Percutaneous fetoscopic closure of large open spina bifida using a bilaminar skin substitute.

OBJECTIVE: We have described previously our percutaneous fetoscopic technique for the treatment of open spina bifida (OSB). However, approximately 20-30% of OSB defects are too large to allow primary skin closure. Here we describe a modification of our standard technique using a bilaminar skin substitute to allow closure of large spinal defects. The aim of this study was to report our clinical experience with the use of a bilaminar skin substitute and a percutaneous fetoscopic technique for the prenatal closure of large OSB defects. METHODS: Surgery was performed between 24.0 and 28.9 gestational weeks with the woman under general anesthesia, using an entirely percutaneous fetoscopic approach with partial carbon dioxide insufflation of the uterine cavity, as described previously. If there was enough skin to be sutured in the midline, only a biocellulose patch was placed over the placode (single-patch group). In cases in which skin approximation was not possible, a bilaminar skin substitute (two layers: one silicone and one dermal matrix) was placed over the biocellulose patch and sutured to the skin edges (two-patch group). The surgical site was assessed at birth, and long-term follow-up was carried out. RESULTS: Percutaneous fetoscopic OSB repair was attempted in 47 consecutive fetuses, but surgery could not be completed in two. Preterm prelabor rupture of membranes (PPROM) occurred in 36 of the 45 (80%) cases which formed the study group, and the mean gestational age at delivery was 32.8 ± 2.5 weeks. A bilaminar skin substitute was required in 13/45 (29%) cases; in the remaining 32 cases, direct skin-to-skin suture was feasible. There were 12 cases of myeloschisis, of which 10 were in the two-patch group. In all cases, the skin substitute was located at the surgical site at birth. In five of the 13 (38.5%) cases in the two-patch group, additional postnatal repair was needed. In the remaining cases, the silicone layer detached spontaneously from the dermal matrix (on average, 25 days after birth), and the lesion healed by secondary intention. The mean operating time was 193 (range, 83-450) min; it was significantly longer in cases requiring the bilaminar skin substitute (additional 42 min on average), although the two-patch group had similar PPROM rate and gestational age at delivery compared with the single-patch group. Complete reversal of hindbrain herniation occurred in 68% of the 28 single-patch cases and 33% of the 12 two-patch cases with this information available (P < 0.05). In four cases there was no reversal; half of these occurred in myeloschisis cases. CONCLUSIONS: Large OSB defects may be treated successfully in utero using a bilaminar skin substitute over a biocellulose patch through an entirely percutaneous approach. Although the operating time is longer, surgical outcome is similar to that in cases closed primarily. Cases with myeloschisis seem to have a worse prognosis than do those with myelomeningocele. PPROM and preterm birth continue to be a challenge. Further experience is needed to assess the risks and benefits of this technique for the management of large OSB defects. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Identification of essential steps in laser procedure for twin-twin transfusion syndrome using the Delphi methodology: SILICONE study.

OBJECTIVE: To determine, by expert consensus, the essential substeps of fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) that could be used to create an authority-based curriculum for training in this procedure among fetal medicine specialists. METHODS: A Delphi survey was conducted among an international panel of experts (n = 98) in FLS. Experts rated the substeps of FLS on a five-point Likert-type scale to indicate whether they considered them to be essential, and were able to comment on each substep, using a dedicated online platform accessed by the invited tertiary care facilities that specialize in fetal therapy. Responses were returned to the panel until consensus was reached (Cronbach's α ≥ 0.80). All substeps that were rated ≥ 4 by 80% of the experts were included in the evaluation instrument. RESULTS: After the first iteration of the Delphi procedure, a response rate of 74% (73/98) was reached, and in the second and third iterations response rates of 90% (66/73) and 81% (59/73) were reached, respectively. Among a total of 81 substeps rated in the first round, 21 substeps had to be re-rated in the second round. Finally, from the initial list of substeps, 55 were agreed by experts to be essential. In the third round, the 18 categorized substeps were ranked in order of importance, with 'coagulation of all anastomoses that cross the equator' and 'determination of fetoscope insertion site' as the most important. CONCLUSIONS: A total of 55 substeps of FLS for TTTS were defined by a panel of experts to be essential in the procedure. This list is the first authority-based evidence to be used in the development of a final training model for future fetal surgeons.

L-2-Hydroxyglutaric aciduria presenting with severe autistic features.

