CSF bacterial cultures were negative. Due to persistent fever and irritability, a lumbar puncture was performed on postoperative day 5. Routine CSF studies and CSF HSV PCR were sent. Empiric vancomycin and ceftazidime were initiated but discontinued when bacterial CSF, urine, and blood cultures were negative after 48 hours. Acyclovir was continued at 20 mg/kg/dose every 8 hours. Fever persisted daily, and he was extremely irritable. On postoperative day 8, CSF HSV PCR was positive for type 1. Dexamethasone was discontinued. Repeat lumbar puncture performed on postoperative day 11 had a negative CSF HSV PCR (Table 1). Magnetic resonance imaging on postoperative day 13 showed no evidence of new disease compared with prior scans. He completed a 3 week course of IV acyclovir therapy. At 3 weeks posthemispherectomy he was doing well, with daily improvement, no seizures, and resolution of irritability and fevers. Surgical pathology of the resected tissue demonstrated multiple remote infarctions consistent with remote ischemic injury and microglial nodules, suggestive of a history of HSE. Immunohistochemical stain for HSV did not reveal viral inclusions.

TABLE 1: Cerebrospinal Fluid Results

DISCUSSION

Reactivation of HSV after HSE is an unusual occurrence, almost always reported immediately after completion of initial treatment of a primary encephalitis.³ Ito et al reported data for 27 children, 3 months to 16 years of age, who experienced HSE relapse.⁴ Two of these children had confirmatory positive CSF HSV PCR on days 6 and 13 of the relapse, with prior negative CSF HSV PCR results and after completion of acyclovir therapy. Other cases were diagnosed clinically. Duration of acyclovir therapy was approximately 3 days shorter in the relapse group than the control group. Additionally, the daily dose was slightly lower in the relapse group (26.2 mg/kg/d vs. 30.8 mg/kg/d). In this study, a second relapse was described in a 12-year-old girl who had received a second course of acyclovir from 30 to 45 mg/kg/d for 10 to 21 days. She received a third course of acyclovir at 45 mg/kg/d for an additional 14 days and recovered. Valencia et al reported 2 cases of HSE relapse with resulting neurovegetative states in previously healthy children 2 years and 6 months of age at presentation, respectively. The 2-year-old child received acyclovir 45 mg/kg/d for 14 days with dexamethasone for 3 days, and relapsed 14 days after treatment. The 6-month-old child was treated for 21 days with acyclovir 45 mg/kg/d and dexamethasone for 4 days, with relapse 3 days after stopping acyclovir. All the cases reviewed above relapsed within 2 weeks of stopping primary therapy.³

A single case of HSV reactivation in the CSF after epilepsy surgery in a pediatric patient with a prior history of HSE and mesial temporal sclerosis has been reported in the literature.⁵ In this case, a diagnosis of HSE had been made at 16 months of age, and reactivation occurred 6 years later after a left amygdalohippocampectomy for intractable partial epilepsy performed through a medial temporal gyrus corticotomy, the previous site of herpes infection. After 3 weeks of acyclovir, a new persistent receptive dysphasia remained.

Postoperative HSE has also been reported without a prior history of HSE, including a 35-year-old woman who underwent posterior fossa decompression for a Chiari malformation.⁶ Two weeks postoperatively, she developed progressive bifrontal and occipital headaches and was readmitted. Three weeks postoperatively, she had meningism and photophobia. CSF PCR was obtained and positive for HSV type 2. Acyclovir therapy was initiated, with an improvement in her meningitic symptoms. Perioperative dexamethasone had been given previously. Her headaches resolved after 3 months, but leg and lower back pain continued at 15 months. Of interest is that HSV type 2 was isolated from CSF as HSE is typically due to HSV type 1 beyond the neonatal period.² Such a finding supports proposed mechanisms of transient immunosuppression related to perioperative steroid therapy, surgical stress, and trauma leading to HSV reactivation after neurosurgery.^5,7,8,9

Our case, presenting with fever and irritability after surgery, illustrates the importance of considering HSV reactivation as a contributor to postoperative symptoms in neurosurgical patients, particularly in those with a prolonged hospital stay and ongoing complications. The diagnostic procedure of choice in identifying HSE is CSF PCR. Sensitivity and specificity have been reported at over 90%.^2,10 However, nonstandardized methods of performing HSV PCR have been employed, with various primers in use and thereby gene expression.¹⁰ Negative CSF HSV PCR results must be interpreted with caution, as these results can be seen within 72 hours of onset of symptoms. Positive CSF HSV PCR results have been reported 4 to 7 days later. Repeat CSF HSV PCR should be obtained after therapy to ensure eradication of replicating HSV. After 14 days of therapy, CSF HSV PCR has been noted to be negative in 80% of cases.