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Congenital Zika virus infection can cause microcephaly and severe brain abnormalities (1). Congenital Zika syndrome comprises a spectrum of clinical features (2); however, as is the case with most newly recognized teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly (3). To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (4). Thirteen infants with laboratory evidence of congenital Zika virus infection and normal head size (less than or equal to 2 standard deviations [SD] below the mean for sex and gestational age) at birth (during October 2015–January 2016) are included in this report. The infants were evaluated by multidisciplinary teams at two referral centers in Brazil: the Rehabilitation Center of Association for Assistance of Disabled Children of Pernambuco, Recife, Pernambuco State, and the Infantil Albert Sabin Hospital, Fortaleza, Ceará State during the months of October 2015–October 2016. Eleven of the infants came to clinical attention because their birth head circumference was below the level established by the Brazilian Ministry of Health as requiring further evaluation for possible congenital Zika virus infection (http://combateaedes.saude.gov.br/images/sala-de-situacao/Microcefalia-Protocolo-de-vigilancia-e-resposta-10mar2016-18h.pdf). This level was 33 cm before December 2, 2015, and 32 cm for gestational age ≥37 weeks after that date; however, all of these infants had head circumferences at birth that did not exceed 2 SD below the mean for gestational age, and therefore did not meet the definition for microcephaly (more than 2 SD below the mean). These 11 infants were referred for neurologic evaluation and neuroimaging. The remaining two infants who had head circumferences in the normal range at birth were referred for neurologic evaluation at ages 5 and 7 months because of developmental concerns. A standard form was used to collect demographic and clinical information, including whether the mothers recalled having had a rash during pregnancy. All information was obtained as part of the clinical protocol or as the result of clinical indication. Informed consent was obtained for the collection, use, and publication of clinical photographs of the infants. Laboratory evidence of congenital Zika virus infection was defined as negative laboratory test results for five infectious causes of congenital microcephaly (toxoplasmosis, cytomegalovirus, rubella, syphilis and human immunodeficiency virus) and serologic evidence of Zika virus infection (a positive Zika virus-specific immunoglobulin M (IgM) capture enzyme–linked immunosorbent assay (MAC-ELISA) result on infant cerebrospinal fluid [CSF] or serum). Conventional reverse transcription–polymerase chain reaction (RT-PCR) was performed for the detection of Zika virus and dengue virus RNA, and real-time RT-PCR was performed for chikungunya virus in the Recife location. Monoplex real-time RT-PCR for Zika virus was performed in the Fortaleza location (5,6). Maternal testing for evidence of Zika virus infection was not available during the time of the 13 pregnancies. For this report, microcephaly was defined as head circumference (HC) (also known as occipitofrontal circumference) more than 2 SD below the mean for gestational age and sex, according to the Fetal International and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) for fetal and newborn growth (https://intergrowth21.tghn.org/) and the World Health Organization Child Growth Standards for infants (www.who.int/childgrowth/en/). Birth weight was evaluated and classified as appropriate, small, or large for gestational age and sex, also using INTERGROWTH-21st standards. All infants had clinical neurologic and orthopedic evaluations, and brain imaging with computerized tomography (CT) scan without contrast, magnetic resonance imaging (MRI) without contrast, or both, and radiographs of the hips to identify congenital dislocation. In