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Letters to the Editor  |   October 2010
Atypical Presentation of Herpes Simplex Encephalitis in an Infant
Author Affiliations
  • Cindy Holt, MD
    Western University of Health Sciences College of Osteopathic Medicine of the Pacific, Pomona, California
    Arrowhead Regional Medical Center, Department of Neurosurgery, Colton, California
    Inland Neurological Consultants Inc, Upland, California
    Riverside County Regional Medical Center, Department of Pediatrics, Riverside, California
Article Information
Neuromusculoskeletal Disorders / Pediatrics
Letters to the Editor   |   October 2010
Atypical Presentation of Herpes Simplex Encephalitis in an Infant
The Journal of the American Osteopathic Association, October 2010, Vol. 110, 615-617. doi:10.7556/jaoa.2010.110.10.615
The Journal of the American Osteopathic Association, October 2010, Vol. 110, 615-617. doi:10.7556/jaoa.2010.110.10.615
To the Editor:  
Most childhood cases of herpes simplex virus type 1 (HSV-1) infection are caused by oral transmission. In children, neurologic infections induced by HSV-1 represent either primary or reactivated viral states. A more serious sequela of HSV-1 infection is herpes simplex encephalitis (HSE). The most common symptoms in clinical presentations of HSE in children are altered mental status, dysphasia, fever, headache, irritability, seizure, and visual field defects.1 
Examination of cerebral spinal fluid (CSF) is the gold-standard laboratory test for diagnosing HSE. This serum analysis typically yields lymphocytic pleocytosis, normal to slightly elevated total protein concentration, normal glucose concentration, and normal to mildly elevated CSF opening pressure.2 Arguably even more important in diagnosis is magnetic resonance imaging (MRI) of the brain. In patients with HSE, MRI will often demonstrate an abnormal appearance in the temporal lobes resulting from edema, in addition to the so-called transsylvian sign, which represents edema across the sylvian fissure.3 
In the present letter, we discuss the case of an infant with HSE who had unremarkable CSF test and neuroimaging results. To our knowledge, this case report is the first to describe clinical HSE in an individual with a normal CSF profile and no diagnostic imaging support. 
Report of Case
An infant girl aged 17 months presented to the emergency department with an acute body rash. According to her mother, the patient had been in her usual state of health until 1 week before hospital admission, when a 2-day fever of 103.1°F (39.5°C) developed. The mother reported signs of weakness in the infant, including difficulty walking and sitting independently. The mother also reported that the infant wanted to be held constantly. The patient's fever had resolved 5 days before admission. However, her neurologic symptoms had worsened. 
On physical examination, the patient was afebrile, and all her vital signs were stable. She was found to be a well-nourished, well-developed infant. She was awake, alert, and oriented to person, place, and circumstances. Before the onset of illness, the patient was appropriately following her normal developmental milestones and was able to sit, stand, and walk independently. 
Neurologic examination was notable for lack of ability to stand or sit. Fundoscopic examination revealed no papilledema. Cranial nerves II through XII were intact. The patient's strength was full in all muscle groups, and motor testing showed normal muscle bulk and tone. Sensation was grossly intact in all dermatomes, and deep tendon reflexes were bilaterally symmetrical at 2/4. She had a papular rash around her mouth, with a small ulcer on her right palatine tonsil. No lesions were seen on the patient's tongue or buccal mucosa. 
Laboratory test values immediately after admission included the following: 
  • white blood cell count, 8400 cells/μL
  • hemoglobin level, 9.1 mg/dL
  • hematocrit concentration, 27.5%
  • platelet count, 338,000 cells/μL
  • erythrocyte sedimentation rate, 124 mm/h
The CSF test results were also unremarkable, with a white blood cell count of 200 cells/μL (lymphocytes, 50%; monocytes 50%), a red blood cell count of 0, a total protein level of 22 mg/dL, and a glucose level of 53 mg/dL. Results of brain MRI and electroencephalography (EEG) were unremarkable. 
Because of a high index of suspicion for HSV-1 infection, the patient was immediately started on acyclovir (20 mg/kg intravenously every 8 hours for 21 days). One week after acyclovir initiation, a polymerase chain reaction (PCR) test for HSV-1 yielded positive results. At discharge, 21 days later, the patient's altered mental status and generalized weakness had resolved, and much improvement was observed in her gait. 
