Published online April 10, 2006
PEDIATRICS Vol. 117 No. 5 May 2006, pp. e1045-e1048 (doi:10.1542/10.1542/peds.2005-1867)
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EXPERIENCE & REASON

Herpes Simplex Virus Central Nervous System Relapse During Treatment of Infantile Spasms With Corticotropin

Joshua L. Bonkowsky, MD, PhDa, Francis M. Filloux, MDa and Carrie L. Byington, MDb

a Divisions of Pediatric Neurology
b Pediatric Infectious Diseases, Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah

ABSTRACT

Here we report an infant who had herpes simplex virus (HSV) encephalitis and sustained severe bilateral damage to the posterior frontal lobes, postcentral gyri, and the thalami despite intravenous acyclovir treatment. At 7 months of age, the patient developed infantile spasms and was treated with corticotropin injections. After 10 days of corticotropin treatment, she developed lethargy, fever, and opisthotonic posturing. Her cerebrospinal fluid again was positive for HSV DNA, indicating recurrent HSV encephalitis, and repeat MRI revealed new lesions of the right frontal, parietal, temporal, and occipital lobes. Immunosuppression by corticotropin may have led to the reactivation of the HSV encephalitis. Corticotropin should be relatively contraindicated for use when a patient has a history of HSV infection, or intravenous acyclovir should be administered concurrently.

Key Words: herpes simplex virus • encephalitis • corticotropin • infantile spasms • relapse • neonatal

Abbreviations: HSV, herpes simplex virus • EEG, electroencephalogram • CNS, central nervous system • CSF, cerebrospinal fluid • WBC, white blood cell • RBC, red blood cell • PCR, polymerase chain reaction

Neonatal herpes simplex virus (HSV) encephalitis causes considerable morbidity and mortality. Without antiviral therapy, the mortality rate is 70% or higher.1 Even with acyclovir therapy (introduced in the mid-1980s), 15% of infants die, and 17% to 32% experience moderate or severe long-term motor and intellectual impairments.2,3

Survivors of neonatal HSV encephalitis can develop seizures, including infantile spasms. Infantile spasms consist of brief generalized tonic or myoclonic spasms in clusters, often accompanied by hypsarrhythmia pattern on electroencephalogram (EEG), and arrest and/or regression of development. HSV encephalitis causes ~2% of infantile spasms.4 Treatment of infantile spasms is difficult and only moderately effective. Long-term, only one quarter of patients are able to participate in regular or special education school.5 Furthermore, in patients with an infectious cause for their infantile spasms, both response to treatment and long-term outcome are poor (38% response rate and 90% mental retardation, respectively).4 Corticotropin is recommended as the first-line treatment for infantile spasms.5–7

Here we report an infant who had a history of neonatal HSV encephalitis and in whom infantile spasms developed at 7 months of age. Although the spasms stopped with corticotropin therapy, the infant had recurrence of her HSV encephalitis 10 days after starting corticotropin. Brain MRI showed evidence of additional cortical injury. This report examines the potential link between corticotropin treatment and HSV central nervous system (CNS) recurrence, the risks of corticotropin-induced immunosuppression, and the need for additional studies to explore the treatment of HSV latency.

CASE REPORT

A 7-month-old girl presented to the emergency department with sleepiness, fevers, and opisthotonic posturing. Her medical history was significant for neonatal HSV encephalitis at age 14 days. At that time, the patient was lethargic and had had several episodes of apnea, prompting admission; no skin lesions were noted. Cerebrospinal fluid (CSF) analysis showed 108/mm3 white blood cells (WBCs; differential: 53% lymphocytes, 43% monocytes, and 4% neutrophils), 0/mm3 red blood cells (RBCs), protein 194 mg/dL, and glucose 36 mg/dL. Liver-function tests were normal. She was started on intravenous acyclovir (20 mg/kg every 8 hours). CSF cultures, Gram stain, and polymerase chain reaction (PCR) for enterovirus and cytomegalovirus all were negative. CSF PCR testing for HSV was positive, and subsequent typing showed that it was HSV-1.

MRI 7 days after admission showed hemorrhage with intermixed tissue edema in the posterior frontal lobes, thalami, basal ganglia, and pre- and postcentral gyri (Fig 1 A and B). The patient was treated with 21 days of intravenous acyclovir and then with oral acyclovir (50 mg/kg per day, divided 3 times per day), through 3 months of age. A follow-up lumbar puncture was performed after 19 days of intravenous acyclovir; PCR for HSV was negative, and indices were: WBCs, 18/mm3; RBCs, 135/mm3; protein, 121 mg/dL; and glucose, 40 mg/dL.


