Author’s Accepted Manuscript A 20-Month-Old Girl with Fever, Seizures, Hemiparesis and Brain Lesions Requiring a Diagnostic Brain Biopsy Sat suki Matsumoto, Eiyu Matsumoto www.elsevier.com/locate/enganabound PII: DOI: Reference: S1071-9091(17)30039-6 http://dx.doi.org/10.1016/j.spen.2017.03.012 YSPEN635 To appear in: Seminars in Pediatric Neurology Cite this article as: Sat suki Matsumoto and Eiyu Matsumoto, A 20-Month-Old Girl with Fever, Seizures, Hemiparesis and Brain Lesions Requiring a Diagnostic Brain Biopsy, Seminars in Pediatric Neurology, http://dx.doi.org/10.1016/j.spen.2017.03.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Title: A 20-month-old girl with fever, seizures, hemiparesis and brain lesions requiring a diagnostic brain biopsy Authors Satsuki Matsumoto, MD Eiyu Matsumoto, MB Sat suki Matsumoto, MD Clinical Assistant Professor Department of Pediatrics Division of Pediatric Neurology University of Iowa Carver College of Medicine Eiyu Matsumoto, MB Clinical Assistant Professor Department of Internal Medicine Division of Infectious Diseases University of Iowa Carver College of Medicine Key words: Herpes Encephalitis, Seizures, Hemiparesis, fever, Brain Biopsy Abstract We report a case of a 20-month-old girl with atypical presentation of a fairy common condition. She presented with acute onset of fever, seizures and hemiparesis. Her cerebrospinal fluid (CSF) showed total nucleated cells 10/mm3 with lymphocyte dominance. Herpes simplex virus (HSV) polymerase chain reaction (PCR) result was negative. Computed tomography (CT) of head showed a cerebral hemorrhage of the left frontal lobe and small subarachnoid hemorrhage in right frontal region. Brain MRI revealed multiple foci of hyperintensity in bilateral parietal lobes and right basal ganglia. She remained clinically stable without a specific therapy. Her diagnosis was made after a brain biopsy. Case Report A 20-month-old girl presented with acute onset of fever, seizures and hemiparesis. Her past medical history was only remarkable for premature birth at 34 weeks by Caesarian section due to maternal preeclampsia. Her neonatal course was unremarkable. Developmentally, she was normal prior to the current illness. Her family and social history were unremarkable. On day 1, she presented to a local emergency room with a brief generalized seizure and twoday history of rhinorrhea and fever. She was diagnosed with a febrile seizure associated with upper respiratory infection and was discharged home. On day 2, she had focal motor seizure involving her left face, arm and leg which lasted for one hour until she received diazepam in the local emergency room. She was loaded with phenobarbital. After resolution of the seizure, she was noted to have left hemiparesis. Computed tomography (CT) of head showed a cerebral hemorrhage of the left frontal lobe as well as a small subarachnoid hemorrhage in right frontal region. The imaging raised the concern for non-accidental trauma. Complete blood count with differential, C-reactive protein and coagulation panel were all normal. Bone survey and ophthalmologic exam were also unremarkable. She was admitted locally. On day 3, she had another left sided focal motor seizure. Electroencephalogram (EEG) showed slow waves on the left central parietal region and focal epileptiform discharge in the right central region. Levetiracetam was added to phenobarbital with good seizure control. CSF obtained on day 3 showed total nucleated cells 10/mm3 (neutrophil 1, lymphocyte 6, monocyte 3), red blood cells 9/mm3, protein 15 mg/dL, glucose 55 mg/dL. CSF stains (gram stain, fungal, mycobacterium) were negative for organisms. CSF HSV PCR and Enterovirus PCR were negative. MRI showed hemorrhage in the right frontal lobe and acute cortical changes at the right parietal vertex with subtle diffusion abnormality. MRI findings raised a concern for possible vasculitis. Erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA) were unremarkable. Magnetic resonance angiogram (MRA) of the head and magnetic resonance venogram (MRV) of the head were negative for vasculitis. Echocardiogram was normal. Broadspectrum antimicrobials (vancomycin, ceftriaxone, and metronidazole) were started. Extensive infectious disease