Fetal heart rate evolution and brain imaging findings in preterm infants with severe cerebral palsy.

BACKGROUND: Cerebral palsy is more common among preterm infants than among full-term infants. Although there is still no clear evidence that fetal heart rate monitoring effectively reduces cerebral palsy incidence, it is helpful to estimate the timing of brain injury leading to cerebral palsy and the causal relationship with delivery based on the fetal heart rate evolution patterns. Understanding the relationship between the timing and the type of brain injury can help to identify preventive measures in obstetrical care. OBJECTIVE: This study aimed to examine the relationship between the timing of insults and the type of brain injury in preterm infants with severe cerebral palsy. STUDY DESIGN: This longitudinal study was based on a nationwide database for cerebral palsy. The data of infants with severe cerebral palsy (equivalent to levels 3-5 of the Gross Motor Function Classification System-Expanded and Revised), born between 2009 and 2014 at 28 to 33 weeks of gestation, were included. The intrapartum fetal heart rate evolution patterns were evaluated by 3 obstetricians blinded to clinical information other than gestational age at birth, and these were categorized after agreement by at least 2 of the 3 reviewers into (1) continuous bradycardia, (2) persistently nonreassuring (prenatal onset), (3) reassuring-prolonged deceleration, (4) Hon's pattern (intrapartum onset), (5) persistently reassuring (pre- or postnatal onset), and (6) unclassified. Infant brain magnetic resonance imaging findings at term-equivalent age were assessed by a pediatric neurologist blinded to the background details, except for gestational age at birth and corrected age at image acquisition, and these were categorized as (1) basal ganglia-thalamus, (2) white matter, (3) watershed cortex or subcortex, (4) stroke, (5) normal, and (6) unclassified based on the predominant site involved. The risk factors for the basal ganglia-thalamus group were compared with those of the combined white matter and watershed injuries group. RESULTS: Among 1593 infants with severe cerebral palsy, 231 were born at 28 to 33 weeks of gestation, and 140 met the eligibility criteria. Fetal heart rate evolution patterns were categorized as bradycardia (17% [24]); persistently nonreassuring (40% [56]); reassuring-prolonged deceleration (7% [10]); reassuring-Hon (6% [8]); persistently reassuring (7% [10]); and unclassified (23% [32]). Cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in 13% of infants. Magnetic resonance imaging showed that 34% (n=48) of infants developed basal ganglia-thalamus-dominant brain injury. Of the remaining 92 infants, 43% (60) showed white matter injuries, 1% (1) showed watershed injuries, 4% (5) showed stroke, 1% (1) had normal findings, and 18% (25) had unclassified findings. Infants with continuous bradycardia (adjusted odds ratio, 1033.06; 95% confidence interval, 15.49-68,879.92) and persistently nonreassuring fetal heart rate patterns (61.20; 2.09-1793.12) had a significantly increased risk for basal ganglia-thalamus injury. CONCLUSION: Severe cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in only 13% of infants born at 28 to 33 weeks of gestation. Although the white matter-watershed injury was predominant in the study populations, severe acute hypoxia-ischemia may be an important prenatal etiology of severe cerebral palsy in preterm infants.

Correlation between fetal heart rate evolution patterns and magnetic resonance imaging findings in severe cerebral palsy: A longitudinal study.

OBJECTIVE: To investigate the association between hypoxic-ischaemic insult timing and brain injury type in infants with severe cerebral palsy (CP). DESIGN: Longitudinal study. SETTING: Database of the Recurrence Prevention Committee, Japan Obstetric Compensation System for Cerebral Palsy. SAMPLE: Infants with severe CP born at ≥34 weeks of gestation. METHODS: The intrapartum fetal heart rate (FHR) strips were categorised as continuous bradycardia; persistently non-reassuring (NR-NR); reassuring-prolonged deceleration (R-PD); Hon's pattern (R-Hon); persistently reassuring (R-R); and unclassified. The brain magnetic resonance imaging (MRI) scans were categorised based on the predominant site involved: basal ganglia-thalamus (BGT); white matter (WM); watershed (WS); stroke; normal; and unclassified. MAIN OUTCOME MEASURES: Manifestations of the brain MRI types and the association between FHR evolution pattern and MRI type were analysed. RESULTS: Among 672 eligible infants, 76% had BGT-dominant injury, 5.4% WM, 1.2% WS, 1.6% stroke, 1.9% normal, and 14% unclassified. Placental abruption and small-for-gestational age were associated with an increased (adjusted odds ratio [aOR] 8.02) and decreased (aOR 0.38) risk of BGT injury, respectively. The majority of infants had BGT injury in most FHR groups (bradycardia, 97%; NR-NR, 75%; R-PD, 90%; R-Hon, 76%; and R-R, 45%). The risk profiles in case of BGT in the NR-NR group were similar to those in the R-PD and R-Hon groups. CONCLUSION: BGT-dominant brain damage accounted for three-fourths of the cases of CP in term or near-term infants, even in prenatal onset cases. Hypoxic-ischaemic insult has a major impact on CP development during the antenatal period. TWEETABLE ABSTRACT: Basal ganglia-thalamus injury constitutes 76% of severe cerebral palsy cases, predominant even in antenatal-onset cases.

