Editorial
Enterovirus and neurological complications
Enterovirus y complicaciones neurológicas
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The arrows point at dorsal involvement at the level of the pontine (A) and bulbar tegmentum (B) as well as the entire medulla oblongata (C) with grey matter predominance (D) (Courtesy of Ignacio Delgado, Radiology Dept.).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Enterovirus epidemic outbreaks</span><p id="par0005" class="elsevierStylePara elsevierViewall">Every year, there are more than 200<span class="elsevierStyleHsp" style=""></span>000 new cases of viral encephalitis worldwide, and enteroviruses (EVs) are the main causative agents. Traditionally, a diagnosis of infection by EV, such as herpangina or hand, foot and mouth disease (HFMD) was a source of relief in the evaluation of children with aseptic meningoencephalitis due to its generally good prognosis.</p><p id="par0010" class="elsevierStylePara elsevierViewall">This perspective has changed after several epidemics by EV in different parts of the world evinced that a significant number of patients develop neurologic manifestations, with a mortality and incidence of sequelae that are far from insignificant. Enteroviruses are single-stranded RNA viruses that belong to the <span class="elsevierStyleItalic">Picornaviridae</span> family. There are more than one hundred serotypes that exhibit variable degrees of neurotropism, as demonstrated by the damage inflicted by poliomyelitis, which has been eradicated in most of the world at this point. Enterovirus infections, including those by poliovirus, are asymptomatic in most cases. They spread by the faecal–oral route and by respiratory droplets. There are two main serotypes that can cause neurologic complications and have caused public alarm in Spain in the past year: enterovirus 71 (EV-71) type A71, and enterovirus D68 (EV-D68).</p><p id="par0015" class="elsevierStylePara elsevierViewall">Enterovirus 71 was identified in 1969, and in four decades it has given rise to outbreaks in Eastern Europe, Asia, Oceania and the United States, leading to considerable mortality in all instances. Suffice it to say that of the 130<span class="elsevierStyleHsp" style=""></span>000 cases of infection by EV-71 in Taiwan in 1998, 405 led to severe neurologic complications and 78 to death in children, and that more than seven million cases of HFMD were diagnosed in China between 2008 and 2012, with 2457 cases resulting in death.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> There is a reason that EV-71 is referred to as “the polio of the 21st century.”</p><p id="par0020" class="elsevierStylePara elsevierViewall">Enterovirus D68 is an emerging pathogen worldwide. First identified in 1962, the incidence of respiratory infection by EV-D68 has increased in recent years, and the virus has been associated with cases of acute flaccid paralysis in the United States and Canada.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> While EV-71 primarily affects children aged 1–2 years (approximate range, 3 months–5 years),<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> EV-D68 affects older children and adults, who in many cases suffer from asthma.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Neurologic disease associated with enterovirus 71</span><p id="par0025" class="elsevierStylePara elsevierViewall">There are four clinical stages of infection by EV-71: 1) HFMD/herpangina, 2) central nervous system involvement, 3) cardiopulmonary failure and 4) convalescence. Most cases resolve during stage 1, some progress to stage 2, few progress to stage 3 and, if the latter patients survive, they may suffer permanent sequelae, which would correspond to stage 4. The typical presentation is brainstem encephalitis with or without myelitis, or, in some cases, pure myelitis (acute flaccid paralysis). In addition to manifesting with fever, mild forms of brainstem encephalitis may be associated with drowsiness, myoclonus and/or tremors. Ataxia, when present, is mild and transient, as occurs in other acute post-infectious ataxias in children. Stretch reflexes are usually overactive. In moderate forms, patients also experience weakness and manifestations of bulbar involvement (dysarthria, dysphagia, hypopnoea) or involvement of other cranial nerves (VI, VII), while severe disease manifests with cardiopulmonary failure, acute haemorrhagic pulmonary oedema of neurologic origin and/or myocarditis. Given the rapid progression of the latter forms and that most deaths occur within the first 24<span class="elsevierStyleHsp" style=""></span>h, it is crucial that brainstem encephalitis secondary to EV-71 infection is diagnosed early and followed by immediate initiation of monitoring and supportive care. It is important that providers recognise myclonic jerks, as they are an early sign of brainstem involvement.