Selected clinical research involving the central nervous system

This paper updates three clinical research projects involving the central nervous system. Discussions of conditions with encephalocele include several associations: encephalocele/craniostenosis, transsphenoidal encephalocele/hypothalamic-pituitary dysfunction, encephalocele/oculo-auriculo-vertebral spectrum, and encephalocele/frontonasal dysplasia. The relationship between oculo-auriculo-vetebral spectrum with encephalocele and frontonasal dysplasia with epibulbar dermoids and ear tags is also discussed and an explanation for encephalocele formation in the Apert syndrome is provided. Studies of the central nervous system in Apert syndrome indicate that distortion ventriculomegaly is common, but progressive hydrocephalus occurs infrequently. A recurrent pattern of abnormalities was discerned consisting of megalencephaly, gyral abnormalities, and defects of the corpus callosum and limbic structures. Five neuropathologic studies lend further support to this pattern of CNS anomalies in the Apert syndrome. In a study of holoprosencephaly, eight principles governing associated facial dysmorphism were derived. Each diagnostic category was shown to have its own frequency and range of holoprosencephalic faces. Some categories, such as del(13q), have narrow ranges; others, such as trisomy 13 syndrome, have broad ranges. However, no broad diagnostic range is known to include agnathia-holoprosencephaly and other severe forms of facial dysmorphism without agnathia. Absent maxillary incisors and a single maxillary central incisor are extremely common in holoprosencephaly with severe facial dysmorphism and may occur on occasion as a striking microform of holoprosencephaly, most commonly in the autosomal dominant form.     

重型颅脑损伤患者阶梯式减压策略下行去骨瓣减压术的应用效果及术中急性脑膨出的影响因素分析

摘要 目的：观察阶梯式减压策略下行去骨瓣减压术在重型颅脑损伤中的临床应用效果,并分析患者术中急性脑膨出的影响因素。方法：回顾性分析2020年1月~2021年8月期间我院收治的103例重型颅脑损伤患者的临床资料。根据手术方式的不同分为A组（常规去骨瓣减压术,n=50）和B组（阶梯式减压策略下行去骨瓣减压术,n=53）,比较两组手术相关指标、并发症发生率以及患者预后情况。此外,根据开颅术中是否出现急性脑膨出将患者分为膨出组（n=41）和未膨出组（n=62）,采用多因素Logistic回归分析重型颅脑损伤患者术中急性脑膨出的影响因素。结果：B组的迟发性颅内血肿、急性脑膨出发生率低于A组,术中出血量少于A组,手术时间短于A组（P<0.05）。B组的预后良好率高于A组（P<0.05）。单因素分析结果显示：重型颅脑损伤患者术中急性脑膨出与年龄、受伤至手术时间、合并迟发性外伤性颅内血肿（DTIH）、合并对侧颅骨骨折、入院后首次格拉斯哥昏迷指数（GCS）评分、合并外伤性弥漫性脑肿胀（PADBS）、高血压病史、术前体温、术前颅内压、血小板计数（PLT）、凝血酶原时间（PT）有关（P<0.05）。多因素Logistic回归分析结果显示：合并对侧颅骨骨折、合并DTIH、合并PADBS、受伤至手术时间＜3 h、入院后首次GCS评分＜6分、术前颅内压偏高、术前体温偏高是重型脑损伤患者术中急性脑膨出的危险因素（P＜0.05）,而阶梯式减压策略下行去骨瓣减压术则是其保护因素（P＜0.05）。结论：采用阶梯式减压策略下行去骨瓣减压术治疗重型颅脑损伤,可减少术中出血量,缩短手术时间,降低并发症发生率,改善患者的预后。重型颅脑损伤患者术中是否发生急性脑膨出受到合并对侧颅骨骨折、合并DTIH、合并PADBS、受伤至手术时间、入院后首次GCS评分、术前体温、术前颅内压等因素影响。     

Proctalgia fugax: a cause of marital dysharmony.