Comment
Based on the clinical presentation of the patient in the present case, viral encephalitis was deemed to be the most likely etiologic condition. Viral encephalitis is a medical emergency. The prognosis for patients with this condition depends on correct, immediate diagnosis, with introduction of appropriate treatment to decrease the extent of permanent brain damage. The 6-month mortality rate following treatment with acyclovir is 0% if the medication is initiated within 4 days of symptom appearance. This rate climbs to 35% if treatment is initiated after 4 days.4 
Herpes simplex encephalitis is at the top of the differential diagnosis, because it is the most common etiologic factor for sporadic nonepidemic encephalitis in immunocompetent hosts, with an incidence of 0.1 to 0.4 per 100,000 individuals.5 Level A recommendations for diagnosing HSE, by the Scientific Committee of the European Federation of Neurological Societies, call for performing a thorough medical history and physical examination and an analysis of CSF.5 As previously stated, CSF test results in patients with HSE typically reveal lymphocytic pleocytosis, normal to slightly elevated total protein concentration, normal glucose concentration, and normal to mildly elevated CSF opening pressure. In the present case, results from the patient's lumbar puncture were within normal limits. 
Level B recommendations for diagnosing HSE call for performing MRI of the patient's brain.5 Electroencephalography and computed tomography (CT) of the head are also acceptable, though CT is less sensitive than MRI. Typical neuropathologic findings found with MRI for patients with HSE are unilateral or bilateral T2 prolongation in the medial temporal or frontal lobes. By contrast, typical CT findings for such patients consist of widespread patchy areas of decreased attenuation of the cerebral cortex.6,7 Eighty percent of patients with HSE show abnormalities in the temporal lobe, and 10% have extratemporal abnormalities.7 Results of EEG are abnormal in 80% of patients with HSE, usually showing periodic lateralizing epileptiform discharges from the temporal lobe.8 For the patient in the present case, results of the CT, MRI, and EEG were all unremarkable. 
Other viral etiologic agents besides HSV-1, including human herpesvirus type 6 (HHV-6), were considered in this case, because the CSF and neuroimaging results did not point to HSE. In a retrospective study, Noguchi et al9 concluded that neuroimaging serves as the main discriminator between patients with HHV-6 infection and those with HSE. Neuroimaging, specifically MRI, in patients with HSE shows persistent abnormal intensity in the mesangial temporal lobes and extratemporal regions, whereas neuroimaging in cases of HHV-6 infection shows transient abnormal activity in the temporal lobes.9 Computed tomography in patients with HSE shows such abnormal findings as parenchymal swelling, decreased attenuation of affected regions, and gyral enhancement. In patients with HHV-6 infection, CT shows no abnormal activity.9 
Thus, neuroimaging is a useful measure to distinguish between the viral etiologic factors of encephalitis.10 However, imaging results for the patient in our case did not fit the standard picture of either HHV-6 infection or HSE. 
One week before the PCR results of the CSF analysis were available in the present case, the etiologic origin of the infant's encephalitis was thought to be idiopathic. Pleumpanupat et al10 demonstrated that no single history or lab result can differentiate HSE from other forms of viral encephalitis—except for temporal involvement detected via MRI. However, we found no such abnormalities with MRI. 
With the negative results from imaging and CSF tests during the first week after admission (before PCR yielded positive results for HSV-1), our suspicion for HSE had declined. Nevertheless, acyclovir treatment had been started soon after admission in consideration of the fact that HSE is the most common cause of nonsporadic encephalitis. Had we not initially had a high index of suspicion for HSE and administered acyclovir soon after the onset of symptoms, the patient would have suffered serious neurologic sequelae.8,11 Typically, the best treatment outcomes are observed when acyclovir is administered to patients before development of stupor or coma, within 24 hours of the onset of symptoms. Good treatment outcomes are also observed when acyclovir is administered to patients who have a Glascow Coma Scale score of 9 to 15. 
Conclusion
We believe that several important clinical lessons can be elicited from the present case—most notably two main points. First, empirical acyclovir treatment should be initiated immediately in patients who have any symptoms of HSE, regardless of whether the neurodiagnostic imaging and CSF findings are either positive or negative. Second, a high degree of suspicion for HSE encephalitis is required in all age groups for patients with altered mental status, ataxia, focal neurologic deficits, headaches, rashes, rapid-onset fever, and/or seizures. 
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