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Neuroimaging tests show involvement of the dorsal region of the pons, medulla, midbrain and dentate nuclei, with hyperintense foci in T2-weighted and FLAIR images. Cases of flaccid myelitis manifest with hyperintensity in the anterior horn of the spinal cord. The presence of restriction patterns in diffusion-weighted images is associated with severe forms of disease and increased risk of sequelae.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In 2016, more than 100 cases of EV-71 encephalitis were reported in Spain. Since the definition of a case is, as one would expect, quite strict (confirmation by virology testing and positive findings in neuroimaging, which in our experience can be subtle or even negative) it is likely that the actual number of cases is underestimated.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Of the 45 patients that received the diagnosis in our hospital between March and July 2016, all with rhombencephalitis experienced a complete or nearly full recovery, two out of four with acute flaccid paralysis suffer from monoparesis as a sequela, and a patient with fulminant brainstem failure and heart abnormalities suffers from severe sequelae. Only one patient died in the Autonomous Community of Catalonia, in September 2016.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Neurologic disease associated with enterovirus D68</span><p id="par0045" class="elsevierStylePara elsevierViewall">Neurologic disease associated to infection by EV-D68 is different and less frequent (5 confirmed cases since late 2015 in Spain). However, it has been widely covered by the media due to its severity, comparable to that of poliomyelitis. Its manifestations often complicate lower respiratory tract infections. The clinical presentation consists of acute flaccid paralysis and arreflexia. Neuroimaging (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) reveals longitudinally extensive myelitis with predominant involvement of the anterior horn. Features of rhombencephalon involvement are indistinguishable from those caused by EV-71. Electromyography can confirm motor neuron damage at one week from onset and signs of denervation at three to four weeks. The prognosis is very poor, with a high mortality and variable degrees of flaccid tetraparesis and involvement of respiratory muscles.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Diagnosis and treatment</span><p id="par0050" class="elsevierStylePara elsevierViewall">Early diagnosis is paramount. The pharynx must be assessed for the presence of EV within one week from the onset of symptoms, and the faeces two weeks or more later. The findings of cerebrospinal fluid examination are abnormal in only five to twenty percent of cases. Rapid detection of EV can be achieved by means of real time PCR and serotyping by sequencing of the 5′UTR region of the virus (VP1). CSF examination may reveal mild pleocytosis and elevated protein levels, or it may be normal. In fatal cases, the viral antigen has been detected in nerve roots, autonomic ganglia in the intestines, and nuclei of the brainstem and spinal cord.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> It is known that human cells have receptors for EV-71. Host-related factors (polymorphisms in interleukin genes) or certain serotypes that can evade innate immunity could contribute to the susceptibility to severe disease.