BRAIN DISRUPTION SEQUENCE - keywords
brain disruption sequence
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brain disruption sequence: references
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Abdel-Salam GMH, Abdel-Hamid MS, El-Khayat HA, Eid OM, Saba S, Farag MK, Saleem SN, Gaber KR. 2015. Fetal brain disruption sequence versus fetal brain arrest: A distinct autosomal recessive developmental brain malformation phenotype. Am J Med Genet Part A 167A:1089–1099.
Alarcón A, Carreras N, Muehlbacher T, Casas-Alba D, Arena R, Roca-Llabrés P, Navarro-Morón J, de Vries LS, Govaert P; EurUS.Brain group. Foetal disruptive brain injuries: Diagnosing the underlying pathogenetic mechanisms with cranial ultrasonography. Dev Med Child Neurol. 2025 Nov;67(11):1383-1408.
Alexander IE, Tauro GP, Bankier A (1995) Fetal brain disruption sequence in sisters. Eur J Pediatr 154: 654–657.
Chimelli L, Avvad-Portari E (2018) Congenital zika virus infection: a neuropathological review. Child's Nerv Syst 34: 95-99.
Corona-Rivera JR, Corona-Rivera E, Romero-Velarde E, Hernandez-Rocha J, Bobadilla-Morales L, Corona-Rivera A (2001) Report and review of the fetal brain disruption sequence. Eur J Pediatr 160: 664–667.
Culjat M, Darling SE, Nerurkar VR, Ching N, Kumar M, Min SK, Wong R, Grant L, Melish ME, Gabis L, Gelman-Kohan Z, Mogilner M (1997) Microcephaly due to fetal brain disruption sequence. J Perinat Med 25: 213–215.
Hughes HE, Miskin M (1986) Congenital microcephaly due to vascular disruption: in utero documentation. Pediatrics 78: 85–87.
Jervis GA (1954) Microcephaly with extensive calcium deposits and demyelination. J Neuropathol Exp Neurol 13: 318–329.
Kalyanasundaram, S, Dutta, S, Narang, A, Katariya, S (2002) Microcephaly with plate-like cortical calcification, Brain & Development 25 (2003) 130–132
Moore CA, Weaver DD, Bull MJ (1990) Fetal brain disruption sequence. J Pediatr 116: 383–386.
Rasmussen SA, Frias JL (1990) Fetal brain disruption sequence: a brief case report. Dysmorphol Clin Genet 4: 53–56.
Russell LJ, Weaver DD, Bull MJ, Weinbaum M (1984) In utero brain destruction resulting in collapse of the fetal skull, microcephaly, scalp rugae,
and neurologic impairment: the fetal brain disruption sequence. Am JMed Genet 17: 509–521.
Soares de Souza A, Moraes Dias C, Braga FD, Tercian AC, Estofolete CF, Oliani AH, Oliveira GH, Brandao de Mattos C, de Mattos LC, Nogueira ML, Vaz-Oliani DC (2016) Fetal Infection by Zika Virus in the Third Trimester: Report of 2 Cases. Clin Infect Dis 63(12):1622-1625.Weidenheim KM, Bodhireddy SR, Nuovo GJ, Nelson SJ, Dickson DW (1995) Multicystic encephalopathy: review of eight cases with etiologic considerations. J Neuropath Exp Neurol 54(2):268-275.
Van Allen MI (1997) Vascular disruptions. In: Gilbert-Barness E, editor. Potter’s Pathology of the Fetus and Infant. Philadelphia: Mosby, p. 368.
de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM, Coeli RR, Rocha MA, Sobral da Silva P, Durce Costa Gomes de Carvalho M, van der Linden A, Cesario de Holanda A, Valenca MM. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ. 2016 Apr 13;353:i1901.
Villo N, Beceiro J, Cebrero M, de Frias EG (2001) Fetal brain disruption sequence in a newborn infant with a history of cordocentesis at 21 weeks gestation. Arch Dis Child Fetal Neonatal Ed 84: F63–F4.