Expression of thymidylate synthase predicts clinical outcomes of S-1-based chemotherapy in squamous cell lung cancer.

Non-small cell lung cancer (NSCLC) patients with squamous cell carcinoma (SCC) histology have limited chemotherapeutic options. Treatment with S-1 combined with carboplatin (CBDCA) has been shown to provide a significant survival benefit in SCC patients compared with treatment with combined CBDCA and paclitaxel. The aim of the present study was to investigate the association between the expression of molecular markers related to the pharmacological action of S-1, including thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD), and the clinical efficacy of S-1-based chemotherapy in SCC patients. The immunohistochemical expression of TS, OPRT and DPD were retrospectively analyzed in tumor biopsy and resection specimens from patients with advanced SCC (n=32). Immunohistochemical H-scores were calculated and their association with S-1/CBDCA response was evaluated. Median progression-free survival time was significantly longer in patients with low TS H-scores than in those with high TS H-scores (162.5 vs. 97 days; P=0.004); by contrast, overall survival time was not observed to differ significantly between these groups (P=0.185). In the multivariate analysis, low TS expression was a significant positive factor for progression-free survival rate (hazard ratio, 0.40; P=0.021). A low TS H-score was also associated with an increased response to S-1-based chemotherapy compared with a high TS H-score (P=0.002). This indicates that SCC patients with low TS expression can benefit significantly from S-1-based chemotherapy, and that H-score measurement of intratumoral TS expression may represent a useful predictive biomarker for response to S-1-based chemotherapy by patients with SCC-type NSCLC.

[Analysis of predominant bacterial species and clinical backgrounds in lung abscess patients].

We reviewed the clinicopathological characteristics of lung abscesses retrospectively. We analyzed 89 patients hospitalized from July 1984 to May 2009. Most were men (76/89). There were large proportions with alcohol consumption (29.2%) and dental caries or gingivitis (60.7%). Furthermore, those without other diseases accounted for only 13.5%. Predominant infectious species were clear in 43 cases (48.3%) including identification of bacteria. The identification rate of predominant bacteria improved from 38.5% to 56.0% after initiation of the introduction of expectoration culture, bronchoscopic specimen collection and gingival culture in 2003, facilitating clarification of the predominant bacteria. The Streptococcus anginosus group with predominant bacteria being slightly aerobic streptococci, anaerobic bacterium, and aerobic bacterium was detected in 10, 12, and 31 cases, respectively. The improvement in the identification rate of predominant bacteria was achieved by carrying out examination with close liaison with the staff of our inspection room. In selecting antimicrobials based on diagnostic significance, we should focus on positive identification of predominant bacteria, a factor which appears to have major clinical significance.

The outcome and prognostic factors of twin-twin transfusion syndrome following fetoscopic laser surgery.

OBJECTIVES: To evaluate the outcome and preoperative risks of twin-twin transfusion syndrome (TTTS) following fetoscopic laser surgery (FLS). METHODS: A retrospective cohort study of a series of 181 consecutive cases of TTTS before 26 weeks' gestation subjected to FLS at four centers in Japan between July 2002 and December 2006. RESULTS: The chances of survival of at least one twin at 28 days of age and 6 months of age were 91.2% and 90.1%, respectively. The rate of major neurological complications in survivors at 6 months of age was 4.7%. Preoperative findings that were significant risk factors for death were as follows: (1) being donor [odds ratio (OR): 3.01, 95% confidence interval (CI): 1.24-7.31, P = 0.015]; (2) reversed (OR: 11.78, CI: 3.05-45.55, P < 0.001) and absent (OR: 3.95, CI: 1.66-9.43, P = 0.002) end-diastolic velocity in the umbilical artery (EDV-UA) of the donor; and (3) reversed blood flow in the ductus venosus of the recipient (OR: 2.35, CI: 1.04-5.29, P = 0.040). CONCLUSIONS: FLS leads to high survival rates and low neurological morbidity for fetuses in TTTS. FLS is an effective therapeutic option for TTTS before 26 weeks of gestation. Preoperative Doppler findings of the umbilical artery and the ductus venosus are useful in predicting prognosis following FLS.

Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele.

We report the one case of sepsis caused by Bifidobacterium breve administered as probiotic therapy. Probiotics can be a potential cause of an invasive disease and should be used with care in vulnerable patients.

Evaluating mortality and disease severity in congenital diaphragmatic hernia using the McGoon and pulmonary artery indices.

PURPOSE: Lung hypoplasia is associated with mortality in congenital diaphragmatic hernia (CDH). However, the association between lung hypoplasia and disease severity is unclear. Early prediction of disease severity would provide parents with more precise information about the anticipated course of treatment, minimize treatment disruption, and maximize the efficient management of patients with CDH. We aimed at identifying the relationship between McGoon index (MGI) and pulmonary artery index (PAI) scores and disease severity among infants with CDH. METHODS: We retrospectively reviewed the medical records of 19 high-risk patients with CDH born between January 2006 and December 2007. McGoon index and PAI scores were determined on admission. We evaluated statistically the relationship between these scores and variables representing severity as follows: number of vasodilators, use of inhaled nitric oxide (iNO), closed method of diaphragm, duration of intubation, duration of hospitalization, and use of home oxygen therapy. Statistical significance was P < .05. RESULTS: Overall median MGI and PAI scores were 1.40 and 108, respectively; scores for nonsurvivors were significantly (P < .05 and P < .01, respectively) lower than those for survivors. Among survivors, PAI scores were significantly (P < .05) lower in infants requiring iNO than in infants not requiring iNO and patch repair. The PAI scores were significantly correlated with the number of vasodilators (r = -0.789; P < .01) and duration of intubation (r = -0.610; P < .05). CONCLUSIONS: McGoon index (cutoff value, 1.31) and PAI (cutoff value, 90) are reliable indices for predicting mortality in CDH. Pulmonary artery index appears to be more useful than MGI for predicting disease severity among survivors.

Live birth prevalence of Down syndrome in Tottori, Japan, 1980-1999.

One hundred sixty-four patients with Down syndrome (DS) were confirmed in Tottori Prefecture, Japan, from 1980 to 1999. The sex ratio of 1.52 (99 males and 65 females) was comparable to that reported in previous studies. The live birth prevalence per 1,000 was 1.52 (95% CI: 1.29-1.75) from 1980 to 1999, with a prevalence of 1.34 (95% CI: 1.05-1.63) recorded between 1980 and 1989, and 1.74 (95% CI: 1.37-2.11) between 1990 and 1999. There was no statistically significant change between these two decades (chi(2)-test). Live birth prevalence in these two decades showed a significant increase (chi(2)-test, P < 0.005) compared with that recorded in 1969-1978 in Tottori Prefecture (0.803, 95% CI: 0.677-0.929). Mean ages of mothers at the birth of a DS patient were 31.0 years in 1980-1989 and 32.4 years in 1990-1999 (t-test, no significant difference). Dispersion analysis on the mean age of mothers at birth for patients born between 1969-1978, 1980-1989, and 1990-1999 showed a significant difference (t-test, P < 0.005), while comparing the mean age of mothers in 1969-1978 to those in 1990-1999 also revealed a significant difference (t-test, P < 0.001). Live birth prevalence has increased due to the rise in fertility rates among older women, although maternal age-specific risk rates remain unchanged. The widespread introduction of induced abortion following prenatal diagnosis decreased live birth prevalence of DS largely in European (and a few Asian) countries after 1990, or kept prevalence steady, despite increasing fertility rates among women aged 30 and over. In contrast, all published studies have reported an increase in live birth prevalence of this syndrome in Japan, probably resulting from the fact that prenatal diagnoses are used only exceptionally in this country (due to the negative attitude toward selection of life in Japanese culture).

[Severe diarrhea associated with X-linked lissencephaly with absent corpus callosum and abnormal genitalia: a case report of successful treatment with the somatostatin analogue octreotide].

We report the clinical course of a case of X-linked lissencephaly with absent corpus callosum and abnormal genitalia (XLAG) exhibiting severe diarrhea. The patient demonstrated lactose intolerance and his intractable seizures were relieved with lactose-free, extensively hydrolyzed whey protein formula. At the age of 2 years while being treated with the antiallergic formula, he was affected with severe diarrhea that resembled watery diarrhea-hypokalemia-acidosis syndrome (WDHA). Administration of octreotide was effective in relieving his secretory diarrhea. Hypoglycemia without hyperinsulinemia was seen during fasting, and plasma vasoactive intestinal polypeptide was not increased when he had WDHA-like diarrhea. Although pancreas of ARX mutant mice revealed an increased number of beta and delta cells, we did not detect the cause of hypoglycemia and secretory diarrhea by pancreatic endocrinology. His urinary findings mimicked the symptoms of Fanconi syndrome, so it was possible that his hyperaldsteronemia affected not only his intestinal tract, but also his renal tubules.

