Published online August 1, 2007
PEDIATRICS Vol. 120 No. 2 August 2007, pp. e442-e446 (doi:10.1542/10.1542/peds.2006-3757)

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EXPERIENCE & REASON

Brainstem Involvement in Neonatal Herpes Simplex Virus Type 2 Encephalitis

Gustavo Pelligra, MD^a, Niamh Lynch, MD^b, Steven P. Miller, MD^b, Michael A. Sargent, MD^c and Horacio Osiovich, MD^a

Divisions of ^a Neonatology
^b Neurology, Department of Pediatrics
^c Department of Radiology, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Herpes simplex virus encephalitis in the newborn typically involves the cerebral cortex in a widespread manner. Herpes simplex virus type 2 rarely involves the brainstem. Here we report a 16-day-old infant with predominant brainstem and cerebellar involvement secondary to herpes simplex virus type 2 infection. Diffusion-weighted MRI performed 3 days after the onset of symptoms revealed restricted diffusion mainly in brainstem and cerebellar structures. No abnormal findings were seen on conventional MRI. Subsequent MRI scans showed evolution of the brain injury with extension along the corticospinal tracts. However, there was no evidence of any other supratentorial gray or white matter injury. This is the first report of predominant brainstem involvement in neonatal herpes simplex virus type 2 encephalitis. In addition, the importance of performing diffusion-weighted sequences to detect early central nervous system involvement and serial MRI to follow the evolution of central nervous system lesions is emphasized.

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Key Words: herpes simplex virus • encephalitis • brainstem • magnetic resonance imaging

Abbreviations: HSV, herpes simplex virus • CNS, central nervous system • CSF, cerebrospinal fluid • PCR, polymerase chain reaction • EEG, electroencephalogram

Herpes simplex viruses (HSVs) are ubiquitous human pathogens that are widespread in the adult population.¹ HSV encephalitis and neonatal HSV disease are the most devastating infections in the vast spectrum of HSV infections in humans.²

Neonatal HSV disease occurs in 1 in 3200 deliveries in the United States.³ In Canada, recent data from the Canadian Paediatric Surveillance Program indicate an incidence of 5.9 cases per 100000 live births and a case fatality rate of 15.5%.⁴ Approximately 70% of neonatal HSV disease is caused by HSV type 2.⁵ In 85% of the cases, neonatal infection is acquired during labor.⁶ Central nervous system (CNS) disease alone occurs in one third of all infants with neonatal HSV infection. HSV encephalitis in the newborn typically involves the cerebral cortex in a widespread manner. With current antiviral therapy (high-dose acyclovir), the mortality rate from neonatal CNS HSV disease is 4%; however, 69% of survivors are left with neurologic sequelae.² HSV type 1 is associated with a better overall prognosis than HSV type 2 as the cause of neonatal encephalitis.⁷

Although 3 cases of brainstem HSV type 2 encephalitis have been described in the adult literature,^{1, 8, 9} to our knowledge no cases have been reported in neonates. Here we describe a neonate with predominant brainstem and cerebellar involvement secondary to HSV type 2 infection.

CASE REPORT

A 1994-g (40th percentile) female infant was born at 34 weeks' gestation to a healthy 22-year-old gravida 4, para 2 mother. Prenatal tests were negative for HIV, hepatitis B surface antigen, syphilis, and group B streptococcus. The mother had no history of genital HSV infection. Membranes were ruptured intrapartum, and amniotic fluid was clear. No active genital HSV lesions were noted at delivery.

The infant was delivered vaginally and had Apgar scores of 8 and 8 at 1 and 5 minutes, respectively. In the delivery room she experienced mild respiratory distress that resolved after 10 minutes with the use of continuous positive airway pressure by mask.

The infant was admitted to a level 2 NICU and remained well for the first 2 weeks of age. Cranial ultrasound was normal at 4 days of age.

At 16 days of age, the infant developed lethargy, hypotonia, and feeding intolerance. She also had several episodes of apnea, bradycardia, and desaturations, some of which required positive-pressure ventilation by bag and mask. Intravenous fluids and antibiotics (ampicillin, gentamicin, and cefotaxime) were started after blood cultures were taken. Abnormal paroxysmal movements were noted, and a 20 mg/kg dose of phenobarbital was given.

