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Objective: To assess the gross motor development of children with presumed congenital Zika virus (ZIKV) infection over the first 2 years of their lives., Methods: Seventy-seven children were assessed at the median ages of 11, 18, and 24 months, using the evaluative instrument Gross Motor Function Measure (GMFM-66). At the third assessment, the children with diagnoses of cerebral palsy (CP) were classified by severity through the Gross Motor Function Classification System (GMFCS) and stratified by topography indicating the predominantly affected limbs. With these instruments in combination and using the motor development curves as reference, the rate of development and functional ability were estimated., Results: At 2 years of age, all children had the diagnosis of CP. Seventy-four (96.1%) presented gross motor skills similar to those of children aged 4 months or younger, according to the World Health Organization's standard. The GMFM-66 median score among the 73 (94.8%) children with quadriplegia and GMFCS level V showed significant change between 11 and 18 months (p < 0.001) and between 11 and 24 months (p < 0.001). No significant difference (p = 0.076) was found between 18 and 24 months., Conclusion: Despite showing some gross motor progress during the initial 18 months of life, these children with presumed congenital ZIKV infection and CP experienced severe motor impairment by 2 years of age. According to the motor development curves, these children with quadriplegia have probably already reached about 90% of their motor development potential.

Structural rearrangements of chromosome band 1p31p32 are rare, and their phenotypic consequences remain poorly delineated. Up to 12 patients with learning difficulties, developmental delay, multiple congenital anomalies and microdeletion of the chromosome band 1p31p32 have been described. Inheritance of this deletion has not been reported previously. We describe the inheritance of the 1p32 deletion and discuss the relevance of this deletion to the described phenotype. The differences in clinical and molecular characteristics between the proband and other published reports are reviewed. Patients were evaluated in Genetics Clinic with history, examination and investigation. The existing literature on interstitial deletions of 1p was reviewed. Here, we report on a three-generation family, where the index patient was an adult female with learning difficulty, dysmorphic features, microcephaly, ambiguous genitalia, congenital hip dislocation and brachydactyly in whom a maternally inherited 1.45 Mbp interstitial deletion was detected at 1p32.3. Both her mother and maternal grandmother have learning difficulties and dysmorphic features. There are 14 OMIM genes in the deleted region including LRP8 and DMRTB1. The NFIA gene is not deleted in this family. The first report of a familial 1p32 microdeletion in three generations of a family carrying the smallest reported a deletion involving this region and brachydactyly as a previously unreported feature.

Objective: To study the effect of prenatal Zika virus (ZV) infection on brainstem function reflected in brainstem auditory evoked potentials (BAEPs)., Methods: In a cross-sectional study in 19 children (12 girls) with microcephaly related to ZV infection, aged between 12 and 62 weeks, the brainstem function was examined through BAEPs. The latencies of wave peaks I, III, and V of the left and right ears (n = 37) were standardized according to normative data, and compared between them by 2-tailed t test. The confounding variables (cephalic perimeter at the born and chronological age) were correlated with the normalized latencies using Pearson test., Results: All patients showed, in general, clear waveforms, with latencies within 3 SDs of the normative values. However, statistically increased latencies of waves I and III (I > III, p = 0.031) were observed, relative to wave V ( p < 0.001), the latter being closer to respective normative value. The latency of wave I was observed to increase with age ( r = 0.45, p = 0.005). The waves, in turn, did not depend on cephalic perimeter., Conclusions: These results are consistent with the functional normality of the brainstem structure and its lack of correlation with microcephaly, suggesting that the disruption produced by the ZV infection does not act in the cell proliferation phase, but mostly in the processes of neuronal migration and differentiation in the telencephalon., (© 2018 American Academy of Neurology.)

Purpose of Review: The aim of this review is to report the most recent observations concerning intrauterine Zika virus (ZIKV) infection and associated neuroimaging., Recent Findings: ZIKV outbreak in Brazil in 2015 was associated with an impressive registration of cases of congenital microcephaly in women with symptoms suggestive of ZIKV infection. Clinical and laboratory testing for ZIKV and hypothetic etiopathogenetic mechanisms are described. Diagnostic tests on blood, urine and amniotic fluid should be performed in all mothers with symptoms suggestive of intrauterine ZIKV infection. ZIKV causes multiple teratogenic malformations, mainly affecting the developing brain., Summary: Neuroimaging investigation contributes to the prenatal detection of microcephaly and other brain abnormalities in cases of intrauterine ZIKV infection. Neuroimaging is based antenatally on two-dimensional and three-dimensional ultrasound and fetal MRI, whereas computed tomography scan is performed postnatally. Although neuropathology associated with intrauterine ZIKV infection is characterized by nonspecific findings of brain disorder, reduced cortical gyration and white-matter hypomyelination or dysmyelination and cerebellar hypoplasia have been consistently observed in the majority of fetuses and newborns. Prenatal or postnatal genetic workup should be carried out to exclude cases of primary microcephaly. Follow-up should rely upon MRI and computed tomography scan as well as neuropediatrician to better define developmental outcome in survivors.