A survey of the records of all hospitals with obstetric services in Nova Scotia revealed that during 1980-84 there were 122 pregnancies involving a neural tube defect. The mean rate was 2/1000 births. Of the affected fetuses or infants 54% had spina bifida, 35% had anencephaly and 11% had encephalocele. The records showed that in the early part of the period studied at least one prenatal ultrasonographic examination had been performed in 60% of the pregnancies; in 1984 the rate was 74%. When examinations done before 16 weeks'' gestation were excluded, the overall detection rates at the first ultrasonographic examination were 100% for anencephaly and 73% for spina bifida and encephalocele; the rates improved toward the end of the study period.     

Proboscis lateralis: a case report

A lateral proboscis usually occurs in the region of the inner canthus. We present a case of holoprosencephaly accompanied by an oblique facial cleft and an anterior encephalocele in which a proboscis lateralis occurred in a very lateral location.     

Heterogeneity of neural tube defects in Europe: the significance of site of defect and presence of other major anomalies in relation to geographic differences in prevalence.

In the period 1980-1987, neural tube defects were two to three times more prevalent in populations covered by EUROCAT registries in the United Kingdom and Ireland (UKI) than in Continental Europe and Malta (CEM). 1864 NTD cases in a total population of 580,000 births in UKI and 455 cases in a population of 380,000 births in CEM were analysed to find if there were differences in the ratio of prevalence rates between UKI and CEM according to site of the defect and association with non-central nervous system (CNS) anomalies. The prevalence rate ratio was high for anencephaly with accompanying spina bifida, iniencephaly, and upper spina bifida, and low for encephalocele, lower spina bifida, and anencephaly without other neural tube defects. There was a greater female excess for anencephaly with accompanying spina bifida, iniencephaly, and upper spina bifida than for other defects in both geographic areas. There was a female excess for encephalocele in UKI but a male excess in CEM. Certain sites (anencephaly with accompanying spina bifida, iniencephaly, and encephalocele) were more likely to have accompanying non-CNS anomalies. The prevalence rate ratio of multiply malformed NTD was in general lower than for isolated NTD but showed the same pattern by site. The prevalence rate ratio was high for multiply malformed anencephaly with accompanying spina bifida, iniencephaly, and upper spina bifida. The sex ratio was similar between isolated and multiply malformed cases when site of the defect is taken into account. It is concluded that the geographic prevalence pattern and sex ratio differ according to site of NTD but do not differ substantially according to whether NTD is isolated or associated with non-CNS anomalies.     

A girl with del(4)(q33) and occipital encephalocele: clinical description and molecular genetic characterization of a rare patient

We present clinical and developmental data on a girl with a de novo terminal deletion of the long arm of chromosome 4, del(4)(q33). The patient was evaluated at birth and followed up until 5 years of age. She showed facial and digital dysmorphism, a complex congenital heart defect, a large occipital encephalocele, and postnatal growth deficiency. Her neuropsychomotor milestones were delayed, and she developed learning difficulties. Apart from standard Giemsa banding, a molecular genetic analysis was performed using a comparative genomic hybridization (CGH) array. This revealed a terminal deletion at the band 4q32.3, which is directly adjacent to 4q33. The clinical findings in our patient differ from those described previously in patients with del(4)(q33) and del(4)(q32), respectively. In particular, the prominent occipital encephalocele has not been observed before in a terminal 4q deletion.     

Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China

BACKGROUND: In the past, northern China's Shanxi Province has reported the highest incidence of neural tube defects (NTDs) in the world. However, little is known about the epidemiology of NTDs in this area in recent years. METHODS: Data were collected from a population-based birth defects surveillance system in 4 counties that captures information on all live births, stillbirths of at least 20 weeks' gestation, and pregnancy terminations at any gestational age resulting from prenatal diagnosis of a birth defect. We also surveyed mothers of NTD case patients to determine their use of folic acid before and during early pregnancy. RESULTS: During 2003, 160 NTD cases were identified among 11,534 births (NTD birth prevalence = 138.7/10,000 births). The rates of anencephaly, spina bifida and encephalocele were 65.9, 58.1, and 14.7 per 10,000, respectively, and a female predominance was observed among anencephaly cases (male-to-female relative risk [RR], 0.49; 95% confidence interval [CI], 0.30-0.79), but not among spina bifida (RR, 0.90; 95% CI, 0.55-1.45) and encephalocele (RR, 1.03; 95% CI, 0.40-2.69) cases. The percentages of pregnancy termination following prenatal diagnosis of anencephaly, spina bifida, and encephalocele were 50%, 41.8%, and 35.3%, respectively. NTD birth prevalence tended to be higher among mothers aged <20 or > or =30 years (P = .06) and was markedly associated with lower levels of maternal education (P < .001). Among 143 NTD mothers, only 6 (4.2%) used folic acid supplements during the periconceptional period. CONCLUSIONS: The NTD birth prevalence rate in the study area is among the highest worldwide. Folic acid deficiency may be one important risk factor.     