L-2-Hydroxyglutaric aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder characterized by psychomotor delay, ataxia, macrocephaly and typical neuroradiological findings of subcortical leucoencephalopathy. Recently, the disease causing gene has been discovered (L2HGDH) encoding L-2-hydroxyglutarate dehydrogenase. We present a 3-year-old boy with L-2-HGA, who demonstrated macrocephaly, noted already in utero with ultrasound. Cranial MRI demonstrated diffuse subcortical encephalopathy with increased signal of the subcortical white matter. Subsequent metabolic screening revealed increased levels of L-2-HGA, and genomic DNA analysis demonstrated two missense mutations in L-2-HGDG. Patient's further motor development was mildly impaired, whilst his speech development was profoundly impaired (first words at the age of 2 years). Since the age of 2 years he started demonstrating autistic repetitive behaviors and movements, increasing aloofness to his environment and limitations in the variety of spontaneous activity (CARS score: 44/60-severe autism). Autism has not so far been described in L-2-HGA and may be considered as an additional feature of the phenotypic spectrum.

Percent absent end-diastolic velocity in the umbilical artery waveform as a predictor of intrauterine fetal demise of the donor twin after selective laser photocoagulation of communicating vessels in twin-twin transfusion syndrome.

OBJECTIVE: Absent end-diastolic velocity (AEDV) in the umbilical artery of the donor twin is a known risk factor for intrauterine fetal demise (IUFD) of this fetus after selective laser photocoagulation of communicating vessels (SLPCV) for twin-twin transfusion syndrome (TTTS). The aim of this study was to assess the proportion of time, expressed as a percentage, of the cardiac cycle spent in AEDV (%AEDV) as a predictor of IUFD of the donor. METHODS: All patients referred for possible SLPCV underwent complete preoperative staging evaluation including Doppler assessment of the umbilical artery. %AEDV was calculated retrospectively as 100 x (time of the cycle spent in AEDV divided by duration of total cardiac cycle). Patients without AEDV were considered to have a %AEDV of 0. Follow-up Doppler studies were performed 16-24 h after SLPCV. IUFD of the donor was recorded if the donor twin died any time prior to delivery. RESULTS: Of 401 patients undergoing SLPCV, 127 had AEDV. Preoperative AEDV of the donor twin was associated with an increased risk of IUFD of the donor (40.9% vs. 14.2%, P < 0.0001). %AEDV was measured in 72/127 (56.7%) donors with AEDV for whom digital images were available. Within these 72 patients, the mean %AEDV was significantly higher in patients with IUFD of the donor (36.5% vs. 29.6%, P = 0.01). IUFD of the donor was similar in patients with AEDV, regardless of whether %AEDV was measured (36% vs. 47%, P = 0.2). A %AEDV > 30 was associated with a 4.3-fold increase in the risk of IUFD of the donor (95% CI, 1.4-12.7), a sensitivity of 77% and a negative predictive value of 81.3%. Logistic regression showed that %AEDV, but not number of anastomoses, placental location, presence of artery-to-artery anastomoses or the presence or absence of EDV was associated significantly with IUFD of the donor. CONCLUSION: %AEDV is a novel Doppler parameter in the assessment of patients with TTTS. %AEDV, rather than AEDV alone, is a significant risk factor for IUFD of the donor twin and %AEDV > 30 is associated with an increased risk of IUFD of the donor in TTTS patients treated with SLPCV. Assessment of %AEDV should be considered part of the preoperative evaluation of TTTS patients.

Management of twin-twin transfusion syndrome in pregnancies with iatrogenic detachment of membranes following therapeutic amniocentesis and the role of interim amniopatch.

