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Severe Human Herpesvirus 6-associated Encephalopathy in Three Children

Analysis of Cytokine Profiles and the Carnitine Palmitoyltransferase 2 Gene

Matsumoto, Hiroshi MD, PhD; Hatanaka, Daisuke MD; Ogura, Yumi MD; Chida, Ayako MD; Nakamura, Yasuko MD; Nonoyama, Shigeaki MD, PhD

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The Pediatric Infectious Disease Journal: November 2011 - Volume 30 - Issue 11 - p 999-1001
doi: 10.1097/INF.0b013e3182242065


Human herpesvirus 6 (HHV-6) infection is the cause of benign febrile illness exanthema subitum in young children. Some patients with HHV-6 infection present with central nervous system (CNS) complications.1 We herein report 3 young children with acute encephalopathy associated with HHV-6 infection who developed severe neurologic complications. We examined the serum TH1/TH2 cytokine concentrations during the acute phase of the disease. We also performed analysis of the carnitine palmitoyltransferase 2 (CPT 2), which is a genetic risk factor for encephalopathy associated with high body temperature.2


Case 1.

The patient was a 26-month-old previously healthy female. She developed generalized seizures and status epilepticus with a high-grade fever. She showed a deep coma state (Glasgow coma scale [GCS] 4). A blood examination showed decreased platelet counts, elevated transaminase, and coagulopathy (Table, Supplemental Digital Content 1, Intensive treatment against encephalopathy and disseminated intravascular coagulation was administered including high-dose methylprednisolone. A brain magnetic resonance image (MRI) on day 2 showed diffuse abnormal signals (Fig. 1 A–C). Polymerase chain reaction (PCR) for multiplex herpes viruses (herpes simplex 1/2 virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, HHV-6/7) was performed, and only HHV-6 was detected in the serum (4.4 × 103 copies/mL). At 16 hours after admission, an uncontrollable elevation of the intracranial pressure and brain herniation occurred. Thereafter, voluntary respiration and brain stem reflexes disappeared, and she became brain dead.

Brain MRI of case 1 (A–C), case 2 (D–F), and case 3 (G–I). Magnetic resonance spectroscopy of case 3 (J). A diffusion-weighted image of case 1 showed symmetrical reduced diffusion in the basal ganglia and parietal cortices (A and C, arrows: TR/TE = 2990/73, b factor = 1000). The reduced diffusion was noted on an apparent diffusion coefficient map (B). The serial brain MRI of case 2 and case 3 showed reduced diffusion in cerebral white matter in the acute phase (D, G, arrows). One week later, the reduced diffusion moved to the cortices and caudate nucleus (E, H). Marked brain atrophy was noted in the convalescent phase (F, I, T1-weighted images: TR/TE = 2100/10). Magnetic resonance spectroscopy during the acute phase showed a decreased peak of NAA and the appearance of lactate peaks (J). NAA indicates N-acetylaspartate; Cho, choline; Cr, creatine; Glx, glutamine/glutamate complex.
Case 2.

The second patient was a 14-month-old previously healthy female. She had generalized seizures and status epilepticus with a high-grade fever. She was in a deep coma (GCS 4). On day 3 after admission, a blood examination showed decreased platelet counts, extremely elevated serum transaminase values, and coagulopathy. A brain MRI showed diffuse abnormalities in the cerebral white matter (Fig. 1D). Intensive treatments against encephalopathy were administered. A multiplex PCR analysis for herpes viruses revealed HHV-6 in the cerebrospinal fluid (6.0 × 102 copies/mL) and in the whole blood (2.8 × 103 copies). She has persistent neurologic sequelae; she cannot sit, walk, or speak.

Case 3.

The patient was an 18-month-old previously healthy female. She developed generalized seizures and status epilepticus with a high-grade fever. She was in a deep coma (GCS 4). An electroencephalogram showed extremely high-voltage diffuse slow activities. Intensive treatments including high-dose methylprednisolone were administered. A Multiplex PCR analysis for herpes viruses revealed HHV-6 in whole blood (3.9 × 102 copies). After treatment, however, her consciousness level did not improve. A brain MRI showed diffuse abnormalities in the cerebral white matter (Fig. 1G). She continues to exhibit severe neurologic sequelae with spastic quadriplegia, epilepsy, and mental retardation.

