The Role of Neurotechnology In Mitigating Developmental Progression of Brain Disease - Research Paper Example

? The role of neurotechnology (inclusive of in-utero diagnoses and treatment) in mitigating developmental progression of brain disorders of the student Under the guidance of University Chicago Format Outline Aim-3 Objective-3 Introduction-3 Methods-4 Discussion-4 Conclusion-15 Bibliography-16 Topic: The role of neurotechnology (inclusive of in-utero diagnoses and treatment) in mitigating developmental progression of brain disorders Aim: The aim of the study is to evaluate and ascertain the role of neurotechnology in mitigating developmental progression of brain disorders. Objectives: The objectives of the study are to infer the benefits of fetal therapy in mitigating the progression of brain disorders in the postnatal period. Introduction Several disorders and malformation in the fetus are detectable through routine ultrasound screening and this has become a standard practice by most obstetricians all over the world.1 While detection of some disorders warrants termination of pregnancy due to poor prognosis in the postnatal period, several conditions are potential candidates for treatment in utero and can decrease the risk of postnatal complications and improve postnatal prognosis and functional outcome. One such condition which has been studied thoroughly is congenital diaphramatic hernia2. Of recent interest is fetal investigation and therapy of neurological disorders like spina bifida which are potential candidates for fetal therapy and there is some evidence that fetal interventions, when compared to postnatal interventions can improve postnatal neurological outcomes. This study aims to ascertain the role of neurotechnological advances in mitigation of the progression of neurological disorders, through review of suitable literature. Methods In order to retrieved articles for review, the electronic databases PUBMED and Google Scholar were used. The words used for search were “fetal therapy” or “fetal intervention” or “neurotechnology” with “brain disorders of fetus”. Several articles were displayed. Based on the contents of the abstracts, some of the articles were selected and studied. Both reviews and controlled studies were picked up for this research project to gain overall information about the topic and the research aim in study. Discussion Advances in technology in the form of powerful imaging strategies and improved sampling techniques have revealed the mystery of the fetus that was once secretive3. Most of the malformations that are diagnosed prenatally are managed best by appropriate medical and surgical therapy after birth. This may required planned delivery at a tertiary care after safe maternal transport. However, a few anatomic abnormalities with predictable consequences after birth may require surgical intervention before birth itself4 . In early 1980s, developmental pathophysiology of several anomalies which were potentially correctable was ascertained in animal models.5 The natural history of these diseases was determined through serial observation among animal models. Thereafter, selection criteria for prenatal intervention were developed. In the process, various anesthetic and tocolytic regimens were refined and protocolised and also surgical aspects of hysterotomy and fetal repair were refined and developed. In the later stages, minimally invasive techniques for fetal intervention were developed and refined. All these advances in technology have benefited several fetal patients and it is hoped that more advances are made in this novel strategy allowing advanced forms of treatment on the fetus like tissue engineering, stem cell transplantation and gene therapy in both anatomic and non-anatomic defects (Harrison, 2003).6 During the previous decade, 3 important trends pertaining to fetal therapy have emerged for congenital diaphragmatic hernia7. In the first trend, the surgeons moved away from total surgical repair of the anatomical defect, especially in those liver herniation where repair was technically difficult, and developed induction of lung growth by preventing fetal lung fluid egress. The next trend is from open fetal surgery through hysterotomy to minimally invasive surgery using a combination of sonographic and videofetoscopic visualization. Minimally invasive surgical techniques were developed because of the need for reversible, and temporary tracheal occlusion. Two minimally invasive surgeries which merit importance are Fetendo clip procedure and Fetendo baloon procedure. Technical problems which needed to be addressed while performing Fetendo surgery are development of small dissecting instruments and trocars appropriate for the surgical repair and also development of continuous perfusion hysteroscope so that surgical procedures can be performed in the native fluid environment of the fetus, rather than the usual CO2 gas environment and also development of fixation and positioning techniques for the free-floating fetus. The latest advancement in this field is the successful placement of a tracheal baloon with detachable attributes through one fetobronchoscopic port. The third trend that is worth discussing is the number of randomized controlled trials that have aimed to ascertain the efficacy and safety of new fetal procedures8. Fetal surgery for congenital diaphragmatic hernia was the first