Magnetic resonance imaging regional T1 abnormalities at term accurately predict motor outcome in preterm infants.

OBJECTIVE: The aim of this study was to assess whether periventricular leukomalacia findings are sufficiently sensitive for predicting the severity of motor prognosis by conventional MRI in the near term. METHODS: Preterm infants with T1 hyperintensity or cysts in the periventricular regions on term MRI were selected, and their gross motor functions were evaluated at the age of 3 to 5 years. Sixty-two infants had findings of T1 hyperintensity or cysts, and except for infants with these findings, none were diagnosed later as periventricular leukomalacia. RESULTS: All 37 patients with cerebral palsy had periventricular lesions with T1 hyperintensity or cysts in the corona radiata above the posterior limb of the internal capsule on coronal sections. Small T1 hyperintensity lesions were seen on coronal slices and were often difficult to detect on axial slices. All of the 17 infants with T1 hyperintensity findings sparing the corona radiata above the posterior limb of the internal capsule showed normal motor development, irrespective of findings of ventriculomegaly. There was a tendency for the presence of widespread lesions in corona radiata above the posterior limb of the internal capsule to be correlated with the severity of motor handicap. CONCLUSIONS: Lesions in the corona radiata above the posterior limb of the internal capsule on a coronal view by term MRI were useful for predicting motor prognosis in preterm infants with periventricular leukomalacia.

[X-linked lissencephaly with absent corpus callosum and abnormal genitalia: a report of siblings followed from the prenatal period].

X-linked lissencephaly with absent corpus callosum and abnormal genitalia (XLAG) is caused by a mutation in the ARX gene. We herein report the clinical course of siblings with XLAG with a splicing mutation in ARX. Seizures were observed in utero. Cerebral atrophy was progressive postnatally, and fetal echoencephalography indicated that the atrophy might have started in the prenatal period. They had a typical phenotype, except that the genital abnormality of the younger brother was not remarkable. A portal-systemic shunt that has not been reported in cases with XLAG was seen in the older brother. The siblings had the different complications and severity of disease in spite of possessing the same mutation.

Acute encephalitis with refractory, repetitive partial seizures: case reports of this unusual post-encephalitic epilepsy.

We report on three acute encephalitis patients with refractory, repetitive partial seizures (AERRPS). All three suffered acute febrile episodes associated with status epilepticus, which necessitated high-dose barbiturate therapy under artificial ventilation for several weeks. Electroencephalography (EEG) revealed a predominance of diffuse epileptiform discharges initially, subsequently developing into periodic bursts of these discharges. Reduction of the barbiturate dosage resulted in clinical and subclinical partial seizures appearing repetitively in clusters. Prolonged fever persisted for 2-3 months, even several weeks after normalization of cell counts in the cerebrospinal fluid. The EEG showed an improvement after resolution of this fever, and seizures became less frequent, although still intractable. Oral administration of high-dose barbiturate and benzodiazepines were partially effective during the acute phase, and a barbiturate dependency, lasting for years, was noted in one patient. Steroid administration was effective in stopping the febrile episodes in one patient, with concurrent improvement in seizure control. Magnetic resonance imaging showed enhancement of bitemporal cortical areas in one patient, and high signal intensity on T2 weighted image in the bilateral claustrum in another patient. Diffuse cortical atrophy appeared within two months after the onset of encephalitis in all patients. The evolution of the seizures and EEG findings suggested a high degree of cortical excitability in AERRPS. In this report, we propose a tentative therapeutic regimen for seizure control in this condition. We also hypothesize that a prolonged inflammatory process exists in the cerebral cortex with AERRPS, and may be pivotal in the epileptogenesis.

A patient with simplified gyral pattern followed by progressive brain atrophy.

We present the case of a three-year-old boy who suffered from intractable epilepsy from birth, and who displayed microcephaly and severe developmental delay. Neuroradiological examination revealed the presence of simplified gyri of the cerebral cortex, and increased signal intensity changes in the cerebral white matter on T2-weighted magnetic resonance imaging. A tentative diagnosis of congenital cortical malformation was made, but unexpectedly, the cerebrum, cerebellum, and pons showed a progressive atrophy during the follow-up period. The basal ganglia and thalamus were relatively spared. Investigations could find no evidence of leukodystrophies, metabolic disorders, hereditary brain anomalies, or congenital central nervous infections. This case may represent a novel type of neurodegenerative disease with malformation of cortical development.

Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.