addition, all infants had clinical noninstrumental evaluation of dysphagia by a speech therapist, ophthalmologic examination with ophthalmoscopy assessment, and 11 of 13 infants had auditory evaluation by screening (auditory short latency brainstem evoked response [ABR] to click stimuli) and diagnostic tests (confirmatory frequency-specific ABR with tone burst stimuli) using the routine recommended by Brazilian Heath Ministry and the American Academy of Pediatrics Joint Committee on Infant Hearing (7). Infants clinically suspected of having seizure activity had an electroencephalogram to confirm. The case series included nine male infants and four female infants (Table 1). Eleven patients were born at term (37–41 weeks’ gestation) and two were preterm (35 and 36 weeks’ gestation). Six of 13 mothers described a cutaneous rash between the second and fifth months of pregnancy. All infants had birth weights that were appropriate for gestational age (i.e., within 2 SD of the mean for sex and gestational age). Craniofacial disproportion was noted in six infants; three had redundant skin on the scalp at birth. Three infants had hip dysplasia, including one infant with arthrogryposis who had bilateral dislocated hips. All infants had positive tests for Zika virus–specific IgM in either CSF only (nine infants), serum only (two infants) or CSF and serum (two infants). Seven CSF specimens were tested for Zika virus RNA by RT-PCR and all were negative; two of these infants also had negative RT-PCR testing in serum collected at the same time as CSF. RT-PCR testing results on the two serum-only specimens are pending. No Zika virus testing was performed on urine. Most infants (eight of 13) were tested within the first month of life; however, the date of testing of CSF for two infants is not known. Three infants were tested for Zika virus outside the neonatal period. Although identified at birth because of head size, one infant was not tested until age 4 months; two infants were tested at ages 5 months and 7 months when they were first evaluated because of developmental delay. One infant with both CSF and serum IgM testing positive at birth tested negative on serum re-testing at 6 months of age; another remained positive on re-testing at age 5 months. HCs at birth ranged from 0.30 to -2.00 SD from the mean for gestational age and sex (Table 1). All infants showed a decrease in the rate of HC growth between birth and the time of the last examination. In 11 of 13 infants, postnatal microcephaly was diagnosed because of an HC measurement more than 2 SD below the mean for age and sex. Neuroimaging (CT scan in 13 infants and MRI in 10 infants) showed malformations of cortical development, which were most predominant anteriorly, and calcifications, predominantly in the subcortical region (especially in the transition area between the cortex and white matter). All neuroimaging showed evidence of decreased brain volume, with ventriculomegaly in all infants, and increased extra-axial CSF space in two of 13 infants (Table 2) (Figure). Dysphagia was found on clinical evaluation in 10 of 13 infants. Seven infants had a diagnosis of epilepsy. Five infants had some degree of irritability, which improved by age 4 months. Most infants (12 of 13) had good visual interaction; one infant exhibited no eye contact. Three of 13 infants had chorioretinal abnormalities. All 11 infants tested had normal hearing evaluations. All infants had some degree of hypertonia; 12 of 13 had pyramidal and extrapyramidal signs with dystonic movement. One infant had spastic hemiparesis and another had bilateral hemiparesis, more severe on the left side. One infant with arthrogryposis was difficult to assess because of increased tone in some muscles and decreased in others. Nine of 13 infants had no voluntary movement of the hands and had a grasp reflex. Good head control was present in eight of 13 infants (supplemental material at https://stacks.cdc.gov/view/cdc/42517).