OBJECTIVE: Detachment of membranes may occur after therapeutic amniocentesis for twin-twin transfusion syndrome (TTTS). Subsequent amniocenteses or endoscopic fetal therapy may be hindered or made altogether impossible by this complication. The purpose of this study was to describe our experience in the assessment and management of TTTS patients with iatrogenic detached membranes (IDM). METHODS: Patients with IDM referred for fetal surgery for TTTS were considered ineligible for standard surgery and were offered different alternatives, including expectant management, serial amniocentesis, or an attempt at surgery with or without prior amniopatch. Pregnancy outcomes were compared between surgical and non-surgical patients. RESULTS: Nine hundred and forty-four patients with a diagnosis of TTTS were referred between July 1997 and December 2004, of whom 322 (34.1%) had a prior therapeutic amniocentesis. Twenty-six of the 322 patients (8%) had IDM. Ten patients opted to be managed with subsequent amniocenteses, two of which had an amniopatch. One patient had voluntary interruption of pregnancy. Fifteen patients underwent surgery, 10 of whom underwent an amniopatch. Overall, resealing of membranes occurred in 8/12 (66%) patients treated with an amniopatch. Survival of at least one fetus was greater in patients treated surgically with or without an amniopatch (12/15, 80% vs. 4/11, 36%, P = 0.04). CONCLUSION: Membrane detachment is an important complication of therapeutic amniocentesis in the treatment of TTTS. Although successful treatment of IDM can be achieved with an interim amniopatch, this alternative is not without risks. Therapeutic amniocenteses should be discouraged in patients considering endoscopic fetal surgery for TTTS.

The impact of route of delivery and presentation on twin neonatal and infant mortality: a population-based study in the USA, 1995-97.

OBJECTIVE: We examined whether the route of delivery for near-term (> or = 34 weeks' gestation) twins, as candidates for vaginal delivery, affected neonatal and infant mortality rates. We further evaluated whether these mortality rates were modified by fetal presentation. METHODS: A population-based retrospective cohort study based on the matched multiple births data in the USA (1995-97) was performed. Analyses were restricted to non-malformed liveborn twins delivered at (> or = 34 weeks' gestation. Twins with breech-breech and breech-vertex presentations were excluded, since they are not candidates for vaginal delivery. Neonatal mortality rates (death within the first 27 days) and post-neonatal mortality rates (death between 28 and 365 days) per 1000 twin live births, by route of delivery and fetal presentation, were derived. The associations between neonatal mortality, post-neonatal mortality and the route of delivery for vertex-breech versus vertex-vertex presentations were expressed based on relative risks (RR) and 95% confidence intervals (CI) derived from logistic regression models based on the method of generalized estimating equations. RESULTS: Of the 177,622 twins analyzed, 87% (n = 154,531) presented as vertex-vertex. Fifty-five per cent (n = 97,692) of twins were both delivered vaginally, 41% (n = 72,825) were both delivered by Cesarean section and, of the remaining 4% (n = 7,105), the first twin was delivered vaginally and the second by Cesarean section. Twins with vertex-breech presentations delivered by Cesarean-cesarean sections, as well as those with vertex-vertex presentations delivered vaginally, had the lowest neonatal mortality rate (1.6 per 1000 live births). The highest neonatal mortality rate in the vertex-breech pairs occurred with vaginal-Cesarean deliveries (2.7 per 1000 live births). Among twins with vertex-vertex presentations, twins delivered via the vaginal-Cesarean route experienced the highest neonatal mortality (3.8 per 1000 live births). The RR for neonatal mortality in this group was 2.24 (95% CI 1.35, 3.72) compared with twins both delivered vaginally. CONCLUSION: Route of delivery and fetal presentation both confer an impact on twin infant mortality rates. Strategies to reduce discordant routes in complicated vaginal deliveries may lead to improved neonatal survival.

Clinical features, laboratory findings and differential diagnosis of benign acute childhood myositis.

We report clinical and laboratory data from 32 children with benign acute childhood myositis (BACM), children who presented with calf tenderness and gait abnormality. Laboratory evidence of a viral infection was evident in 23 patients, while serum creatine phosphokinase was uniformly increased (558 to 6800 U/L). Twenty-five patients (78.1%) were given a diagnosis other than BACM by their general practitioner or paediatrician. All patients made a rapid recovery within one week. We conclude that BACM should be encountered among the main causes of sudden-onset gait abnormality in young children.

Atypical and variable clinical presentation of glutaric aciduria type I.

We report atypical and variable clinical presentation of glutaric aciduria type I (GA I) in four children from two Greek families. In one family, a boy with typical biochemical and neuroradiological features of GA I suffered a metabolic crisis at 16 months of age resulting in a severe movement disorder. His sister, two years older and showing identical biochemical features, has remained neurologically normal throughout childhood and at six years of age is attending normal primary school. Both children are homozygous for P217 L, a novel mis-sense mutation in exon 7 of the glutaryl-CoA dehydrogenase (GCDH) gene. In the other family, monozygotic twins presented at 6 years of age with mild developmental delay and a single episode of hypoglycaemia. Cranial magnetic resonance imaging (MRI) scans in both twins revealed almost identical high-signal alterations in the periventricular white matter and in the centrum semiovale. Biochemical analyses showed massive urinary excretion of glutaric and 3-hydroxyglutaric acids and carnitine depletion. Molecular studies showed compound heterozygosity for two novel putative null mutations, IVS6-1 G > A and Y413 X, in the GCDH gene. The milder clinical course of GA I in three of the four Greek patients demonstrates the phenotypic heterogeneity of the disease even within families. Asymptomatic siblings of GA I patients should always be investigated, and molecular studies may be useful for confirming the diagnosis, particularly when the presentation is atypical.