Magnetic resonance spectroscopy was performed during the acute and convalescent phases. During the acute phase, the N-acetylaspartate (NAA) showed a lower peak than creatine and choline; the ratio of NAA/creatine was 0.99 in the white matter of the affected frontal lobe (Fig. 1J). The lactate peaks were also found. During the subacute phase, the NAA was further decreased (NAA/creatine = 0.63).


We evaluated the TH1/TH2 cytokines in the 3 patients' serum during the acute phase, using a beads assay with a flow cytometer (FlowCytomix, Bender Med Systems, Vienna) (Table, Supplemental Digital Content 2, The soluble interleukin-2 receptor (sIL-2R) and the soluble tumor necrosis factor receptor 1 (sTNFR1) were measured by enzyme-linked immunosorbent assay. Case 1 showed markedly increased multiple cytokines, including TH1 cytokines (IFN-γ and IL-2), TH2 cytokines (IL-4 and IL-6), IL-8, and regulatory T cytokine (IL-10). TNF-α was not elevated, but an increased sTNFR1 was noted. Case 2 showed increased IFN-γ, IL-4, IL-8, IL-10, sIL-2R, and sTNFR1. Case 3 showed no apparent elevation of cytokines except for mildly increased IL-8.


CPT2 regulates mitochondrial fatty acid β-oxidation. Chen et al2 reported a thermolabile variation of CPT2 (p.F352C and p.V368I), which lead to reduced CPT2 activity (about 25%–30% of the wild-type protein) under high body temperatures. To clarify their possible genetic predisposition due to the CPT2 variation in HHV-6 associated encephalopathy, analysis of CPT2 was performed after informed consent was obtained from patients' parents. Only case 2 had the heterozygous thermolabile genotype of CPT2 (p.F352C), while the other 2 did not have it. The CPT2 variation seen in case 2 could have affected her energy metabolism during the HHV-6 infection, and could have contributed to the occurrence of encephalopathy and multiple organ failure.3


Several inflammatory cytokines such as TNF-α and IL-6 have been shown to be elevated during encephalopathy associated with viral infection.4 With regard to HHV-6 encephalopathy, the serum IL-6, IL-10, and sTNFR1 were significantly higher in infants who had neurologic sequelae.5 In our 3 cases, cases 1 and 2 showed hypercytokinemia, and they were also complicated with coagulopathy.

Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic disease in childhood, which is characterized by fever, depression of all 3 blood cell lineages, deranged liver function, intravascular coagulation, and CNS dysfunction. The clinical and laboratory findings in cases 1 and 2 were similar to those of MAS. Hyperferritinemia (>1000 ng/mL) is an important laboratory hallmark of MAS, which was noted in both case 1 (9554 ng/mL) and case 2 (11,591 ng/mL). It is thus possible that the mechanism of encephalopathy in cases 1 and 2 is related to the abnormal immunologic response triggered by HHV-6 infection. The activation and uncontrolled proliferation of T lymphocytes and macrophages cause the unrestricted release of inflammatory cytokines, which then cause severe encephalopathy and multiple organ dysfunctions through the induction of apoptosis in the vascular endothelium in the CNS and other organs.6

Case 3 showed no increase of cytokines. The serial MRI findings in case 3 are consistent with those of a distinctive encephalopathy syndrome reported by Takanashi et al.7 Patients with this syndrome show prolonged febrile seizures as an initial symptom, followed by a wide variety of neurologic outcomes. Although the pathogenic mechanism of this type of encephalopathy is unclear, magnetic resonance spectroscopy in case 3 revealed progressively decreased NAA and elevated lactate in the acute phase. These findings suggest the presence of anaerobic metabolism and neuronal damage in the affected brain, caused by ischemic damage and/or excitotoxicity of the neurons.7

Finally, we also discuss PCR testing. The chromosomal integration of HHV-6 leads to an inaccurate diagnosis of HHV-6 infection by the PCR testing of body fluids.8

Due to the lower prevalence of chromosomal integration of HHV-6 in Japan (0.21%)9 and the particular viral loads seen in the 3 cases, it is likely that the positive PCRs represent an acute infection of HHV-6.


The authors thank Dr. H. Kido (Tokushima University, Tokushima) for performing the gene analysis of CPT2.


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9.Tanaka-Taya K, Sashihara J, Kurahashi H, et al. Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA. J Med Virol. 2004;73:465–473.

human herpesvirus 6; encephalopathy; hypercytokinemia; carnitine palmitoyltransferase 2; macrophage activation syndrome

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© 2011 by Lippincott Williams & Wilkins, Inc.