Holoprosencephaly in a fetal macaque (Macaca nemestrina) following weekly exposure to ethanol

Previous studies in rodents have indicated that the facial changes of fetal alcohol syndrome (FAS) closely resemble those of a mild form of holoprosencephaly. In order to examine this relationship in non-human primates, we evaluated a 133-day gestation macaque (Macaca nemestrina) with holoprosencephaly, median cleft lip and palate, and encephalocele. The mother had been given ethanol once per week (1.8 g/kg body weight) from weeks 2 to 19 postconception. Diagnosis of holoprosencephaly was made following ultrasound evaluation for polyhydramnios and delivery of the female fetus by caesarean section. Another fetus of identical age was delivered by caesarean section for use as a control. Both fetuses were studied by anthropometric, gross, radiographic, and histologic techniques. In the fetus exposed to alcohol, no extracranial anomalies were identified and the karyotype was normal. The brain was micrencephalic, with absent olfactory bulbs, tracts, optic nerves and chiasma, fused frontal lobes, and a single, dilated lateral ventricle; a parietooccipital encephalocele consisted of thin, dysplastic cortex bordering the ventricle; the cerebellum was dysplastic and superiorly displaced. Within the craniofacial complex, anophthalmia was bilateral; premaxillary components were absent, palatal shelves separate, the maxillae closeset, and the ethmoid bone small and deformed. Most of these defects are similar to those encountered in humans with holoprosencephaly and support the hypothesis of shared etiologic and pathogenetic relations between the facial anomalies of fetal alcohol syndrome and holoprosencephaly.     

Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome

Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.     

Comparative teratogenicity of triamcinolone acetonide and dexamethasone in the rhesus monkey (Macaca mulatta)

Pregnant rhesus macaques were treated with 0.5 or 2.5 mg/kg triamcinolone acetonide (TAC) or 1.0 or 10.0 mg/kg dexamethasone sodium phosphate (DEX) between 20 and 50 gestational days (GD). Treatment with TAC at 2.5 mg/kg resulted in a fetal loss of 71%; 3/5 recovered fetuses displayed an encephalocele or meningocele. All other treatment groups displayed minor cranial skeletal abnormalities consistent with glucocorticoid-mediated teratogenesis. DEX was shown to have a lower teratogenic potential than TAC in this species.     

The induction of microphthalmia, encephalocele, and other head defects following hyperthermia during the gastrulation process in the rat

The aim of this study was to ascertain whether there is a period during early embryonic development of the rat that is particularly sensitive to hyperthermia. Pregnant Sprague-Dawley rats were partially immersed in a water bath at 43.5 degrees C until their core temperatures, monitored by a rectal thermistor probe, were elevated to 43.5 degrees C. The procedure was repeated 6 hours later. The regimen of two heatings was performed over a range of development from early gastrulation (8 days 18 hours) to about the 12 somite stage (10 days 18 hours). The rats were killed on days 17-19 and the fetuses were examined. Each group contained a minimum of five litters. The main teratogenic effect of the hyperthermia was the induction of one or more head defects, notably microphthalmia, encephalocele (either a single, large, parietal encephalocele or multiple small protuberances), and maxillary hypoplasia. Microphthalmia was the most common defect with approximately 90% of surviving fetuses having small eyes when heating occurred between 9 days 6 hours and 10 days 0 hours (9.06 and 10.00). Encephaloceles were induced by heating between 9.00 and 10.00 with a peak sensitivity between 9.12 and 9.18 when 57% of surviving fetuses were affected. Maxillary hypoplasia resulted from heating between 9.06 and 10.06 with up to 20% of surviving fetuses being affected. Control rats were exposed to the same experimental procedure in a water bath at 38 degrees C on 9.12 and 9.18, the gestational time most sensitive to hyperthermia induced malformations. There were no abnormal fetuses in the controls. The critical period identified spans 9 days 6 hours to 10 days 0 hours gestational age. In developmental terms this includes a large proportion of the gastrulation process.     