intervention that was evaluated through a randomized controlled trial and as of now, it is under clinical investigation9. Ideally randomized trials are the best to evaluative the benefits of fetal therapeutic interventions. However, it is difficult to conduct such trials in view of ethical challenges, difficulty in organization and finances and problems associated with execution. Other than congenital diaphragmatic hernia, fetal procedures have been tried for lower urinary tract obstruction, cystic lung lesions, sacrococcygeal teratoma and meningomyelocele. Sacrococcygeal tearatomas actually do not cause any prenatal problems. However, they are large tumors and grow very fast and can lead to increased metabolic demands and increased fetal anemia. they also act as a large arteriovenous shunt causing high output cardiac failure. Thus, eventually hydrops, polyhydrmanios and intrauterine fetal death occur. The mother may develop mirror syndrome. There are some reports that presence of placentomegaly and fetal hydrops are indicators of poor outcome10. Some other researchers have indicated that rate of the growth of tumor is one of the prognostic indicator11. Some of the fetal therapeutic interventions which may be useful for the fetus and the mother are amniodrainage for polyhydramnios, intrauterine transfusion for anemia and bladder shunting for urinary tract obstruction. In some cases, open fetal resection of type-1 extrapelvic tumors have been reported.12 The mean age of birth in such patients is 30 weeks. there is some anecdotal evidence about the benefits of less invasive techniques like arresting flow in feeding vessels either by interstitial thermocoagulation, fetoscopic laser and radiofrequency ablation. Radiofrequency coagulation can cause damage to collateral tissue. Some researchers have reported needle-guided intravascular embolisation with histoacrylor coils or alcohol with some measurable success. Another condition which is suitable for fetal intervention is myelomeningocele. Meningomyelocele is a condition that affects several thousands of children all over the world with devastating consequences. In an effort to improve the neurological outcomes in these patients, fetal surgery is being performed for almost a decade now. There are conflicting reports about the benefits of fetal surgery for this condition. It has been reported that sensorimotor function is not improved appreciably in most cases. However, the surgery decreases the risk of hind brain herniation and also decreases the need for ventriculoperitoneal shunting (Hirose et al, 2003)13. Meningomyelocele can be staged based on its location or extent. Severe forms of the anomaly can contribute to significant morbidity and burden later in life. As of now, there are very little prospects of improvements in the postnatal management of this condition. There is very little progress in the surgical management of meningomyelocele in the postnatal period14. There is enough evidence to suggest the fact that prenatal intervention can improve clinical outcomes. Several observational studies have shown that microsurgical layer repair in the prenatal phase reverses herniation of the hind brain, decreases the need for shunting, improves the function of leg and bladder and also improves cognitive function outcomes15. According to a randomized controlled trial by the Management of Myelomeningocoele Study, in which the primary outcome that was measured was either death at one year or the need for shunting at one year of age and the secondary outcome that was measured was neurodevelopmental and neurological function at 6 months and 2 years of age, the intervention that is useful in meningomyelocele is covering the patch of defect using fetoscopy (Deprest et al, 2010)16. Danzer et al (2008) conducted a study to evaluate the benefits of reversal of hind brain herniation following fetal meningomyelocele closure. The main outcome measured in this study was reduction in the incidence and severity of hindbrain herniation-associated brainstem dysfunction manifesting as neurogenic dysphagia, apnea, neuro-ophthalmologic disturbances and gastro-esophageal refulx disease. In this structured survey, it was shown that majority of patients with meningomyelocele closure devloped mild or no brainstem dysfunction at follow-up. The researchers opined that neurodevelopmental deficits associated with meningomyelocele are actually partially acquired and reversal of hindbrain herniation subsequent to fetal meningomyelocele repair reduced not only the incidence, but also the severity of brain stem disease. According to Adrick (2010)17, fetal surgery for meningomyeolocele reverses hind brain herniation, decreases hydrocephalus that is shunt-dependent and improves leg function. Despite advances in the diagnosis, prevention and intervention, neural tube defects continue to be a major source of mortality and morbidity through out the world in both developed and developing countries18. Though there is enough evidence to shown that daily consumption of 400 micrograms of folic acid prior to conception decreases the risk of development of neural tube defect in the fetus19, the number of children born with neural tube defects is yet significant. the prevalence rate is atleast 3-4 per 1000 live births and is based on the ethnicity of the mother. There are reports that 23 percent of pregnancies diagnosed with neural tube defect