The infant was intubated because of poor respiratory effort and then transferred to a level 3 NICU.

On admission (10 hours after the onset of symptoms) the infant was encephalopathic. She had no spontaneous movements. She was easily ventilated with no sedation and had no spontaneous respiration. She was unresponsive to vigorous cutaneous stimulation. Her pupils were symmetric and equally reactive to light. There was a mild facial diplegia. Suck and gag reflexes were not elicited. The infant was markedly hypotonic, and there were bilaterally brisk, symmetrical tendon reflexes. Her head circumference was 30 cm (10th percentile), and her anterior fontanelle was flat. No skin lesions or organomegaly were noted.

A lumbar puncture was performed, and intravenous acyclovir at 60 mg/kg per day was added to the antimicrobial agents. Blood work revealed a total white cell count of 6.6 x 10⁹/L (neutrophils: 4.2 x 10⁹/L; lymphocytes: 1.9 x 10⁹/L), a platelet count of 373 x 10⁹/L, an aspartate aminotransferase level of 40 U/L, an alanine aminotransferase level of 10 U/L, and a normal coagulation profile. A lumbar puncture yielded bloody cerebrospinal fluid (CSF); microscopic examination showed 28276 x 10⁶/L red blood cells, 344 x 10⁶/L white blood cells (34% neutrophils, 27% lymphocytes, 39% monomacrophages), and glucose and protein concentrations of 3.6 mmol/L and 2.1 g/L, respectively. A polymerase chain reaction (PCR) of the CSF detected HSV type 2 DNA. CSF-culture results were negative for HSV and other viruses. Serum enzyme immunoassay results were reactive to HSV immunoglobulin G and nonreactive to HSV immunoglobulin M. Blood, urine, and CSF cultures did not grow any bacteria. All antibacterial agents were discontinued 2 days after admission.

Cranial ultrasound performed on the day of admission was normal.

Electroencephalograms (EEGs) recorded on the first and fourth days of the NICU stay were consistent with moderate diffuse cerebral dysfunction showing a suppressed, discontinuous, asymmetric and asynchronous background. No electrical seizure activity was noted.

MRI of the brain performed 3 days after the onset of symptoms (second day of acyclovir therapy) showed markedly restricted diffusion in the pons, middle cerebellar peduncles, and medial right cerebellar hemisphere, possibly involving the vermis (Fig 1). Restricted diffusion was also shown just anterolateral to the left posterior limb of internal capsule in the corticospinal tract. T1, T2, and gadolinium-enhanced sequences were normal.

View larger version (60K): [in this window] [in a new window]   FIGURE 1 Axial echoplanar diffusion-weighted image 3 days after the onset of symptoms (b = 1500 m2·seconds–1) shows hyperintensity caused by restricted diffusion in the pons (arrows, a), cerebellar peduncles (arrow, b), and right medial cerebellar hemisphere (arrow, c). The patient had been receiving acyclovir therapy for 2 days at the time of this scan.

 
On the seventh day of acyclovir therapy another brain MRI was performed and showed a similar pattern of restricted diffusion within the same areas shown in the previous study. The T1-weighted images demonstrated bright signal of T1 shortening in these regions that was not evident on the first study (Fig 2). Gadolinium administration revealed leptomeningeal enhancement around the pons and over the surface of the cerebellar folia.

View larger version (85K): [in this window] [in a new window]   FIGURE 2 An axial spin-echo T1-weighted magnetic resonance scan (repetition time/echo time: 800/20 milliseconds) 8 days after the onset of symptoms shows hyperintensity of T1 shortening in the pons (arrows, a) and cerebellar peduncles (arrows, b). Low signal of edema is shown in the cerebellar white matter.

 
A third MRI performed on the 18th day of acyclovir therapy showed evolution of the brain injury. T1 shortening was seen in the corticospinal tracts bilaterally, extending to the left Rolandic cortex (Fig 3A). There was extensive abnormal T1 and T2 signal with tissue loss involving the pons and ventral medulla, the middle cerebellar peduncles, and the gray and white matter of the cerebellar hemispheres (Fig 3B). Hypointensity in the ventral pons on T2 and echoplanar images was in keeping with susceptibility artifact from hemorrhage. There was interval normalization of diffusion in the affected areas.