Neurophysiology and MRI in late-infantile metachromatic leukodystrophy.

We present serial clinical, radiologic, and neurophysiologic findings of a patient with late-infantile metachromatic leukodystrophy who was first admitted at 30 months of age because of gait disturbance. The neurologic findings were consistent with mild spastic diplegia (occasionally with toe walking). Magnetic resonance imaging disclosed diffuse high intensity in the cerebral white matter on T2-weighted images. Nerve conduction velocity studies and evoked-potential studies were markedly abnormal. Assay of arylsulfatase A activity in leukocyte culture disclosed a marked deficiency of the enzyme, confirming the diagnosis of late-infantile metachromatic leukodystrophy. Serial neurophysiologic studies demonstrated a marked decrease of nerve conduction velocities, both motor and sensory, as well as prolongation or disappearance of brainstem auditory-, visual-, and somatosensory-evoked potential latencies. Magnetic resonance imaging studies revealed initially diffuse increased signal intensity of periventricular and subcortical white matter on T2-weighted images, progressing to cortical atrophy with involvement of the arcuate fibers and the cerebellar white matter, correlating with the clinical deterioration (severe spastic tetraplegia with optic atrophy and epilepsy).

Plantar response profile of high-risk infants at one year of life.

To clarify the plantar reflex profile at 1 year of life in different categories of neurodevelopmental abnormalities, plantar responses were examined prospectively in 204 high-risk infants, of whom 58 developed cerebral palsy, 22 had developmental retardation without motor disturbance, and 124 were normal at a follow-up examination at 3 years of age. The plantar response was extensor in 82.3% of infants subsequently found to be neurologically normal at the first month of life, becoming flexor at the age of 9 and 11 months in 68.5% and 86.3%, respectively. Twenty-one (42.9%) of 49 patients with various types of spastic cerebral palsy demonstrated a combined extensor response (ie, dorsiflexion of the great toe with fanning of the remaining toes) as early as the first month of life. Children with spastic quadriplegia and hemiplegia more frequently demonstrated a combined extensor response compared to diplegic patients. The combined extensor plantar response remains a reliable prognostic clinical tool that contributes to an earlier diagnosis of spastic cerebral palsy as early as the first month of life.

Protracted course of N-acetylaspartic aciduria in two non-Jewish siblings: identical clinical and magnetic resonance imaging findings.

Canavan disease (CD) or N-acetylaspartic aciduria (NAA) is a severe, progressive, autosomal recessive leukodystrophy, occurring mainly among Ashkenazi Jewish individuals. We report clinical and MRI findings in two, non-Jewish, Greek siblings, 7 and 5 years, respectively, with a protracted form of NAA. The constellation of identical clinical course and identical MRI findings with involvement of the basal ganglia, the brainstem, the dentate nucleus and the subcortical white matter in both siblings, as well as the absence of the three commonest mutations found in both Jewish and non-Jewish CD patients, give support to the existence of a protracted form of NAA with a milder clinical course, presumably genetically determined.

Corticotropin-releasing hormone deficiency unmasks the proinflammatory effect of epinephrine.

Traditionally, the adrenal gland has been considered an important endocrine component of the pathway to inhibit acute inflammation via hypothalamic corticotropin-releasing hormone (CRH)-mediated secretion of glucocorticoid. Immunoreactive CRH found in inflamed tissues is a potent proinflammatory factor. Using genetic and pharmacological models of CRH deficiency, we now show that CRH deficiency unmasks a major proinflammatory effect of epinephrine secreted from the adrenal medulla. Together, epinephrine and peripheral CRH stimulate inflammation, and glucocorticoid acts as a counterbalancing force in this regard. Our findings suggest that stimulation of the acute inflammatory response should be included with the other "fight-or-flight" actions of epinephrine.