land up in elective termination. prenatal management of neural tube defects is different in different parts of the world with most aggressive management in Asia and United States than in Europe. the five year mortality rate with spina bifida is 79 per 1000 live births. The mortality rate touches 35 percent in those with brain stem dysfunction secondary to Chiari II malformation. Complications of spina bifida include lower extremity paralysis, sphincter dysfunction and hydrocephalus. Those with hydrocephalus need shunts and they develop problems related to shunts. Only 70 percent of these individuals have IQ levels above 80 percent and 37 percent individuals are able to live independently as adults. however, one third individuals need care daily20. Early detection of neural tube defects has been possible through rampant use of screening ultrasonography and amniocentesis21. Use of fetal Magnetic resonance imaging or MRI has resulted in accurate diagnosis. It is possible to make accurate diagnosis at 18 weeks of age, giving enough time for thorough discussion about the likely outcome with parents and relatives. standard options include termination of pregnancy, continuation of pregnancy until term with vaginal or cesarean delivery options and fetal closure of the defect as part of the Management of Myleomeningocle Study22. As of now, spina bifida is considered as a potential candidate for in-utero treatment. This is because; it is detectable much before 20 weeks of gestation. Pathological studies of human fetuses and embryos with meningomyelocele in early gestation stages reveal an open but undamaged neural tube defect with normal cytoarchitecture. This is suggestive of the fact that neural degeneration occurs during some point of time during gestation itself. In a study by Osaka and co-workers (cited in Sutton, 2007)23, everted neural plate was detected in 18 embryos with a diagnosis of classical caudal myelodysplasia. In most of these embryos, there was preservation of membrane coverings. One interesting finding in this study was that Chiari II malformation, a condition with significant neurodevelopmental impact, was not seen in the embryos, whereas this malformation was evident in a couple of fetuses with caudal myelodysplasia from the same series. Also, hydrocephalus was seen in one of the fetuses but not in any embryo. Other researchers who examined the spinal cords of human fetuses that were born still born with meningomyeolocele reported different degrees of neural tissue loss at the site of defect24. However, normal ventral and dorsal horns were reported at the proximal aspects of the lesion. Even gliosis, inflammation and fibrosis were demonstrated by some researchers. Some studies performed serial sonograms to ascertain leg function of the baby in utero. While some authors reported about normal movement of the knees and hips as early as 16 weeks of gestation in fetus with established diagnosis of meningomyelocele, another important study reported abnormal leg movement only in one in 13 fetuses with meningomyelocele in the prenatal period. However, in this study, 11 of 13 fetuses were noticed to have abnormal leg motion after birth. The authors proposed that some aspects of the environment of the intrauterine region caused injury to the spinal cord portion that was exposed. This was evident in some rate studies in which spinal cord of rats exposed to human amniotic fluid resulted in cell injury. This aspect is further stressed by the fact that neural tissue damage is most evident in the dorsal parts of the cord. As the pregnancy progresses, there is decrease in the quantity of amniotic fluid which can lead to frequent contact of the spinal cord to the uterine wall, causing more pathological changes25. The first cases of repair of spina bifida in utero was reported in 1994 with the help of an endoscopic technique. However, this technique was abandoned because neither the procedure, nor the results were satisfactory. Some researchers have tried percutaneous fetoscopic patch coverage, but with problematic results. In 1997, a couple of famous studies evaluated the role of fetal for spina bifida defects26. While one study was performed in the Vanderbilt University, the other was done at CHOP. In the former study, there was no exclusion of patients based on late gestational age, prenatal ventricular size, spinal level or even presence or absence of fetal leg motion as determined by an in-utero sonogram. In the latter university, certain inclusion criteria were applied for fetal surgery and they were gestation age at the time of surgery less than 26 weeks, transatrial ventricular diameter of less than 16 mm, lesion at S1 or above that, convincing leg motion or foot motion or absence of any deformity of the foot as determined by ultrasound. Based on the reports of these studies, it was inferred that babied treated in utero had significant decrease in the risk of hind brain herniation. Also, serial MRI done in the postoperative period demonstrated ascent of the structures of the hind brain within 3 weeks of fetal closure. However, the re4searchers were unable to ascertain whether this translated to improved outcomes functionally and improved survival rates. It has been hypothesized that in those with fetal meningomyelocele, the posterior fossa is small and can be expanded by fetal surgery27. Other than posterior fossa, even the overall size