Summary What is already known about this topic? Congenital Zika virus infection can cause microcephaly and severe brain abnormalities. As more information about the associated clinical syndrome becomes available, the phenotype is expanding to include other, sometimes less severe features, such as brain abnormalities without congenital microcephaly. What is added by this report? Although infants with congenital Zika virus infection who have a normal head size have been described in large series, sufficient description of the features of congenital Zika syndrome in these infants has not been available. This report of a series of 13 infants with laboratory evidence of congenital Zika virus infection with normal head size at birth includes the findings from extensive imaging, neurologic, ophthalmologic, auditory, and orthopedic examinations. Follow-up of these infants has shown that for most, head growth deceleration occurs to the point of microcephaly after birth and significant neurologic sequelae are evident. What are the implications for public health practice? Additional information is needed to fully describe the spectrum of findings associated with congenital Zika virus infection; however, microcephaly might not be evident at birth but can develop after birth in infants with underlying brain abnormalities. These findings underscore the importance of early neuroimaging for infants exposed to Zika virus prenatally.

Vanessa van der Linden, MD1*; André Pessoa, MD2*; William Dobyns, MD3; A. James Barkovich, MD4; Hélio van der Linden Júnior, MD5; Epitacio Leite Rolim Filho, MD, PhD1,6; Erlane Marques Ribeiro, MD, PhD2; Mariana de Carvalho Leal, MD, PhD6,7; Pablo Picasso de Araújo Coimbra, MD8; Maria de Fátima Viana Vasco Aragão, MD, PhD9,10; Islane Verçosa, MD11; Camila Ventura, MD, PhD12,13; Regina Coeli Ramos, MD12; Danielle Di Cavalcanti Sousa Cruz, MD13; Marli Tenório Cordeiro, PhD14; Vivian Maria Ribeiro Mota15; Mary Dott, MD16; Christina Hillard, MA17; Cynthia A. Moore, MD, PhD17 Corresponding author: Cynthia A. Moore, [email protected]; 770-488-7100. Top 1Association for Assistance of Disabled Children, Recife, Pernambuco, Brazil; 2Hospital Infantil Albert Sabin, Fortaleza, Ceará, Brazil; 3University of Washington and Seattle Children’s Research Institute, Seattle; 4University of California-San Francisco; 5Dr. Henrique Santillo Rehabilitation Center, Goiania, Brazil; 6Federal University of Pernambuco, Recife, Pernambuco, Brazil; 7Agamenon Magalhães Hospital (HAM), Recife, Pernambuco Brazil; 8Uniclinic Diagnóstico por Imagem, Fortaleza, Brazil; 9Centro Diagnóstico Multimagem, Recife, Pernambuco, Brazil; 10Mauricio de Nassau University, Recife, Pernambuco, Brazil; 11Caviver Clinical, Fortaleza, Ceará, Brazil; 12Altino Ventura Foundation, Recife, Pernambuco, Brazil; 13Pernambuco’s Eye Hospital, Recife, Pernambuco, Brazil; 12Oswaldo Cruz University Hospital, Recife, Pernambuco, Brazil; 13Professor Fernando Figueira Integral Medicine Institute, Recife, Pernambuco, Brazil; 14Centro de Pesquisas Aggeu Magalhães-Fiocruz, Recife, Pernambuco, Brazil; 15University of Fortaleza, Fortaleza, Brazil; 16Center for Surveillance, Epidemiology and Laboratory Services, CDC; 17National Center on Birth Defects and Developmental Disabilities, CDC. Top * These authors contributed equally to this report.

Description of 13 Infants Born During October 2015–January 2016 With Congenital Zika Virus Infection Without Microcephaly at Birth — Brazil Early Release / November 22, 2016 / 65 http://www.cdc.gov/mmwr/volumes/65/wr/mm6547e2.htm?s_cid=mm6547e2_w

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Intense surveillance of microcephaly and other defects Congenital central nervous system Review on November 18, 2016 Between the epidemiological weeks 01 to 45 of 2016, Confirmed (58) fifty-eight cases of associated microcephaly To the Zika virus, 227 cases were discarded and 424 cases were study. http://www.ins.gov.co/boletin-epidemiologico/Boletn Epidemiolgico/2016 Boletín epidemiológico semana 45.pdf

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Tuesday, November 22, 2016 Press release from: Senate Administration for Justice and Consumer Protection Four dead salvaged from the Landwehr Canal swans of influenza virus was yesterday in the State Laboratory Berlin-Brandenburg detected type H5. The final confirmation by the National Reference Laboratory - the Friedrich Loeffler Institute - (FLI) is still pending. All animals are swans from the Landwehrkanal near the Baerwald bridge. Thus, the boundaries of the restricted area on Friday set up accordingly up to this north-south connection: Underground station Alt Tempelhof, Schöneberg Street / Manteuffelstraße , Kreuz Schöneberg Bayerischer Platz, wittenbergplatz, S-Bahn station Bellevue, Central Station, S-Bahnhof Oranienburger Str. Since the first outbreak of avian influenza pollen of type H5N8 in wild animals on Lake Plön in Schleswig-Holstein on 08.11.2016 37 wild birds from Berlin were examined for the presence of the virus of avian influenza of subtype H5 in the state laboratory Berlin-Brandenburg. Up to now, 5 animals have been positively evaluated. The risk that by this hotspot of the virus could be introduced into poultry flocks are mitigated by the establishment of a Sperrbezirks, an observation area and a freewheeling prohibition of dogs and cats in the forbidden area. Poultry farmers throughout Berlin have aufzustallen their animals and the locations with the prescribed Biosafety measures. For further information, please contact your local office. http://www.xhain.net/pm/senatsverwaltung-fur-justiz-und-verbraucherschutz