evaluation all came back negative (CSF studies including bacterial/fungal/mycobacterium cultures, Histoplasma capsulatum antibody, Taenia solium antibody, galactomannan. Blood and urine bacterial cultures. Blood fungal culture.) She was transferred to our facility on day 8. Her physical examination was unremarkable except for left hemiparesis. Her mental status was normal. She had her second lumbar puncture on day 9 which showed elevated total nucleated cell count of 45/mm3 (neutrophils 0/mm3, lymphocytes 29/mm3, histiocytes 16/mm3) with red blood cells of 77/mm3. Because only small amount of CSF was obtained, CSF protein and glucose were not sent. Serum Borrelia burgdorferi antibody, serum Toxocara canis antibody and serum galactomannan were negative. Rheumatology was consulted for a concern of vasculitis, but workup including repeated brain MRA was essentially negative. Repeat brain MRI showed progressing cerebritis. Brain MRI [figure 1] revealed multiple foci of hyperintensity in bilateral cerebral hemispheres and right basal ganglia on fluid-attenuated inversion recovery (FLAIR) images with some enhancement on T1 post gadolinium sequences. These lesions were associated with restricted diffusion. Gradient echo (GRE) sequences suggested hemorrhage in more locations than appreciated on head CT [figure 2]. Brain biopsy was performed on day 9 given diagnostic uncertainty. This showed necrotizing hemorrhagic meningoencephalitis with positive immunostaining for HSV. In the face of positive immunostain result for HSV on the brain tissue, HSV PCR was added on the stored CSF sample obtained during the second lumbar puncture on day 9. The HSV PCR came back positive. Bacterial, fungal, acid-fast bacilli and viral cultures of the brain tissue were all negative. Although her neurological condition appeared to be slightly improving despite the lack of antiviral therapy, acyclovir was started. The patient completed a 21 days of intravenous acyclovir. At one-month-follow up, she had residual mild left-sided hemiparesis and was seizure free on a low dose of levetiracetam. Discussion Herpes simplex encephalitis (HSE) is regarded as the most common cause of sporadic fatal encephalitis in patients > 6 months of age in the Western world. The incidence of HSE is ~1 case per 250,000 to 500,000 persons per year with one-third of cases occurring in children [1]. Early recognition and prompt antiviral therapy are critical to reduce morbidity and mortality. In the absence of effective antiviral therapy, the mortality for this encephalitis is >70%, with only 2·5% of individuals returning to normal function [2]. HSE is classically associated with fever, altered mental status and seizures with or without focal deficits. CSF often shows lymphocytic pleocytosis with elevated protein. On imaging, temporal lobe involvement is classically described [3]. Intranuclear inclusion bodies consistent with HSV infection were demonstrated first in the brain of a neonate with encephalitis in 1941 followed by the isolation of virus [4]. Brain biopsy is both sensitive and specific means of its diagnosis and remained as the “gold standard” until mid1990’s. The availability of PCR has revolutionized the diagnosis of herpes simplex encephalitis. It has allowed the definitive and rapid diagnosis of HSE, eliminating the need of routine brain biopsy [5-8]. Despite advances in diagnostic techniques including PCR and MRI, diagnosing HSE remains a challenge in some cases. Clinicians need to be aware of following caveats in the diagnosis of HSE. Caveat 1: “non-specific” symptoms and “wide-range” in clinical presentations. The clinical hallmark of HSE is fever, encephalopathy, seizures and focal neurologic symptoms. With wide use of HSV PCR, instead of brain biopsy, milder cases have been recognized [9,10]. Although early treatment with acyclovir is thought to be essential to reduce mortality and morbidity, some patients do not seem to deteriorate despite the lack of acyclovir treatment. There is even a report of two children aged 3.5 and 15 years who recovered fully without treatment with acyclovir [11]. Our case did not have encephalopathy and the patient was stable without clinical deterioration despite the lack of antiviral therapy