of fetal head has been shown to be decreased in fetuses with meningomyelocele. There is evidence that this increases after surgery. However, whether this is an important aspect clinically is yet to be determined. Some researchers have proposed that enlargement of the head results due to restoration of cerebrospinal fluid volume, which is again, suggestive of reversal of herniation of hind brain. however, as of now there is no consideration of placement of shunts in the antenatal period itself. In studies performed at Vanderbilt and CHOP, it was found that following fetal surgery, the incidence of shunts was 54 percent, compared to 86 percent in the control group28. Such an effect was more evident in the lumbar lesions because of increased statistical power due to large number of lesions. Also, the incidence of shunting was seen in 42.7 percent of patients in whom the closure was done before 26 weeks of gestation. But in those who had fetal surgery after 25 weeks of gestation, shunting requirement was seen in 75 percent cases. The main reason for such difference has been attributed to development of back-pressure on the hind brain due to early elimination of leakage from the back29. In the study by Sutton et al, about 57 percent of patients reported better-than-predicted leg function at birth in patients with lumbar and thoracic meningomyelocele. However, the follow up was short and more further information was unavailable. All patients who underwent fetal surgery for spina bifida demonstrated tethering on MRI and some patients developed epidermoid inclusion cysts necessitating repeat surgery. It has been presumed that preservation of the neurological functioning of the lower extremities by fetal closure is likely to be worsened by tethering and this is more a problem because; there is more function to be lost. As far as cognitive functioning is concerned, the impact of fetal surgery is yet inconclusive and difficult to assess. The average IQ of those with meningomyelocele is much lower than those without the condition and this is mainly because of the disease process itself, rather than various associated problems like shunt infection30. Fetal surgery decreases the incidence of hydrocephalus and thus is likely to improve cognitive outcomes. However, some researchers have opined that fetal treatment increases incidence of prematurity which decreases cognitive function31. One coincidental finding following fetal surgery is enhanced wound healing and decreased scar formation, thus contributing to a back wound that is more favorable cosmetically32. Fetal surgery is not without risk and the estimated perinatal mortality is about 6 percent. Causes of mortality include intrauterine infection and extreme prematurity. Mean gestational age of delivery is 34 weeks and 4 days. fetal surgery is not associated with maternal mortality, uterus rupture or hysterotomy dehiscence. However, those subjected to fetal surgery will need cesarean section delivery33. Conclusion Recent advances in science and technology have allowed early detection of various disorders in prenatal stage itself, as early as less than 20 weeks gestation, giving scope for wide range of therapeutic decisions that can be taken much before the baby is delivered. Ultrasound and fetal MRI have helped in early detection of several structural neurological problems, some of which like spina bifida and meningomyelocele are potential candidates for fetal interventions. Most of the lessons for fetal surgeries have been learnt from therapies for congenital diaphragmatic hernia. Neural tube defects are a major source of mortality and morbidity despite advances in the prevention, diagnosis and treatment of these diseases and various preventive interventions like folic acid supplementation before conception have reduced the incidence of these diseases, but not to significantly low levels and thus, this group of disorders continue to be a source of distress. Main postnatal problems with these conditions are defective leg function, bladder and bowel problems, cognitive impairment and other such problems. There is some evidence to show that fetal therapy in the form of application of patch over the opening, reverses herniation of hind brain and causes decreased postnatal neurological complications. The mortality for the fetus and the mother associated with fetal interventions are low. however, one risk is premature delivery which itself may be a risk factor for poor neurological outcome. On the whole, this review ascertains the fact that, fetal therapeutic interventions based on preliminary investigations can lower the risk of postnatal problems. Bibliography Adzick NS. "Fetal myelomeningocele: natural history, pathophysiology, and in-utero intervention." Semin Fetal Neonatal Med. 15(1) (2010): 9-14. Adzick NS, Walsh DS. "Myelomeningocele: prenatal diagnosis, pathophysiology and management.” Semin Pediatr Surg. 12(3) (2003):168-74. Bruner JP, Tulipan N, Reed G, Davis GH, Bennett K, Luker KS, Dabrowiak ME. "Intrauterine repair of spina bifida: preoperative predictors of shunt-dependent hydrocephalus." Am J Obstet Gynecol. 190(5) (2004):1305-12. Cochrane DD, Irwin B, Chambers K. “Clinical outcomes that fetal surgery for myelomeningocele needs to achieve”. Eur J Pediatr Surg.11(Suppl 1) (2001):S18–20. Danzer, E., Finkel, R.S., Rintoul, N.E., et al. 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