The spectrum of neuropathological changes associated with congenital Zika virus infection.
A major concern associated with ZIKV infection is the increased incidence of microcephaly with frequent calcifications in infants born from infected mothers. To date, postmortem analysis of the central nervous system (CNS) in congenital infection is limited to individual reports or small series. We report a comprehensive neuropathological study in ten newborn babies infected with ZIKV during pregnancy, including the spinal cords and dorsal root ganglia (DRG), and also muscle, pituitaries, eye, systemic organs, and placentas. Using in situ hybridization (ISH) and electron microscopy, we investigated the role of direct viral infection in the pathogenesis of the lesions. Nine women had Zika symptoms between the 4th and 18th and one in the 28th gestational week. Two babies were born at 32, one at 34 and 36 weeks each and six at term. The cephalic perimeter was reduced in four, and normal or enlarged in six patients, although the brain weights were lower than expected. All had arthrogryposis, except the patient infected at 28 weeks gestation. We defined three patterns of CNS lesions, with different patterns of destructive, calcification, hypoplasia, and migration disturbances. Ventriculomegaly was severe in the first pattern due to midbrain damage with aqueduct stenosis/distortion. The second pattern had small brains and mild/moderate (ex-vacuo) ventriculomegaly. The third pattern, a well-formed brain with mild calcification, coincided with late infection. The absence of descending fibres resulted in hypoplastic basis pontis, pyramids, and cortico-spinal tracts. Spinal motor cell loss explained the intrauterine akinesia, arthrogryposis, and neurogenic muscle atrophy. DRG, dorsal nerve roots, and columns were normal. Lympho-histiocytic inflammation was mild. ISH showed meningeal, germinal matrix, and neocortical infection, consistent with neural progenitors death leading to proliferation and migration disorders. A secondary ischemic process may explain the destructive lesions. In conclusion, we characterized the destructive and malformative consequences of ZIKV in the nervous system, as reflected in the topography and severity of lesions, anatomic localization of the virus, and timing of infection during gestation. Our findings indicate a developmental vulnerability of the immature CNS, and shed light on possible mechanisms of brain injury of this newly recognized public health threat.
Laboratory of Neuropathology, State Institute of Brain Paulo Niemeyer and Federal University of Rio de Janeiro (UFRJ), Rua do Resende 156, Rio de Janeiro, RJ, CEP 20231-092, Brazil. chimelli@hucff.ufrj.br.
Leila
L
Chimelli
Research Institute Prof. Amorim Neto, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.|Health Secretary Campina Grande, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.
Adriana S O
ASO
Melo
Fernandes Figueira Institute-FioCruz, Avenida Rui Barbosa, 716, Flamengo, Rio De Janeiro, RJ, CEP 22250-020, Brazil.
Elyzabeth
E
Avvad-Portari
Division of Neuropathology, UPMC Presbiterian Hospital, S701 Scaife Hall 200 Lothrop Street, Pittsburgh, PA,  15213, USA.
Clayton A
CA
Wiley
Laboratory of Neuropathology, State Institute of Brain Paulo Niemeyer and Federal University of Rio de Janeiro (UFRJ), Rua do Resende 156, Rio de Janeiro, RJ, CEP 20231-092, Brazil.
Aline H S
AHS
Camacho
Department of Pathology, Antonio Pedro University Hospital, Fluminense Federal University, Rua Marques de Paraná, 303, Centro, Niterói, RJ, CEP 24033-900, Brazil.
Vania S
VS
Lopes
Fernandes Figueira Institute-FioCruz, Avenida Rui Barbosa, 716, Flamengo, Rio De Janeiro, RJ, CEP 22250-020, Brazil.
Heloisa N
HN
Machado
Fernandes Figueira Institute-FioCruz, Avenida Rui Barbosa, 716, Flamengo, Rio De Janeiro, RJ, CEP 22250-020, Brazil.
Cecilia V
CV
Andrade
Fernandes Figueira Institute-FioCruz, Avenida Rui Barbosa, 716, Flamengo, Rio De Janeiro, RJ, CEP 22250-020, Brazil.