Figure 1
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  		FIGURE 1 Axial MRIs of the patient. A and B, T1-weighted sequences obtained at 3 weeks of age (1 week after the patient's initial presentation with HSV encephalitis). The images show T1 shortening (confirmed on gradient recall imaging as hemorrhage) in the right thalamus and left basal ganglia (A, arrows) and precentral gyri (B, arrows). C and D, Images obtained at 7 months of age during hospitalization with recurrent HSV encephalitis. C, T1-weighted image with gadolinium showing enhancement of the right frontal, parietal, temporal, and occipital leptomeninges and underlying gyral swelling (arrows point to areas of enhancement). D, Diffusion-weighted image showing diffusion restriction in the right posterior frontal, temporal, and parietal lobes.

 
At the time of discharge from her initial hospitalization, the patient's neurologic examination was normal. A follow-up neurologic examination at 7 weeks of age also was normal. However, by 5 months of age, the patient had increased upper extremity tone, bilateral fisting of her hands, and poor head control.

At the age of 6 months, the patient developed infantile spasms; her EEG showed hypsarrhythmia and an electrodecremental response immediately after the spasms. A brain MRI performed at this time showed mild encephalomalacia with hemosiderin staining involving the thalami and pre- and postcentral gyri. The patient was started on intramuscular injections of corticotropin at a dose of 150 U/m2 per day. Her spasms stopped 2 days after the initiation of corticotropin. Corticotropin was continued according to routine protocol (2 weeks of treatment followed by 2 weeks of dosage taper).

At the time of her admission at 7 months of age the patient was febrile to 38.2°C. Examination was notable for irritability, opisthotonus, and extensor posturing of her arms and legs; her general physical examination was normal. In the emergency department, she had a tonic seizure with eye deviation to the right and head version to the right, which resolved with intravenous lorazepam. The patient's CSF showed 45/mm3 WBCs (differential 70% lymphocytes, 28% monocytes, 2% segmented neutrophils), 48/mm3 RBCs, glucose level of 60 mg/dL, and protein level of 64 mg/dL. Results of liver-function tests were normal. She was started on intravenous vancomycin, ceftriaxone, and acyclovir (20 mg/kg every 8 hours). Her EEG showed periodic lateralized epileptiform discharges from the right posterior temporal region but an absence of hypsarrhythmia. Blood, urine, and CSF bacterial cultures were negative. CSF HSV PCR was positive. An MRI of her brain showed gyral swelling and leptomeningeal enhancement in contiguous areas of the right frontal, parietal, temporal, and occipital lobes (Fig 1 C). Diffusion restriction was seen in an identical pattern (Fig 1 D) and confirmed using apparent diffusion coefficient mapping, consistent with acute cytotoxic edema.

Corticotropin was discontinued, and the patient was treated with phenobarbital (7 mg/kg per day) for seizure prophylaxis. Within 4 days of acyclovir treatment initiation, she had returned to her preadmission neurologic status. The patient was discharged from the hospital on a 6-week course of intravenous acyclovir. She had a repeat CSF analysis 3 weeks after her presentation, which had 29/mm3 WBCs, 0/mm3 RBCs, glucose 46 mg/dL, and protein 53 mg/dL; CSF HSV PCR was negative.

She experienced relapse of infantile spasms that responded to treatment with topiramate (12 mg/kg per day) and subsequently has had persistent seizures that are resistant to multiple antiepileptic medications. The patient's oral acyclovir was discontinued 4 months before her HSV recurrence. Her symptoms started 10 days after the initiation of corticotropin.

DISCUSSION

This is the first published report of a case of recurrent HSV encephalitis associated with corticotropin use. There was a strong temporal relationship between the initiation of corticotropin treatment and HSV recurrence (within 10 days).

The patient in this report developed infantile spasms as a result of her neonatal HSV encephalitis. Infantile spasms is a catastrophic childhood epilepsy disorder that is associated with significant morbidity and mortality.5 Therefore, there is an imperative to treat.