Four dead salvaged from the Landwehr Canal swans of influenza virus was yesterday in the State Laboratory Berlin-Brandenburg detected type H5. The final confirmation by the National Reference Laboratory - the Friedrich Loeffler Institute - (FLI) is still pending. All animals are swans from the Landwehrkanal near the Baerwald bridge. http://www.xhain.net/pm/2016/gefluegelpest-weitere-infizierte-schwaene-im-landwehrkanal

On November 18 FLI confirmed the first H5N8 wild bird case in Berlin (Mute swan that died on November 16 in Landwehr Canal). On November 19 media reports cited collection of six more swans on Saturday, and today media reports cited H5 confirmation in the first four (bringing the total number of H5 confirmations of dead swans in central Berlin to five.

week conf discard untested total weekly increase 44 58 225 389 672 19 43 57 223 373 653 29 42 54 216 354 624 22 41 47 213 342 602 16 40 46 208 332 586 25 39 42 204 315 561 23 38 42 200 296 538 55 37 41 196 246 483 32 36 40 195 216 451 12 35 40 190 209 439 13 34 38 168 220 426 25 33 34 158 209 401 16 32 29 102 254 385 18 31 24 101 242 367 23 30 22 97 225 344 24 29 21 92 207 320 23 28 21 80 196 297 41 27 21 75 160 256 62 26 18 64 112 194 13 25 13 56 112 181 17 24 11 51 102 164 27 23 6 50 81 137 19 22 6 43 69 118 23 21 6 41 48 95 7 20 5 26 57 88 7 19 5 26 50 81 9 18 5 24 43 72 14 17 5 21 32 58 8 16 4 20 26 50 6 15 4 18 22 44 11

Entre las semanas epidemiológicas 01 a la 44 de 2016 se han confirmado cincuenta y ocho (58) casos de microcefalias asociadas al virus Zika, 225 casos fueron descartados y 389 casos están en estudio. http://www.ins.gov.co/boletin-epidemiologico/Boletn Epidemiolgico/2016 Boletín epidemiológico semana 44.pdf

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Highly pathogenic avian influenza, Japan Information received on 22/11/2016 from Dr Kazuo Ito, Director, International Animal Health Affairs Office, Animal Health Division, Food Safety and Consumer Affairs Bureau, Ministry of Agriculture, Forestry and Fisheries, Tokyo, Japan Summary Report type Immediate notification Date of start of the event 15/11/2016 Date of confirmation of the event 21/11/2016 Report date 21/11/2016 Date submitted to OIE 22/11/2016 Reason for notification Reoccurrence of a listed disease Date of previous occurrence 17/02/2015 Manifestation of disease Clinical disease Causal agent Highly pathogenic avian influenza virus Serotype H5N6 Nature of diagnosis Clinical, Laboratory (basic), Laboratory (advanced) This event pertains to a defined zone within the country New outbreaks (2) Outbreak 1 Akita-shi, AKITA Date of start of the outbreak 15/11/2016 Outbreak status Resolved (15/11/2016) Epidemiological unit Zoo Affected animals Species Susceptible Cases Deaths Destroyed Slaughtered Black Swan:Cygnus atratus(Anatidae) 1 1 0 0 Outbreak 2 Akita-shi, AKITA Date of start of the outbreak 17/11/2016 Outbreak status Resolved (17/11/2016) Epidemiological unit Zoo Affected animals Species Susceptible Cases Deaths Destroyed Slaughtered Black Swan:Cygnus atratus(Anatidae) 1 1 0 0 Summary of outbreaks Total outbreaks: 2 Total animals affected Species Susceptible Cases Deaths Destroyed Slaughtered Black Swan:Cygnus atratus(Anatidae) 2 2 0 0 Outbreak statistics Species Apparent morbidity rate Apparent mortality rate Apparent case fatality rate Proportion susceptible animals lost* Black Swan:Cygnus atratus(Anatidae) ** ** 100.00% ** *Removed from the susceptible population through death, destruction and/or slaughter **Not calculated because of missing information Epidemiology Source of the outbreak(s) or origin of infection Unknown or inconclusive Epidemiological comments On 15th November 2016, one death case of Cygnus atratus (black swan) was found in the zoo and its sample was tested by antigen-capture kit with positive result for influenza A virus. On 17th November 2016, another death case of Cygnus atratus was found in the same facility and positive result was gained by antigen-capture kit. On 21st November 2016, the two dead cases were confirmed to be positive for H5N6 subtype influenza A virus. Control measures Measures applied Screening Vaccination prohibited No treatment of affected animals Measures to be applied No other measures Diagnostic test results Laboratory name and type Species Test Test date Result Hokkaido University (OIE Reference Laboratory) Black Swan haemagglutination inhibition test (HIT) 19/11/2016 Positive Hokkaido University (OIE Reference Laboratory) Black Swan neuraminidase inhibition assay 20/11/2016 Positive Hokkaido University (OIE Reference Laboratory) Black Swan reverse transcription - polymerase chain reaction (RT-PCR) 19/11/2016 Positive Hokkaido University (OIE Reference Laboratory) Black Swan reverse transcription - polymerase chain reaction (RT-PCR) 20/11/2016 Positive Hokkaido University (OIE Reference Laboratory) Black Swan virus isolation 19/11/2016 Positive Hokkaido University (OIE Reference Laboratory) Black Swan virus sequencing 21/11/2016 Positive Future Reporting The event is continuing. Weekly follow-up reports will be submitted. Map of outbreak locations