Purpose: To assess visual recovery and donor cell survival after Descemet stripping automated endothelial keratoplasty (DSAEK) for the repair of failed penetrating keratoplasty (PK) grafts., Methods: Best spectacle-corrected Snellen visual acuity results after DSAEK were compared with best-ever documented visual acuity (BDVA) results obtained with the previous PK graft in a prospective cohort study. Donor cell survival after DSAEK for PK repair was compared with cell survival after DSAEK for Fuchs endothelial dystrophy and pseudophakic bullous keratopathy. Differences in the logMAR best spectacle-corrected Snellen visual acuity and endothelial cell loss rates were calculated., Results: Twenty-eight eyes with DSAEK for PK repair were identified, 21 of which lacked vision-limiting comorbidities. The mean follow-up was 18.4 ± 10.6 months. At 3 months postoperatively, 10/21 eyes (48%) regained their BDVA. By 24 months, only 14% remained with 0.2 logMAR below their BDVA. Endothelial cell counts decreased significantly faster in patients with DSAEK for failed PK (P = 0.024) or pseudophakic bullous keratopathy (P = 0.018) than in patients with DSAEK for Fuchs endothelial dystrophy., Conclusions: DSAEK for the restoration of failed PK grafts promotes rapid visual recovery within the visual limits of the previous PK graft. Increased endothelial cell loss is noted relative to other DSAEK indications, which may result in earlier endothelial graft failure in renovated PK.

Objectives: To differentiate onset of CNS involvement in primary hemophagocytic lymphohistiocytosis (HLH) from that of other CNS inflammatory diseases and to identify early symptoms linked to abnormal cognitive outcome., Methods: Forty-six children with primary HLH who had neurologic evaluation within 2 weeks and brain MRI within 6 months of diagnosis were included. Initial symptoms, CSF study, brain MRI, and neurologic outcome were assessed. Brain MRIs were compared with those of 44 children with acute disseminated encephalomyelitis (ADEM)., Results: At disease onset, 29 children (63%) had neurologic symptoms and 7 (15%) had microcephaly. Twenty-three (50%) children had abnormal CSF study, but only 15 (33%) had abnormal brain MRI. The latter showed that patients with HLH, unlike patients with ADEM, had symmetric periventricular lesions, without thalamic and brainstem involvement and with infrequent hyposignal intensity on T1. At the end of follow-up (3.6 ± 3.6 years), 17 of the 28 (61%) surviving patients had normal neurologic status, 5 (18%) had a severe neurologic outcome, and 6 (21%) had mild cognitive difficulties. Abnormal neurologic outcome was not influenced by age or type of genetic defect, but by the presence of neurologic symptoms, MRI lesions, or abnormal CSF study at onset. Early clinical and MRI symptoms may regress after treatment., Conclusion: Neurologic symptoms are frequent at the onset of primary HLH and are mostly associated with abnormal CSF findings, but with normal brain MRI. In cases of abnormal brain MRI, the observed lesions differ from those of ADEM.

