Life-Threatening Enterovirus 71 Encephalitis in Unrelated Children with Autosomal Dominant TLR3 Deficiency.

PURPOSE: Enterovirus A71 (EV71) causes a broad spectrum of childhood diseases, ranging from asymptomatic infection or self-limited hand-foot-and-mouth disease (HFMD) to life-threatening encephalitis. The molecular mechanisms underlying these different clinical presentations remain unknown. We hypothesized that EV71 encephalitis in children might reflect an intrinsic host single-gene defect of antiviral immunity. We searched for mutations in the toll-like receptor 3 (TLR3) gene. Such mutations have already been identified in children with herpes simplex virus encephalitis (HSE). METHODS: We sequenced TLR3 and assessed the impact of the mutations identified. We tested dermal fibroblasts from a patient with EV71 encephalitis and a TLR3 mutation and other patients with known genetic defects of TLR3 or related genes, assessing the response of these cells to TLR3 agonist poly(I:C) stimulation and EV71 infection. RESULTS: Three children with EV71 encephalitis were heterozygous for rare mutations-TLR3 W769X, E211K, and R867Q-all of which were shown to affect TLR3 function. Furthermore, fibroblasts from the patient heterozygous for the W769X mutation displayed an impaired, but not abolished, response to poly(I:C). We found that TLR3-deficient and TLR3-heterozygous W769X fibroblasts were highly susceptible to EV71 infection. CONCLUSIONS: Autosomal dominant TLR3 deficiency may underlie severe EV71 infection with encephalitis. Human TLR3 immunity is essential to protect the central nervous system against HSV-1 and EV71. Children with severe EV71 infections, such as encephalitis in particular, should be tested for inborn errors of TLR3 immunity.

Postencephalitic chronic granulomatous disease.

This report details the evolution of a case of herpes simplex encephalitis to chronic granuloma in a 13-year old female who, at the age of 8, suffered herpes simplex virus type 1 encephalitis. Eight months later, she developed an intracranial hypertension syndrome with the onset of a new lesion in the necrosed zone of her right temporal lobe, with no viral presence in the cerebrospinal fluid. The histologic characteristics were those of chronic granuloma with multinucleated giant cells and calcifications. Initially treated for neurosarcoidosis, the patient remained steroid-dependent for 4 years and the steroids could only be withdrawn by treatment with Infliximab. This type of evolutive pattern has probably been completely overlooked until now; it can only be accurately diagnosed by biopsy. It was initially mistaken for neurosarcoidosis.

[Early relapse of herpes simplex encephalitis. Clinical and therapeutic implications]. / Le ricadute precoci dell'encefalite erpetica. Implicazioni cliniche e terapeutiche.

A case of Herpes simplex virus encephalitis (HSVE) is reported in a 5 year old boy, who relapsed twice during the acute phase of the disease. The second relapse was completely cured by increasing the daily treatment with acyclovir to a dosage of 60 mg/kg intravenously for two weeks and 30 mg/kg by mouth for a further week. The full disappearance of the symptoms and the regression of cerebral lesions could be correlated to a prompt diagnosis and to the dosage of acyclovir employed, higher than that suggested for diseases caused that was by other members of the Herpes virus family.

Herpes simplex virus, meningitis and encephalitis in neonates.

The consequences of neonatal herpes simplex virus (HSV) infection can be severe. Disease can be localized to skin, eye and mouth (SEM disease), involve the central nervous system (CNS) or manifest as disseminated infection involving multiple organs. Most surviving infants in the latter two categories have neurological sequelae, and the mortality rate in the absence of therapy is very high (80%) for babies in the latter category. The International Herpes Management Forum (IHMF) has produced guidelines on the diagnosis, prevention and effective management of neonatal herpes. Neonatal herpes may occur in the absence of skin lesions, so if the infection is suspected, swabs of the oropharynx, conjunctiva, rectum, skin lesions, mucosal lesions and urine should be promptly taken and submitted for virus culture. Cerebrospinal fluid (CSF) should be submitted for polymerase chain reaction (PCR) detection of HSV DNA. Evidence for disseminated or CNS infection should be sought using liver function tests, complete blood cell count, CSF analysis and chest X-ray, if respiratory abnormalities are present. Neonates with suspected HSV infection should be treated with intravenous aciclovir (20 mg/kg) every 8 h for 21 days. If disease is localized to the SEM, treatment should be limited to 14 days. The neutrophil count for children receiving intravenous aciclovir should be monitored. If the absolute neutrophil count falls below 500/mm3, decreasing the aciclovir dose or administering granulocyte colony stimulating factor (GCSF) should be considered. At the end of therapy in CNS and disseminated disease, PCR assessment of CSF should be used and treatment continued if the child remains PCR positive at this site.