The consensus first-line treatment for infantile spasms is corticotropin, although the evidence for this conclusion is limited.7 Vigabatrin also is recommended as being "possibly effective" for infantile spasms, especially for infantile spasms that are associated with tuberous sclerosis.7 However, the Food and Drug Administration has not approved its use in the United States because of its associated retinal toxicity. Other agents that are used to treat infantile spasms, including prednisone, valproic acid, topiramate, zonisamide, and pyridoxine, show lower degrees of efficacy.

The mechanism(s) by which corticotropin stops infantile spasms is not known. Corticotropin has both immunosuppressive and anti-inflammatory properties, mediated primarily via glucocorticoid production.8 However, it is unlikely that corticotropin's anticonvulsant activity is related to its immunosuppressive properties.

Corticotropin therapy has been linked in other cases to herpes family virus reactivation and disease. Corticotropin use in a patient for opsoclonus led to fatal, disseminated HSV infection that did not respond to vidarabine.9 Corticotropin use for infantile spasms has been associated with disseminated cytomegalovirus infection and death.4 The striking temporal relation between the initiation of corticotropin treatment and HSV recurrence in the current case suggests a role for corticotropin immunosuppression in viral reactivation.

HSV becomes latent after primary infection, and there is lifetime persistence of the virus.10,11 Reactivation can lead to recurrent disease. Causes of HSV reactivation include ultraviolet light, stress, immunosuppression, intercurrent infection, hormonal changes during the menstrual cycle, and manipulation of the trigeminal ganglia.11 Documented sites of HSV latency include the trigeminal and sacral ganglia, retina, optic nerve and tract, lateral geniculate nucleus, superior colliculus, and some brainstem nuclei.11

HSV encephalitis relapse is a known complication of HSV encephalitis as well as of disseminated HSV infection.12–16 CNS relapse of HSV encephalitis is estimated to occur in 10% to 26% of infants with CNS disease.14,17

The median time of HSV encephalitis relapse (after cessation of intravenous acyclovir therapy) is 2 weeks, with 81% of relapses occurring in the first month (reviewed in 38 patients16). Three recurrences have occurred while patients were receiving oral acyclovir therapy (30 mg/kg per day).13,15,18

The role of high-dose intravenousacyclovir for treatment of acute HSV infection in neonates and infants is clear. Unfortunately, many infants who have HSV encephalitis go on to develop recurrent HSV infections, including encephalitis. No treatments available to eradicate latent HSV, and the efficacy of oral acyclovir for maintaining suppression of latency after neonatal infection is doubtful.

We cannot exclude the possibility that the corticotropin treatment and HSV recurrence in our patient were coincidental. We think that this unlikely, because the patient's relapse occurred 4 months after the discontinuation of oral acyclovir suppression and >5 months after her course of intravenous acyclovir. Furthermore, as mentioned above, 81% of relapses occur within the first month after intravenous acyclovir.16

Our case highlights that corticotropin may be a significant risk factor for recurrence of HSV encephalitis. Corticotropin and corticosteroids should not be used to treat infantile spasms when there is a known history of HSV CNS infection. Although corticosteroids have been shown in animal models of HSV encephalitis not to increase HSV dissemination,19,20 other reports have linked use of steroids to disseminated HSV infection.21 HSV infection and reactivation seem to be more common in those with cellular (T-cell) immunodeficiency, and acyclovir prophylaxis in such patients (eg, bone marrow transplant recipients) causes a significant reduction in HSV reactivation.11 Therefore, although the patient who is described in this report also had other "stressors" of the immune system at the time of her HSV recurrence, including diagnostic studies, intramuscular injections, etc, the most significant immunosuppressant was the corticotropin itself.

If corticotropin or steroids become unavoidable for the treatment of infantile spasms in a patient with a history of HSV encephalitis, then intravenous acyclovir therapy should be started concurrently. In addition, acyclovir should be considered for any child who has a history of HSV encephalitis and is experiencing significant immunosuppression.

ACKNOWLEDGMENTS

We thank the nurses and housestaff for care of the patient, the patient and her family for involvement, and the editorial assistance of James F. Bale, Jr, MD.

FOOTNOTES

Accepted Oct 24, 2005.

Address correspondence to Joshua L. Bonkowsky, MD, PhD, Division of Pediatric Neurology, Department of Pediatrics, PO Box 581289, 295 Chipeta Way, Williams Building, Salt Lake City, UT 84158. E-mail: joshua.bonkowsky{at}hsc.utah.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

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