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typical
This sequence of events, where post-embryonic antenatal brain destruction results in severe microcephaly, collapse of the cranium and scalp rugae, was first reported in 1984 by Russell et al. Three term newborns presented with hypertonia, hyperreflexia, a high-pitched cry and severe microcephaly (OFC 25–26.2 cm or -6 to -7 sd). Their cranium showed signs of collapse following previous bigger shape, an interpretation of the finding that the occipital squame stood out above the parietal bones as a sail on a boat and that the scalp was wrinkled on top of the flattened vertex (scalp rugae). Brain weight in two infants varied from 33 to 68 g (expected weight at term around 400 g).
For patient 1, CT and postmortem documented hydranencephaly with absence of pyramidal tracts and intact cerebellum. For patient 3, postmortem examination documented a cobbled cerebral surface, colpocephaly, periventricular necrosis and calcification, and cerebellar and optic nerve hypoplasia. CT in patient 2 showed microhydranencephaly. A possible cause for the apparent brain destruction was the death (around the sixth month) of a macerated co-twin in one and in an other the likely cause was fetal CMV infection.
The patency of the aqueduct and of the pericerebral and pericerebellar arachnoid spaces in these cases may explain why the remnant brain sac is not inflated with CSF.
ZIKA
brain disruption sequence
A situation analogous to Russell’s case 1 was described by Hughes and Miskin in 1986. Microcephaly was the end result of death of a co-twin at 18 weeks gestation. Moore et al in 1990 added seven more cases. Their neonatal head circumferences varied between 26 and 30.5 cm (–3 to 6 sd). Scalp rugae, present at birth, disappeared later on in three survivors. In one infant cortical mantle, thalamus and caudate were speckled with calcium deposits.
An interesting association in one infant was with oral contraceptive use throughout pregnancy. A maternal car accident and fetal superior sagittal sinus thrombosis were thought to be causal in cases described by Gabis et al (1997) and Van Allen (1997).
Calcifiation of deep grey matter and cortex is a recurrent observation.
Recent descriptions of brain disruption by zika virus are clearly similar to BDS (Culjat et al. 2016, Alarcon et al. 2025), with similar skull collapse. Brain tropism of this virus has been documented. Brain imaging revealed an almost agyric brain with diffuse parenchymal calcifications, hydrocephalus ex vacuo, and cerebellar hypoplasia. Ophthalmologic examination revealed macular pigment stippling and optic nerve atrophy. Liver, lungs, heart, and bone marrow were not affected.
Familial occurrence of BDS, likely autosomal recessive, has been reported with underdeveloped cerebral hemispheres with increased extraxial CSF, abnormal gyral pattern (polymicrogyria-like lesions in two sibs and lissencephaly in the others), loss of white matter, dysplastic ventricles, hypogenesis of corpus callosum, and hypoplasia of the brainstem, hypoplastic cerebellum in one (Abdel-Salam et al. 2015). These findings are in accordance with arrested brain development rather than disruption. Molecular analysis should exclude mutations in potentially related genes such as NDE1, MKL2, OCLN, and JAM3.
∆∆Clearly, severe microcephaly with skull collapse and evidence of fetal developmental arrest and/or destruction is a group of disorders to be further categorized.
BDS must be differentiated from microcephaly with a simplified gyral pattern, micro-hydranencephaly, atelencephaly and microlissencephaly.
Investigations for mitochondriopathy and peculiar fetopathies (e.g. lymphocytic choriomeningitis virus or zika virus) are warranted.
graphic representation after CT in de Fatima Vasco Aragao et al. 2016
Term girl with microcephaly (OFC 29 cm) and overlapping parietal bones. No other dysmorphic features, no acidosis. Seizures within 24 hours in the absence of asphyxia. The fontanelle was small, leading to poor quality sonograms. The anatomical structures were normally present. Calcified speckles were seen in the basal ganglia and thalamus, while CT also showed calcification in frontal and temporo-occipital white matter. A dysplastic corpus callosum was present. The histology specimens from thalamus show calcification (bottom right) in an area of infarction, surrounded by astrogliosis (top right: GFAP staining in the area around a calcified zone). There were no indications of toxoplasmosis or CMV.
brain disruption sequence: imaging
ZIKA foetopathy (courtesy A. Alarcon Barcelona).
brain disruption sequence: ZIKA virus infection
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