Dione C A
DCA
Dock
Fernandes Figueira Institute-FioCruz, Avenida Rui Barbosa, 716, Flamengo, Rio De Janeiro, RJ, CEP 22250-020, Brazil.
Maria Elisabeth
ME
Moreira
D'Or Institute for Research and Education (IDOR) and UFRJ, Rua Diniz Cordeiro, 30, Botafogo, Rio De Janeiro, RJ, CEP 22281-100, Brazil.
Fernanda
F
Tovar-Moll
Fetal Medicine Research, Foundation Institute for Education and Research in Diagnostic Imaging (FIDI), Rua Napoleão de Barros, 800, Vila Clementino, São Paulo, SP, CEP 04024-002, Brazil.
Patricia S
PS
Oliveira-Szejnfeld
Department of Pathology, Antonio Pedro University Hospital, Fluminense Federal University, Rua Marques de Paraná, 303, Centro, Niterói, RJ, CEP 24033-900, Brazil.
Angela C G
ACG
Carvalho
Department of Pathology, Antonio Pedro University Hospital, Fluminense Federal University, Rua Marques de Paraná, 303, Centro, Niterói, RJ, CEP 24033-900, Brazil.
Odile N
ON
Ugarte
Health Secretary Campina Grande, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.
Alba G M
AGM
Batista
Research Institute Prof. Amorim Neto, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.
Melania M R
MMR
Amorim
Research Institute Prof. Amorim Neto, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.
Fabiana O
FO
Melo
Research Institute Prof. Amorim Neto, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.
Thales A
TA
Ferreira
Health Secretary Campina Grande, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.
Jacqueline R L
JRL
Marinho
Research Institute Prof. Amorim Neto, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.
Girlene S
GS
Azevedo
Health Secretary Campina Grande, Rua Duque de Caxias, 330, Prata, Campina Grande, PB, CEP 58400506, Brazil.
Jeime I B F
JIBF
Leal
D'Or Institute for Research and Education (IDOR) and UFRJ, Rua Diniz Cordeiro, 30, Botafogo, Rio De Janeiro, RJ, CEP 22281-100, Brazil.
Rodrigo F Madeiro
RFM
da Costa
D'Or Institute for Research and Education (IDOR) and UFRJ, Rua Diniz Cordeiro, 30, Botafogo, Rio De Janeiro, RJ, CEP 22281-100, Brazil.
Stevens
S
Rehen
Laboratory of Medical Virology, Departamento de Genética, Instituto de Biologia, CCS, Bloco A, sala 121, UFRJ, Rio De Janeiro, RJ, CEP 21941-902, Brazil.
Monica B
MB
Arruda
Laboratory of Medical Virology, Departamento de Genética, Instituto de Biologia, CCS, Bloco A, sala 121, UFRJ, Rio De Janeiro, RJ, CEP 21941-902, Brazil.
Rodrigo M
RM
Brindeiro
Laboratory of Medical Virology, Departamento de Genética, Instituto de Biologia, CCS, Bloco A, sala 121, UFRJ, Rio De Janeiro, RJ, CEP 21941-902, Brazil.
Rodrigo
R
Delvechio
Laboratory of Medical Virology, Departamento de Genética, Instituto de Biologia, CCS, Bloco A, sala 121, UFRJ, Rio De Janeiro, RJ, CEP 21941-902, Brazil.
Renato S
RS
Aguiar
Laboratory of Medical Virology, Departamento de Genética, Instituto de Biologia, CCS, Bloco A, sala 121, UFRJ, Rio De Janeiro, RJ, CEP 21941-902, Brazil.
Amilcar
A
Tanuri
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D005123:Eye / Q000000981:diagnostic imaging / Q000473:pathology; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008831:Microcephaly / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D018482:Muscle, Skeletal / Q000473:pathology; D010902:Pituitary Gland / Q000000981:diagnostic imaging / Q000473:pathology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D013116:Spinal Cord / Q000000981:diagnostic imaging / Q000473:pathology*; D055815:Young Adult; D000071243:Zika Virus Infection / Q000150:complications / Q000151:congenital* / Q000000981:diagnostic imaging / Q000473:pathology*
Calcification; Congenital ZIKV infection; In situ hybridization; Microcephaly; Neuropathology; Zika virus