Birth prevalence and recurrence rates of neural tube defects in southern Alberta in 1970-81.

Given the observed variation in birth prevalence and recurrence rates of neural tube defects, it is important to obtain such data specific to a given locality for research and genetic counseling purposes. A review of hospital medical charts, the patient lists of the Medical Genetics and Myelomeningocele clinics at Alberta Children''s Hospital and data from the Canadian Congenital Anomalies Surveillance System revealed the annual birth prevalence rate of neural tube defects in southern Alberta in 1970-81 to be 1.62/1000 total births. This figure suggests southern Alberta to be a low-frequency area. There was no significant variation in the annual rates of spina bifida, encephalocele or all neural tube defects combined over the study period. A significant linear decline in the frequency of births of anencephalic infants, however, was noted (p = 0.025). Information on the total reproductive history of the mothers revealed that the empiric risk of recurrence of a neural tube defect was 2.2%, and the risk to all siblings was estimated to be 2.3%. In future prevalence studies multiple sources of case ascertainment should be used, including data on pregnancies terminated because of a fetal neural tube defect.     

Goldenhar syndrome, anterior encephalocele, and aqueductal stenosis following fetal primidone exposure

Fetal exposure to primidone was associated with Goldenhar syndrome, hemifacial microsomia, tetralogy of Fallot, aqueductal stenosis, and anterior encephalocele in this male infant. No similar cases in anticonvulsant-exposed pregnancies were found on literature review, despite the increased incidence of other anomalies following such exposure. Goldenhar syndrome, especially related to rare central nervous system anomalies, is reviewed. Experimental production of hemifacial microsomia by a folic acid antagonist, triaxene, is mediated via hemorrhage in the fetus. Intraventricular hemorrhage was noted in this infant as were dilated lateral and third ventricles. The hemorrhagic diathesis and/or the folic acid depletion of newborns following fetal anticonvulsant exposure may have been the underlying mechanism.     

Women who wish breast reconstruction: characteristics,fears, and hopes

The aims of the present study were to identify the characteristics of a consecutive series of women with newly diagnosed breast cancer and to evaluate the perceived benefits and disadvantages of breast reconstruction. A consecutive series of 125 women completed the Breast Reconstruction Questionnaire, the Hospital Anxiety and Depression Scale, and the Eysenck Personality Questionnaire. The median age was 48 years (range, 28 to 75 years). A total of 49.6 percent (n = 62) indicated that, if it were possible, they would like breast reconstruction. Logistic regression (simultaneous entry) revealed that younger women (p = 0.0001) and more depressed women (p = 0.026) were more likely to wish reconstruction. Marital status, tumor size, extroversion, neuroticism, and tough-mindedness did not independently predict the desire for reconstruction. If given a choice of reconstruction at 3 months or 6 months after mastectomy, of the women who wished reconstruction, 74 percent would prefer it at 3 months. Of the women who wished reconstruction and expressed a preference, 63 percent were afraid reconstruction might mask recurrence, 39 percent were afraid that reconstruction might cause the cancer to return, and 89 percent thought they would be concerned with their appearance after the operation. Positively, 94 percent considered that reconstruction would be beneficial in terms of their self-esteem, 86 percent indicated that reconstruction would give greater freedom to wear any clothing, and 86 percent thought that the cosmetic appearance of breast reconstruction was better than that of a prosthesis. Concerns about recurrence were common. A better understanding of the concerns of women with regard to reconstruction would allow more informed preoperative discussion.     