View larger version (75K): [in this window] [in a new window]   FIGURE 3 A, A coronal T1-weighted magnetic resonance image after 18 days of acyclovir therapy shows T1 shortening bilaterally in the basal ganglia along the course of the corticospinal tracts (arrows, a), with unilateral radiation to the left Rolandic cortex (arrow, b). B, Midline sagittal T1-weighted magnetic resonance image shows volume loss and abnormal signal in the pons (arrow, a), ventral medulla (arrow, b), and cerebellar vermis (arrow, c).

 
The neurologic examination remained unchanged for the first 72 hours after admission. After that, there was gradual improvement in motor function and reflexes.

The infant remained on mechanical ventilation for 11 days mainly because of inadequate respiratory drive. No additional respiratory support was needed after extubation.

A repeat evaluation of the CSF after a 21-day course of acyclovir revealed 28 x 10⁶/L red blood cells per mm³, 2 x 10⁶/L white blood cells (2% neutrophils, 72% lymphocytes, 20% monomacrophages), a glucose level of 2.3 mmol/L, and a protein concentration of 1.2 g/L. Results of CSF HSV PCR and viral culture were negative at that time.

At 38 days of age, the infant was discharged from the hospital on full feeds and oral suppressive acyclovir therapy. On examination she remained slightly hypotonic and hyperreflexic. At follow-up (9 months of age), she was visually alert and interactive. She was babbling but not using words with meaning. She showed signs of stranger anxiety. She had gross motor developmental delay, and was unable to sit unsupported. She could not roll. Fine motor development was also delayed. She had a palmar grasp. She could reach for and grasp objects but was not yet transferring. She could place objects in her mouth. She had a left esotropia but no other cranial nerve deficits. Tone was increased in all 4 limbs, more so on the left than on the right. There was mild axial hypotonia. Muscle-stretch reflexes were brisk throughout. The presence of stranger anxiety and the level of interaction and alertness demonstrated preservation of cognitive function, which reflects the relative cortical sparing in this case. However, the involvement of the brainstem and corticospinal tracts were reflected in the degree of both gross and fine motor developmental delay, as well as the increased tone and hyperreflexia. Given that there was greater involvement of the left-sided corticospinal tracts as well as the left Rolandic cortex, increased tone would have been expected on the right. However, tone was increased throughout, and more on the left than on the right. Follow-up neuroimaging at the age of 2 years, when myelination is more advanced, may offer an explanation for this.

DISCUSSION

CNS disease in neonatal HSV infection can present as a localized brain infection or be associated with disseminated disease. Infants with localized HSV encephalitis typically present in the second or third week after birth. Clinical manifestations of HSV encephalitis include seizures, fever, lethargy, irritability, tremors, poor feeding, temperature instability, bulging fontanelle, and pyramidal tract signs.¹⁰ Our patient presented at 16 days of age with lethargy and hypotonia, poor feeding, and poor respiratory drive.

Neurodiagnostic studies of value in CNS HSV infection include CSF examination, EEGs, and brain-imaging techniques.¹¹ Findings on CSF examination include mononuclear cell pleocytosis, elevated red cells, and protein levels.¹⁰ Hypoglycorrhachia is present in only 5% to 25% of patients.¹¹ The virus can be isolated from the CSF; however, culture results are often negative early in the disease.¹² PCR assay is the optimal method to detect HSV DNA in the CSF and has a sensitivity of 75% to 100% and a specificity of 71% to 100%.^10–12 This technique also allows one to distinguish the 2 viral types, HSV types 1 and 2. In clinical laboratories that have proper experience with PCR and when appropriate controls are used, PCR assay is the method of choice for detection of HSV DNA in CSF for the diagnosis of HSV encephalitis.¹¹ However, clinicians should be aware that 2 studies in newborn infants have found PCR assays to be only 71% to 78% sensitive for detecting HSV DNA at the initial evaluation.^{13, 14} Moreover, clinicians must also recognize that HSV PCR results may be negative early in the course of illness. Therefore, the results of HSV PCR should be interpreted with careful consideration of the clinical findings and the results of other laboratory and radiologic tests.^{4, 10, 11} In our patient, the initial CSF was bloody. However, it was evident that mononuclear cell pleocytosis was present, CSF protein was elevated, and HSV type 2 DNA was detected in the CSF with PCR.