for more than a week after presentation. Caveat 2: “imperfect” CSF study including HSV PCR In majority of patients with HSE, CSF shows pleocytosis with a lymphocytic predominance. The protein is usually elevated (mean 80mg/dL) and the glucose is often normal. However, normal CSF white cell count and protein does not rule out HSV encephalitis. CSF is normal on 5–10 percent of patients on initial lumber puncture. Repeating the lumber puncture at a later time will reveal abnormalities such as pleocytosis and elevated CSF protein in most cases [3]. Regarding CSF HSV PCR, a 1995 publication showed the overall sensitivity and specificity of 98 percent and 94 percent respectively resulting in a positive predictive value of 95 percent and a negative predictive value of 98 percent [12]. However further studies showed that the sensitivity of PCR for detection of HSE varies with the timing of the study. There are reports of repeat CSF samples being positive for HSV PCR, after an initially negative CSF HSV PCR [13,14]. The rate of initially negative HSV PCR results is higher in pediatric patients, compared to 3 %~ 5 % reported for adults. Negative HSV PCR results, especially during the first 3 days of illness, does not exclude the diagnosis. It is prudent to repeat CSF study when clinically indicated [13]. Caveat 3: “temporal lobe” involvement Although temporal lobe involvement is classic for HSE, extra-temporal lobe involvement is also seen both in adults and children [1, 15]. In our case, temporal lobes were not involved and lesions were in bilateral parietal lobes as well as unilateral basal ganglia. Conclusion In summary, HSE still can be a diagnostic challenge. It can have a wide range of clinical presentation with large differentials, non-specific CSF finding, false negative HSV PCR especially early in the course, and extra-temporal involvement, particularly in the infant. It is important to bear this information in mind when evaluating pediatric patients presenting with encephalitis. References [1] Whitley RJ, Kimberlin DW. Herpes simplex encephalitis: children and adolescents. Semin Pediatr Infect Dis. 2005;16 :17– 23 [2] Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet. 2002;359(9305):507-13. [3] Whitley RJ. Herpes simplex encephalitis: adolescents and adults. Antiviral Res. 2006;71(23):141-8. [4] Smith MG, Lennette EH, Reames HR. Isolation of the virus of herpes simplex and the demonstration of intranuclear inclusions in a case of acute encephalitis. Am J Pathol. 1941;17(1):55-68.1. [5] Rowley AH, Whitley RJ, Lakeman FD, Wolinsky SM. Rapid detection of herpes-simplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet. 1990;335(8687):440-1. [6] Aurelius E, Johansson B, Sköldenberg B, Staland A, Forsgren M. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet. 1991;337(8735):189-92. [7] Aurelius E, Johansson B, Sköldenberg B, Forsgren M. Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid. J Med Virol. 1993;39(3):179-86. [8] Puchhammer-stöckl E, Heinz FX, Kundi M, et al. Evaluation of the polymerase chain reaction for diagnosis of herpes simplex virus encephalitis. J Clin Microbiol. 1993;31(1):146-8. [9] Ward KN, Ohrling A, Bryant NJ, Bowley JS, Ross EM, Verity CM. Herpes simplex serious neurological disease in young children: incidence and long-term outcome. Arch Dis Child. 2012;97(2):162-5. [10] Schleede L, Bueter W, Baumgartner-sigl S, et al. Pediatric herpes simplex virus encephalitis: a retrospective multicenter experience. J Child Neurol. 2013;28(3):321-31. [11] Marton R, Gotlieb-stematsky T, Klein C, Lahat E, Arlazoroff A. Mild form of acute herpes simplex encephalitis in childhood. Brain Dev. 1995;17(5):360-1. [12] Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1995;171(4):857-63. [13] Elbers JM, Bitnun A, Richardson SE, et al. A 12-year prospective study of childhood herpes simplex encephalitis: Is there a broader spectrum of disease?. Pediatrics. 2007;119(2):e399407. doi: 10.1542/peds.2006-1494. [14] Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. 2002;34(8):1154-7. [15] Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis. 2002;35(3):254-60. Figure 1: Multiple foci of hyperintensity on FLAIR images. Figure 2: GRE sequence showing areas of hemorrhage.