Epidemiologia, sinais clínicos e distribuição das lesões encefálicas em bovinos afetados por meningoencefalite por herpesvírus bovino-5 / Epidemiology, clinical signs and distribution of the encephalic lesions in cattle affected by meningoencephalitis caused by bovine herpesvirus-5

São descritos sete surtos e um caso isolado de meningoencefalite por herpesvírus bovino-5 (BoHV-5) em bovinos no Rio Grande do Sul entre 2002 e 2004. Foram afetados bovinos de 1-18 meses, de diversas raças e ambos os sexos. A maior freqüência foi observada em bovinos recém-desmamados e submetidos a outros fatores de estresse. Nesses surtos, de uma população total sob risco de 1.359 bovinos, 54 foram afetados, quatro se recuperaram e 50 morreram espontaneamente ou foram submetidos à eutanásia quando moribundos. Os índices gerais de morbidade, mortalidade e letalidade foram, respectivamente, de 3,97 por cento, 3,67 por cento e 92,59 por cento. A evolução clínica variou de 3-10 dias e os sinais eram caracterizados por depressão, corrimento nasal ou ocular, ranger de dentes, andar em círculos, cegueira, febre, nistagmo, tremores, anorexia, disfagia, sialorréia, incoordenação, pressão da cabeça contra objetos, pêlos arrepiados, taquicardia, taquipnéia, dor abdominal, melena, quedas, decúbito, opistótono, convulsões e movimentos de pedalagem. Dezenove bezerros foram necropsiados. Achados de necropsia foram caracterizados por hiperemia das leptomeninges, tumefação das porções rostrais do telencéfalo, com achatamento das circunvoluções dos lobos frontais; nessas áreas havia focos marrom-amarelados e amolecidos (malacia). Nos casos de evolução clínica mais longa era observada acentuada tumefação, amolecimento e extensas áreas de hemorragia nos lobos frontais telencefálicos. Microscopicamente, todos os bovinos afetados apresentaram meningoencefalite não-supurativa e necrosante, que variou quanto à localização e intensidade nos 19 casos examinados e nas seções de encéfalo de um mesmo caso.

Seven outbreaks and an isolated case of meningoencephalitis caused by bovine herpesvirus-5 (BoHV-5) in cattle in Rio Grande do Sul, Brazil, occurring in 2002-2004, are described. From a total population at risk of 1,359 cattle, 54 1-18-month-old calves from both sexes and several breeds were affected and 50 died spontaneously or were euthanatized while moribund. The highest frequency of cases was in recently weaned calves or calves submitted to other stressing factors. General rates of morbidity, mortality and lethality were respectively 3.97, 3.67 and 92.59. Clinical courses varied from 3-10 days and included depression, nasal and ocular discharge, grinding of teeth, circling, blindness, fever, nistagmus, trembling, anorexia, dysphagia, drooling, incoordination, head pressing, rough hair coat, tachycardia, tachypnea, abdominal pain, melena, falls, recumbency, opisthotonus, convulsions and paddling. Nineteen calves were necropsied. Necropsy findings were characterized by hyperemia of leptomeninges, swollen rostral portions of the telencephalon, and flattening of frontal lobes gyri; frequently in these frontal areas there were segmental brown-yellow discoloration and softening (malacia) of the cortex. In cases with more protracted clinical courses there were extensive swelling, softening and hemorrhaging of the telencephalic frontal lobes. Microscopically, all affected cattle had a necrotizing non-suppurative meningoencephalitis with variable distribution among the 19 cases and among the various telencephalic regions of the same case. The severity of these changes were more marked, in decreasing order of intensity, in the telencephalic frontal cortex, basal ganglia (nuclei), thalamus, brain stem, parietal telencephalic cortex, occipital telencephalic cortex and cerebellum. Perivascular inflammatory infiltrate consisted predominantly of lymphocytes, plasm cells, and less frequently of neutrophils. Additional microscopic findings included variable...