An EEG usually shows striking and characteristic changes, mainly focal or multifocal paroxysmal, periodic, or quasiperiodic discharges, consisting of repetitive sharp-slow wave complexes. However, in our patient, EEG findings were atypical for HSV encephalitis. This may be related to the particular pattern of CNS involvement in which there was relatively little supratentorial parenchymal injury.

Neuroimaging techniques can be very useful in defining the presence and extent of CNS abnormalities in herpes encephalitis. Both sonography and computed tomography can show abnormal findings. An MRI scan is sensitive for the detection of parenchymal lesions caused by direct infection and the secondary effects such as laminar cortical necrosis. With contrast there may be meningeal enhancement, as was seen on the second scan for our case. Moreover, diffusion-weighted MRI may prove to be the most sensitive imaging modality for early detection of CNS disease. Typical abnormalities seen by neuroimaging techniques include localized or multifocal areas of edema and/or hemorrhage, evolving to cystic encephalomalacia and atrophy involving the temporal, frontal, parietal, and subcortical regions of the brain.^{10, 12, 15–18} Cerebral calcification is frequent.^{12, 19} Noorbehesht et al²⁰ reported involvement of the cerebellum in up to 50% of cases of neonatal HSV encephalitis.

Encephalitis limited to the brainstem is a rare presentation of HSV encephalitis in adults and is caused mainly by HSV type 1. HSV type 2 CNS infections rarely involve the brainstem. Indeed, there have been only 3 reports of HSV type 2 brainstem encephalitis, all in adults.^{1, 8, 9}

Krolczyk et al²¹ reported opsoclonus as a possible early sign of neonatal HSV type 2 cerebellitis in a 26-day-old term infant. In that patient, evidence of cerebellar involvement was detected by computed tomography and MRI performed 4 days after onset of symptoms, but no brainstem involvement was seen in the initial scans. Twenty-five days after admission, a repeat brain MRI revealed resolution of cerebellar lesions, but disease had progressed to involve the uncus and frontal lobes.

In our case, encephalitis was the initial and only manifestation of HSV type 2 infection. As recently suggested by Kubota et al,¹⁷ diffusion-weighted MRI proved to be a more sensitive tool for demonstrating early CNS lesions in this case than did conventional MRI. The most striking finding in our patient was a significant involvement of the brainstem, which is rarely seen in HSV type 2 CNS infections. Although we also found extension along the corticospinal tracts, our patient did not have evidence of any other supratentorial gray or white matter disease. Only 1 case of HSV type 2 encephalitis with some brainstem involvement has been reported in this age group.²¹ However, the marked predominance of brainstem involvement is a distinguishing feature in our patient. This atypical pattern of CNS involvement can also explain the prolonged period of inadequate respiratory drive seen in our patient and may be a consequence of viral injury to the respiratory centers located in the brainstem.

CONCLUSIONS

To our knowledge, we provide the first description of predominant brainstem involvement in neonatal HSV type 2 encephalitis. This case also highlights the importance of performing diffusion-weighted MRI sequences to detect CNS involvement early in the course of the infection and serial MRI scans to follow the evolution of CNS lesions.

FOOTNOTES

Accepted Apr 3, 2007.

Address correspondence to Horacio Osiovich, MD, Division of Neonatology, Room 1R47, Children's and Women's Health Centre of British Columbia, 4480 Oak St, Vancouver, British Columbia, Canada V6H 3V4. E-mail: hosiovich{at}cw.bc.ca

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

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This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pelligra, G. Articles by Osiovich, H. Search for Related Content PubMed PubMed Citation Articles by Pelligra, G. Articles by Osiovich, H. Related Collections Infectious Disease & Immunity Social Bookmarking                         What's this?