</p><p id="par0055" class="elsevierStylePara elsevierViewall">There is no specific treatment for EV. The good outcomes achieved with pleconaril in a clinical trial in newborn infants await replication. Administration of intravenous immunoglobulin may be somewhat beneficial by contributing neutralising antibodies, attenuating sympathetic activity and reducing cytokine production, but a recently published study did not find high-dose methylprednisolone to be effective in any way,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> which is consistent with our own experience. In cases with cardiac dysfunction, milrinone is the drug of choice due to its inotropic, vasodilatory and anti-inflammatory effects. Fluoxetine has exhibited an anti-EV activity in vitro and was used off-label in some of our patients, with no apparent effect (it has also been used for the treatment of enterovirus encephalitis in patients with sex-linked hypogammaglobulinaemia). In China, phase III clinical trials of inactivated whole-virus vaccines have been completed, demonstrating that the vaccines are efficacious against EV-71 but offer no cross-protection against other genotypes.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="par0060" class="elsevierStylePara elsevierViewall">The experience in other countries shows that EV epidemics can be protracted, and thus, as paediatricians, we must remain alert in the coming months and possibly years. Neuroimaging tests must be performed early in patients presenting with acute neurologic symptoms and on an urgent basis in cases of bulbar palsy or acute flaccid myelitis. All cases of acute flaccid paralysis must be reported by law, and the potential presence of EV must always be assessed. As long as a vaccine is not available, the early detection of outbreaks and the implementation of hygiene measures to stop the spread of EV are the key steps to limit the impact of outbreaks and the development of severe forms of disease. In this regard, educational campaigns on hygiene measures not only in the community, but also in the health field, are of utmost importance.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Enterovirus epidemic outbreaks" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Neurologic disease associated with enterovirus 71" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Neurologic disease associated with enterovirus D68" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Diagnosis and treatment" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusions" ] 5 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Macaya A, Felipe-Rucián A. Enterovirus y complicaciones neurológicas. An Pediatr (Barc). 2017;86:107–109.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2657 "Ancho" => 2421 "Tamanyo" => 541911 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Rhombencephalitis caused by EV-D68: T2-weighted brain and spinal cord MRI scans obtained during the acute phase of disease. The arrows point at dorsal involvement at the level of the pontine (A) and bulbar tegmentum (B) as well as the entire medulla oblongata (C) with grey matter predominance (D) (Courtesy of Ignacio Delgado, Radiology Dept.).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enterovirus 71 infection and neurological complications" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "K.Y. Lee" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3345/kjp.2016.59.10.395" "Revista" => array:6 [ "tituloSerie" => "Korean J Pediatr" "fecha" => "2016" "volumen" => "59" "paginaInicial" => "395" "paginaFinal" => "401" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27826325" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enteroviruses in the early 21st century: new manifestations and challenges" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D. Lugo" 1 => "P. Krogstad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MOP.0000000000000303" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Pediatr" "fecha" => "2016" "volumen" => "28" "paginaInicial" => "107" "paginaFinal" => "113" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26709690" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0040" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical characteristics and functional motor outcomes of enterovirus 71 neurological disease in children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.L. Teoh" 1 => "S.S. Mohammad" 2 => "P.N. Britton" 3 => "T. Kandula" 4 => "M.S. Lorentzos" 5 => "R. Booy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamaneurol.2015.4388" "Revista" => array:6 [ "tituloSerie" => "JAMA Neurol" "fecha" => "2016" "volumen" => "73" "paginaInicial" => "300" "paginaFinal" => "307" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26785318" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathologic studies of fatal encephalomyelitis in children caused