Types of spinal dysraphisms [3].
\r\n\tGlobalization does not represent a pure and generous process for humanity or other species, but rather it implies social exclusion and also provokes situations of vulnerability in groups of people, forced exclusion, and apartheid: poor job opportunities, lack of access to education, worse socio-sanitary conditions. Specifically, it can be said that social segregation entails the apartheid of social groups of different ages, genders, and ethnicities; these groups live a reality manifested through the deepening of poverty, in terms of increased vulnerability of the poor and groups with little economic, social, cultural, labor and health stability.
\r\n\r\n\tThis book aims to talk about some topics that are neglected in the discourses of academic communities and political elites. The inequality process is deeply rooted among humans and is part of many people's lives in the form of modern apartheid, gender segregation, lack of health access, and cultural gap. All those structural inequality processes are the product of the biopower perpetuated and produced in the macrosystem, exosystem, mesosystem, and microsystem. For many people from the academy, the information-consuming public, and the society in general, it is a problem to talk about these processes, since they have either lost interest or have normalized the structural and social inequity. For this reason, we see it as transcendental to explain how this situation occurs from the most internal fibers to the most evident processes, intending to make it more visible and thus expose the situation for possible solutions.
",isbn:"978-1-83768-406-9",printIsbn:"978-1-83768-405-2",pdfIsbn:"978-1-83768-407-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"cefab077e403fd1695fb2946e7914942",bookSignature:"Ph.D. Yaroslava Robles-Bykbaev",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11473.jpg",keywords:"Wage Gap, Gender Segregation, Fundamental Human Rights, Health Access, Social Inequity Processes, Modern Apartheid, Resilience, Cultural Gaps, Globalization, Geopolitics of Social Inequality, Public Policies, Social Vulnerability",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 15th 2022",dateEndSecondStepPublish:"July 13th 2022",dateEndThirdStepPublish:"September 11th 2022",dateEndFourthStepPublish:"November 30th 2022",dateEndFifthStepPublish:"January 29th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Bykbaev is a member of the UNESCO Chair of Politecnica Salesiana University. 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Dr. Bykbaev is an active member of the NODO Ecuadorian Network of Women Scientists (REMCI).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"313341",title:"Ph.D.",name:"Yaroslava",middleName:null,surname:"Robles-Bykbaev",slug:"yaroslava-robles-bykbaev",fullName:"Yaroslava Robles-Bykbaev",profilePictureURL:"https://mts.intechopen.com/storage/users/313341/images/system/313341.jpg",biography:null,institutionString:"Politecnica Salesiana University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Politecnica Salesiana University",institutionURL:null,country:{name:"Ecuador"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444316",firstName:"Blanka",lastName:"Gugic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/444316/images/20016_n.jpg",email:"blanka@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Special interest deserve neural tube defects, that comprise anencephaly, spina bifida and encefalocele.
Spinal dysraphisms comprise a broad spectrum of congenital disorders resulting from impaired structural development of the craniospinal axis during brain and spinal cord growth and differentiation within 2nd and 6th week of gestation and proceed through a complex multistep process [1].
Spina bifida is a group of developmental disorders of neural tube. Neural tube in developing embryo forms future brain, spinal cord and their supporting structures. Under normal circumstances neural tube closes on 28th day after conception. In children with spina bifida neural tube does not develop or close properly causing dorsal defect of spine or spinal cord itself. Severity of symptoms and possible complications depends on location, size and type of defect.
Spina bifida is a complex disorder that requires multidisciplinary aproach in diagnostics, treatment and complications solving.
Spina bifida or spinal dysraphism is a wide spectrum of clinical and imaging findings concerning incomplete fusion of the midline neural and bony structures during early embryogenesis. Spina bifida can be devided into closed and open forms (Table 1).
Tethered cord syndrome |
Dermal sinus |
Diastematomyelia |
Spinal lipoma |
Lipomyelomeningocele |
Lipomyelocele |
Terminal myelocystocele |
Meningocele |
Nonterminal myelocystocele |
Myelomeningocele |
Myelocele |
Hemimyelomeningicele |
Hemimyelocele |
Types of spinal dysraphisms [3].
To closed spina bifida without subcutaneous mass belong: tethered spinal cord, dermal sinus, diastematomyelia and spinal lipoma. Closed spinal dysraphism with subcutaneous mass are: lipomyelomeningocele, lipomyelocele, terminal myelocystocele, meningocele, non-terminal myelocystocele.
Type I has common midline septum or spur, double dural sac and is symptomatic. Type II has both hemicords in a single dural sac [3].
Spinal lipoma can be present in 3 forms:
Incidence of spina bifida varies worldwide between 1 to 10 per 1000 births [6] and between 0,17 to 6,4 per 1000 live births for myelomeningocele [7] but has differences in geogrefical regions with higher rates in less developed countries. In Europe it is around 4500 pregnancies a year that are affected by neural tube defect. Over 90% of more serious spina bifida cases is diagnosed before 22nd gestational week [8]. Overall prevalence of spina bifida is lower in countries with mandatory folic acid fortification of grain products opposite to countries with voluntary or no fortification [9, 10]. More affected are females and whites and Hispanics.