On 15th November 2016, one death case of Cygnus atratus (black swan) was found in the zoo and its sample was tested by antigen-capture kit with positive result for influenza A virus. On 17th November 2016, another death case of Cygnus atratus was found in the same facility and positive result was gained by antigen-capture kit. On 21st November 2016, the two dead cases were confirmed to be positive for H5N6 subtype influenza A virus. http://www.oie.int/wahis_2/public/wahid.php/Reviewreport/Review?page_refer=MapFullEventReport&reportid=21608

South Korea confirms highly pathogenic H5N6 bird flu outbreaks, ramps up quarantine A quarantine vehicle sprays disinfectant along the bank of a stream in Cheonan, Seoul, following the discovery of the avian influenza virus in wild bird excrement.PHOTO: EPA PUBLISHED 22 MIN AGO FACEBOOK0TWITTEREMAIL SEOUL (REUTERS) - South Korea has confirmed the country's first outbreaks of the highly pathogenic H5N6 bird flu virus and has ramped up quarantine measures in response, agriculture ministry officials said on Friday (Nov 18). The outbreaks occurred at two poultry farms in the central and southern parts of the country after the ministry reported last week that the H5N6 strain of the virus had been found in the faeces of migratory birds. Cases of human infection from the H5N6 virus have previously been reported in places including China and Hong Kong, with the virus killing six people in China since April 2014, according to data from the South Korean ministry. The discoveries come as cases of the different H5N8 virus have been reported in several European countries including France. South Korea's ministry said just over 62,000 birds had been culled to prevent the spread of the virus and that it had a issued a "movement control order" within a radius of 10km around the farms. There are no indications that the virus has spread more widely, a ministry official said. South Korea's last bird flu outbreak occurred in March, when the H5N8 strain was detected at a duck farm, leading to the slaughter of at least 11,000 birds. http://www.straitstimes.com/asia/east-asia/south-korea-confirms-highly-pathogenic-h5n6-bird-flu-outbreaks-ramps-up-quarantine

South Korea con firms two H5N6 poultry outbreaks, which follows detection of H5N6 in feces of wild birds.

http://www.renseradio.com/listenlive.htm

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Intensified monitoring of microcephaly and other Congenital defects of the Central Nervous System Review November 4, 2016 Between the epidemiological weeks 01 to 43 of 2016, Confirmed (57) fifty-seven cases of associated microcephaly To the Zika virus, 223 cases were discarded and 373 cases were study. http://www.ins.gov.co/boletin-epidemiologico/Boletn Epidemiolgico/2016 Boletin epidemiologico semana 43.pdf