by enterovirus 71" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Xing" 1 => "D. Liu" 2 => "S. Shen" 3 => "Z. Su" 4 => "L. Zhang" 5 => "Y. Duan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ajcp/aqw089" "Revista" => array:6 [ "tituloSerie" => "Am J Clin Pathol" "fecha" => "2016" "volumen" => "146" "paginaInicial" => "95" "paginaFinal" => "106" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27357294" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy of high-dose methylprednisolone pulse therapy in the treatment of enterovirus 71 encephalitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G. Zhang" 1 => "J. Wang" 2 => "G. Yao" 3 => "B. Shi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pak J Pharm Sci" "fecha" => "2016" "volumen" => "29" "numero" => "Suppl. 4" "paginaInicial" => "S1421" "paginaFinal" => "S1427" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23412879/0000008600000003/v1_201702231638/S234128791730011X/v1_201702231638/en/main.assets" "Apartado" => array:4 [ "identificador" => "25501" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Editorial" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/23412879/0000008600000003/v1_201702231638/S234128791730011X/v1_201702231638/en/main.pdf?idApp=UINPBA00005H&text.app=https://analesdepediatria.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S234128791730011X?idApp=UINPBA00005H" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 13 | 6 | 19 |
| 2024 October | 90 | 32 | 122 |
| 2024 September | 99 | 19 | 118 |
| 2024 August | 85 | 52 | 137 |
| 2024 July | 107 | 30 | 137 |
| 2024 June | 124 | 62 | 186 |
| 2024 May | 108 | 43 | 151 |
| 2024 April | 96 | 42 | 138 |
| 2024 March | 90 | 40 | 130 |
| 2024 February | 82 | 25 | 107 |
| 2024 January | 73 | 21 | 94 |
| 2023 December | 76 | 25 | 101 |
| 2023 November | 104 | 25 | 129 |
| 2023 October | 104 | 33 | 137 |
| 2023 September | 76 | 18 | 94 |
| 2023 August | 76 | 22 | 98 |
| 2023 July | 48 | 26 | 74 |
| 2023 June | 71 | 34 | 105 |
| 2023 May | 97 | 18 | 115 |
| 2023 April | 48 | 22 | 70 |
| 2023 March | 71 | 19 | 90 |
| 2023 February | 74 | 16 | 90 |
| 2023 January | 49 | 18 | 67 |
| 2022 December | 73 | 40 | 113 |
| 2022 November | 74 | 30 | 104 |
| 2022 October | 70 | 47 | 117 |
| 2022 September | 75 | 36 | 111 |
| 2022 August | 62 | 56 | 118 |
| 2022 July | 49 | 40 | 89 |
| 2022 June | 40 | 39 | 79 |
| 2022 May | 45 | 29 | 74 |
| 2022 April | 41 | 45 | 86 |
| 2022 March | 85 | 52 | 137 |
| 2022 February | 47 | 30 | 77 |
| 2022 January | 61 | 39 | 100 |
| 2021 December | 59 | 32 | 91 |
| 2021 November | 60 | 43 | 103 |
| 2021 October | 67 | 83 | 150 |
| 2021 September | 55 | 36 | 91 |
| 2021 August | 72 | 44 | 116 |
| 2021 July | 48 | 35 | 83 |
| 2021 June | 49 | 62 | 111 |
| 2021 May | 58 | 63 | 121 |
| 2021 April | 150 | 98 | 248 |
| 2021 March | 92 | 43 | 135 |
| 2021 February | 47 | 25 | 72 |
| 2021 January | 59 | 42 | 101 |
| 2020 December | 64 | 22 | 86 |
| 2020 November | 53 | 20 | 73 |
| 2020 October | 60 | 25 | 85 |
| 2020 September | 39 | 30 | 69 |
| 2020 August | 62 | 25 | 87 |
| 2020 July | 54 | 25 | 79 |
| 2020 June | 49 | 17 | 66 |
| 2020 May | 53 | 24 | 77 |
| 2020 April | 38 | 12 | 50 |
| 2020 March | 58 | 20 | 78 |
| 2020 February | 63 | 16 | 79 |
| 2020 January | 58 | 18 | 76 |
| 2019 December | 63 | 23 | 86 |
| 2019 November | 59 | 14 | 73 |
| 2019 October | 59 | 55 | 114 |
| 2019 September | 56 | 9 | 65 |
| 2019 August | 57 | 19 | 76 |
| 2019 July | 62 | 22 | 84 |
| 2019 June | 65 | 14 | 79 |
| 2019 May | 93 | 33 | 126 |
| 2019 April | 115 | 23 | 138 |
| 2019 March | 57 | 20 | 77 |
| 2019 February | 48 | 15 | 63 |
| 2019 January | 44 | 20 | 64 |
| 2018 December | 57 | 28 | 85 |
| 2018 November | 77 | 31 | 108 |
| 2018 October | 72 | 41 | 113 |
| 2018 September | 38 | 22 | 60 |
| 2018 August | 4 | 0 | 4 |
| 2018 July | 2 | 0 | 2 |
| 2018 June | 4 | 0 | 4 |
| 2018 May | 10 | 0 | 10 |
| 2018 April | 43 | 0 | 43 |
| 2018 March | 43 | 0 | 43 |
| 2018 February | 18 | 0 | 18 |
| 2018 January | 32 | 0 | 32 |
| 2017 December | 24 | 0 | 24 |
| 2017 November | 32 | 0 | 32 |
| 2017 October | 32 | 0 | 32 |
| 2017 September | 29 | 0 | 29 |
| 2017 August | 18 | 0 | 18 |
| 2017 July | 32 | 0 | 32 |
| 2017 June | 43 | 9 | 52 |
| 2017 May | 44 | 18 | 62 |
| 2017 April | 112 | 94 | 206 |
| 2017 March | 58 | 27 | 85 |
| 2017 February | 8 | 17 | 25 |
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