Detailed etiology of spina bifida is not known but it is assumed to result from a combination of more factors - genetic, nutritional and environmental risk factors. Genetic risk factor is a family history of neural tube defect. Most important nutritional factor is folate deficiency. Even though exact mechanisms leading to spina bifida are not clearly known, there are some of researchers interest [11].
Folate is a natural form of vitamin B9. Its synthetic form is folic acid. Folate is important for proper intrauterine development of fetus. Its deficiency is connested not only with spina bifida, but also with occurence of all neural tube defects. Spina bifida is significantly more common in countries without legislation regulating full-coverage folic acid fortification of the food supply and less common in world regions with mandatory folic acid fortification [9].
Genetic factors seem to play important role in etiology of spina bifida. Couples with child born with spina bifida are at higher risk of having another child born with this defect. At higher risk of having child affected by spina bifida are also women who were born with neural tube defect and also higher frequency is in twins than in singletons. All this indicates a genetic contribution to etiology. But low frequency of families with multiple neural tube defects makes research more difficult [11].
Some drugs are under suspicion in contributing to higher risk of developmental disorders of neural tube. Mostly anti-convulsants (anti-seisure mediacation), such as valproic acid, when taken during pregnancy. They probably interfere with metabolism and utilization of folate and folic acid.
Women with decompensated or inadequatelly compensated glucose levels during early stages of pregnancy are at higher risk of having child with spina bifida.
Spina bifida and all neural tube defects are more common in women with obesity. It is important to have adequate body mass index also prior to pregnancy.
Increased body temperature in early stages of pregnancy due to infection or using of sauna is believed to be potencially risky for having a child with neural tube defect.
Women with present risk factors should be medicated with higher dose of folic acid preconceptionally and also during pregnancy. In women who use more risky medication (f.e. anti-seizure medication) should be pregnancy planed with switch of medication to more safe one.
Severity of symptoms depends on type of spina bifida ranging from no symptoms in spina bifida occulta to most severe in myelomenigocele. There are also interindividual differences. Spina bifida occulta is neurologically asymptomatic because there is no involvement of neurologickal structures.
Cutaneous lesions mostly in lumbar region could be associated with spina bifida or tethered spinal cord. Visible change of skin above the defect is usually an abnormal tuft of hair, dimple, subcutaneous lipoma or a birthmark [12]. Such skin lesion could also be a symptom of spinal cord abnormality that is covered by skin.
Sacral dimple is a common skin lesion and is found in 1,8 to 7,2% of newborns [13]. However, in most of newborns it is only a simple skin lesion without any effect on neurological functions. Possitive ultrasonography findings are usually filar cyst (24,8%), echogenic filum terminale (13,5%) and low-lying spinal cord (11,7%). Some literary sources consider filar cyst as a normal finding [14].
Simple solitaire sacral dimple in asymptomatic newborn with diameter less than 5 mm located no more than 25 mm above anal opening have extremely low risk of having spinal abnormality [15]. Considering this very low risk (approx. 0,34%), more recent guidelines state that sipmple solitaire non risky sacral dimples do not require additional imaging – only in case they are atypical, associated with other skin lesions or multiple. On the other hand around 86% of spinal dysraphisms are associated with overlying cutaneous lesion [16].
Open defect is mostly situated in the lumbar region and is characterized by opened spinal canal along more vertebras. At birth meninges, spinal nerves and spinal cord protrude above surrounding skin level forming a sac. This sac could be also covered by skin. These open defects are easily recognized whereas smaller or closed defects can present only by overlying cutaneous lesions [17].
Degree of neurological impairment, walking disability and muscle weaknes depends on severity and extent of the defect, as well as on accuracy of prenatal or postnatal treatment. Neurological deficit varies from mild paraparesis to paraplegia. Myelomeningocele is the most common congenital anomaly causing physical disability [18].
According to level of defect there are various degrees of motor disability (Table 2). Patients with thoracic defect have flacid lower extremities, patients with high-lumbar defect usually can perform flexion in hip joint, in middle-lumbar defect also extension in knee, in low-lumbar defect is also foot dorsiflection present and sacral defect usually allows to perform also plantar flexion of foot [20].
Level of lesion | Muscle function | Ambulation |
---|---|---|
Lack quadriceps function | Children – ambulation with hip spanning orthosis (hip-knee- ankle – foot orthosis or reciprocating gait orthosis) Adults – majority require wheelchair | |
Lack function of gluteus maximus and medius Retain quadriceps and medial hamstring function | Require crutches for ambulation Most retain comunity ambulation as adults | |
Retain quadriceps and gluteus medius function | ||
High sacral | Lack gastrocnemius function | Ambulate with ankle-foot orthosis and no support |
Low sacral | Retain gastrocnemius function | Ambulate without braces or support |
Functional outcome according to level of spinal dysraphism [19].
Neurological deficit in patients with spina bifida is thought to be result of the primary insult - the congenital anomaly and the second - from direct exposure of spinal cord to amniotic fluid and intrauterine trauma [21].
In a study with 50 years follow up of walking ability half of the patients with severe spina bifida was able to walk for 50 m butthis ability declined with age to 27% in the age of 50 years [22].