Morphological study of the removed fetus after therapeutic abortion for echographic anomalies (apropos of 42 cases)

In 42 cases, fetal abnormalities were diagnosed by obstetric ultrasonography and the pregnancy was terminated. The malformations included: anencephaly (22), severe hydrocephaly (4, one with a spina bifida), encephalocele and meningocele (2) amniotic band syndrome (4; a correct prenatal diagnosis was performed during the second trimester in two cases), major anterior abdominal wall defects (2), Pena-Shokeir syndrome type I? (I), severe renal abnormalities (2), conjoined twins, dicephalus type (2), cystic hygroma and hydrops fetalis (2), osteogenesis imperfecta, type II (I). Thus, there were 23 fetuses with a polygenetically determined status; five fetuses could be affected by an autosomal recessive disorder.     

Prevention of neural tube malformation by genetic counselling, and prenatal diagnostic surveillance.

The aetiology and genetics of the spectrum of dysraphic neural tube malformations from anencephaly through encephalocele, myelocele and meningocele to complicated spina bifida occulta, is outlined. The risk of recurrence, the methods and problems of genetic counselling are discussed. All women known to be at risk for neural tube malformation should be counselled carefully and offered prenatal diagnostic surveillance for any future pregnancy. There is no longer any need for a couple able to accept termination, to go through with a pregnancy in fear of recurrence.     

Clinical, genetic, and epidemiological factors in neural tube defects.

We examined clinical, genetic, and epidemiologic factors among 512 probands with nonsyndromal neural tube defects (NTDs). Data were analyzed after grouping the probands in four different ways with respect to pathological features and putative pathogenic mechanisms. Apparently unrelated congenital anomalies occurred more frequently among probands with craniorachischisis (62%), encephalocele (30%), or multiple NTDs (25%) than among probands with anencephaly (14.7%) or spina bifida (10.1%) (P much less than .0001). Unrelated congenital anomalies occurred less often among probands with low spina bifida (6.7%) than among probands with high spina bifida (19.5%). NTDs were seen in 7.8% of the siblings of probands with high spina bifida but in only 0.7% of the siblings of probands with low spina bifida, in 2.2% of the siblings of anencephalic probands, and in none of the siblings of probands with craniorachischisis, encephalocele, or multiple NTDS (P less than .001). In all 16 families in which two siblings had NTDs, both had either defects of the type associated with abnormal primary neurulation or defects of the type associated with abnormal canalization. High spina bifida and multiple NTDs were found more frequently than expected among the Sikh probands (P less than .02). The frequency of non-NTD congenital anomalies was higher among siblings of Sikh probands (8.8%) than among siblings of other probands (2.4%) (P less than .05). This excess was due to the occurrence of hydrocephalus without spina bifida in four of 68 siblings of Sikh probands.     

Pathomorphological changes in an early spontaneous abortus with triploidy (69,XXX)

Summary Triploid (69,XXX) spontaneous abortus with a gestational age of 14–15 weeks (anatomical age of the embryo was 6 weeks) was analyzed macro- and microscopically. There were hydatidiform swelling and cystic degeneration of the villi, without proliferation of the trophoblast of cells, aplasia of one umbilical artery. The embryo had the following anomalies: cranial and caudal hypoplasia; aplasia of the facial structures (aprosopia), ocular vesicles, nasal stalk, extremity buds, somites, upper jaw, hyoid and pharyngeal arches, esophagus; trachea, Rathke's pouch and oropharyngeal cavity; encephalocele, focal anomalous rudiments of cartilage in the chordamesoderm, atresia of the stomodeal foramen and persistance of the lenticular placode.     

Reconstruction of the crus helicis in mild microtia using a preauricular tag

A preauricular tag accompanying a mild microtia was utilized in reconstruction of the anterior aspect of the helix and the crus helicis. We believe that three-dimensional reconstruction of the crus helicis with a deep cymba conchae in microtia reconstruction is an important component in achieving a normal-looking auricle.     

Prenatal diagnosis of Meckel syndrome

Summary The three main features of Meckel syndrome are encephalocele, polycystic kidneys, and polydactyly. Prenatal diagnosis of a fetus with Meckel syndrome was made in the 16th week of gestation by means of amniotic fluid alpha₁ fetoprotein estimation. The indication for amniocentesis was a previous child with an occipital meningocele and polycystic kidneys. Interpretation of the alpha₁-fetoprotein value (240 g/ml) was difficult due to fetal blood contamination. Prenatal diagnosis is indicated in any pregnancy following the birth of a child with only two major symptoms of Meckel syndrome.