Objective: To make evidence-based recommendations concerning the evaluation of the child with microcephaly., Methods: Relevant literature was reviewed, abstracted, and classified. RECOMMENDATIONS were based on a 4-tiered scheme of evidence classification., Results: Microcephaly is an important neurologic sign but there is nonuniformity in its definition and evaluation. Microcephaly may result from any insult that disturbs early brain growth and can be seen in association with hundreds of genetic syndromes. Annually, approximately 25,000 infants in the United States will be diagnosed with microcephaly (head circumference <-2 SD). Few data are available to inform evidence-based recommendations regarding diagnostic testing. The yield of neuroimaging ranges from 43% to 80%. Genetic etiologies have been reported in 15.5% to 53.3%. The prevalence of metabolic disorders is unknown but is estimated to be 1%. Children with severe microcephaly (head circumference <-3 SD) are more likely ( approximately 80%) to have imaging abnormalities and more severe developmental impairments than those with milder microcephaly (-2 to -3 SD; approximately 40%). Coexistent conditions include epilepsy ( approximately 40%), cerebral palsy ( approximately 20%), mental retardation ( approximately 50%), and ophthalmologic disorders ( approximately 20% to approximately 50%)., Recommendations: Neuroimaging may be considered useful in identifying structural causes in the evaluation of the child with microcephaly (Level C). Targeted and specific genetic testing may be considered in the evaluation of the child with microcephaly who has clinical or imaging abnormalities that suggest a specific diagnosis or who shows no evidence of an acquired or environmental etiology (Level C). Screening for coexistent conditions such as cerebral palsy, epilepsy, and sensory deficits may also be considered (Level C). Further study is needed regarding the yield of diagnostic testing in children with microcephaly.

Congenital bony fusion of the maxilla and mandible is a rare condition. Two classifications were previously proposed dealing exclusively with craniofacial malformations. Most of the reported cases to date represent either aglossia-adactylia or hemifacial microsomia syndromes. We report a young girl with bony syngnathia associated with multiple defects (severe microcephaly, coloboma, vertebral segmentation defects), growth and mental delay. This patient is very similar to the patient described by Dobrow in 1983 and confirms the existence of this extremely rare disorder.

We report two unrelated children with Filippi syndrome. Both show typical facial dysmorphism, syndactyly of fingers and toes, growth retardation, postnatal microcephaly and developmental delay, particularly involving speech. In addition both children have unusual teeth and hair. We review the literature and propose that neurological and ectodermal involvement may be under-recognised features of the syndrome.

Cohen syndrome is a rare genetic disorder caused by autosomal recessive inheritance and is characterized by the following features: mental retardation, infantile hypotonia, micrognathia, narrow and high-arched palate, microcephaly, prominent upper central incisors, poor dentition, short stature, and truncal obesity. Some patients have strabismus, myopia, optic atrophy, and total blindness. A small number of cases present with heart defects or mitral valve prolapse. Only approximately 100 cases have been reported in the world literature. The administration of general anesthesia in patients with Cohen syndrome can be a challenge because most of these patients are mentally retarded and uncooperative and have facial malformations that may make intubation difficult. We present our experience with the anesthetic management of a patient with Cohen syndrome.

Postnatal changes in the fiber distribution and release of 5-HT in the somatosensory cortex (Sm) of methylazoxymethanol acetate (MAM)-induced microencephalic rats were studied. A transient accumulation of serotonergic fibers was observed in the Sm of the control and MAM rats in the first 2 weeks following birth. However, the density of serotonergic fibers was higher in the MAM rats than in the controls, and the distribution pattern of serotonergic fibers was more extensive in the MAM rats. The microdialysis indicated a high basal level and a delayed K+ -evoked 5-HT release in the Sm of MAM rats on postnatal day 10. The present results suggest morphological and functional alterations of serotonergic fibers in the Sm of MAM rats during the critical period of cortical formation.

Details are presented on two brothers who, in many ways, resemble the cases described by Mutchinick (J Med Genet (1972) 9: 60-63). These similarities are explored and other diagnostic possibilities discussed.

The Ohdo syndrome is characterized by blepharophimosis, ptosis, abnormal ears, and mental retardation. This report describes a child with the Ohdo syndrome who, in addition, has microcephaly and growth retardation. Her phenotype probably represents variable expression or genetic heterogeneity of the Ohdo syndrome.

Oxiracetam (4-hydroxy-2-oxo-1-pyrrolidine acetamide) is a novel compound effective in improving learning and memory in normal animals as well as in animals with acute cerebral impairment induced by a variety of noxious stimuli (i.e., electroshock, neurodepressants, metabolic inhibitors, hypoxia). In accordance with a stepwise approach to the pharmacological studies, the compound was also tested in rats with chronic cerebral impairment due to aging, cerebrovascular lesions, and congenital microencephaly. To evaluate the brain telencephalic functions, the learning rate of two conditioned avoidance responses using the pole climbing test and the performance in a multiple-choice water maze were considered. Oxiracetam at doses ranging from 10 to 60 mg/kg i.p. improved the learning rate of these animals with impaired cognitive functions. The compound was active also by oral administration.