Nerve damage in neural tube defect leads to loss of sensation and bladder sphincter control. Very common is neurogenic bladder that leads to symptoms such as urinary retencion, overflow incontinence, urgency, frequency and nocturia. Possible complications are incontinence, repeated or chronic urinary infections, hydronephrosis and in later stages renal damage [23] that all leads to diminished quality of life [24].
Most of patients living with the diagnosis of spina bifida have some degree of bowel problems called neurogenic bowel dysfuntion. The lack of bowel movement results in obstipation and lack of anal sphincter control leads to intermitent or continual incontinence [23]. Bowel dysfunction leads to decreased life quality [19, 25].
Possible complication affect in some degree most of patients with open forms of spina bifida. The severity of complications depend on extent of defect and also on timing of treatment. Fetal surgery gives better prognosis.
The majority of infants with open neural tube defects also has hydrocephalus [26]. Hydrocephalus is defined as an active distension of the ventricular system resulting from inadequate passage of cerebrospinal fluid at some point from its production within ventricles to its absorption into the systemic circulation [27]. In infants it is a condition with ventricular enlargement that leads to rapid growth of head circumference and requires surgical intervention [28]. According to observations only 1 out of 6 infants with myelomenongocele has symptoms of raised intracranial pressure at birth and 1 out of 8 has head circumference above 98th percentille at birth [29]. Many infants develop ventriculomegally that leads to increase of head circumference after postnatal closure of open spina bifida. Slight ventricular enlargement with stable neurological status could be indication for conservative observation – radiological and clinical. Rapidly developed ventricullomegaly with worsening of neurological status and signs of intracranial hypertension requires quick neurosurgical intervention [26].
Surgical treatment possibilities are insertion of ventriculo-peritoneal shunt and endoscopic third ventriculostomy with cauterisation of choroid plexus. Minority of cases is indicated for conservative treatment – only those with relatively stable ventriculomegally [26]. Infants who underwent fetal surgical repair of myelomeningocele were less likely to require ventriculo-peritoneal shunting [30].
Presence of hydrocephalus in children with open spina bifida requires placement of ventriculo-peritoneal shunt in most of the cases. Proper function of shunt is inevitable. Unfortunately, shunt related complications are frequent – mainly shunt malfunction and infection. About 95% of patients who required shunt placement have to undergo at least one shunt revision [26]. Symptoms of shunt-related complications are: headache, irritability, confusion, somnolency, nausea, vomiting, feeding problems, fixed downward gaze, seizures. In case of shunt infections also symptoms like higher body temperature, redness along the shunt catheters, elevated blood parameters of infections.
Myelomeningocele as the most severe open defect is almost invariably associated with this malformation. Chiari malformation type II is a group of disorders that includes herniation of fetal developing cerebellum upwards into the middle cranial fossa or downwards into cervical spinal canal. This malformation is often associated with other abnormalities such as: brainstem kinking, abnormal forth ventricle location and syringomyelia [30]. The research on animal models shows that chronic intrauterine leakage of cerebrospinal fluid can lead to Chiari II malformation [31]. It is common brain malformation in children with myelomeningocele. This malformation worsens the cerebrospinal fluid circulation leading to progression of hydrocephalus. Chiari malformation type II can present with rapidly present symptoms such as: breathing problems or apnoea, bradycardia, swallowing problems and other cranial nerves dysfunction when descending cerebellum presses on brainstem [26]. Under rare circumstances can lead to indication of decompression of craniocervical junction. Chiari malformation type II, its presence and severity can in huge extent determine the outcome of patients [26]. Chiari II malformation is significantly less severe in infants who underwent fetal surgery for myelomeningocele [30]. Improvement of this malformation and subsequent decrease in hydrocephalus in children with prenatal repair of myelomeningocele support the theory of relationship between continual intrauterine abnormal leakage of cerebrospinal fluid and subsequent development of Chiari II malformation and hydrocephalus and underline the importance of fetal surgery [26, 30].
Tethered spinal cord is a neurological disorder that is caused by abnormal attachment of the spinal cord to surrounding structures. In case of patients with myelomeningocele spinal cord is mostly attached to scar from previous operation [32]. Symptoms are caused by increased tension and stretch-induces dysfunction of the caudal spinal cord and conus and include motor and sensitive dysfunction, gait abnormalities, symptoms of cauda equina syndrome and urological symptoms [12, 32].
Filum terminale lipoma can cause cord tethering, lipoma is the most common cause of thick filum terminale. That is why detection of abnormal thickening of filum terminale is important. Initial detection is usually performed by ultrasonography [2] followed by MR imaging [12]. Tethered cord syndrome must be suspected when conus medullaris is placed dorsaly in the spinal canal and terminates below the superior aspect of L3 vertebral body. Also thickened filum terminale can be present. MR imaging is indicated in ultrasonography evidence of tethered cord or in case of doubts [3].
Although some patients with anatomic cord tethering do not develop symptoms, most of the patients are symptomatic and do not naturally improve without surgical untethering. Neurosurgical intervention is the treatment of choice, though with varying results [33]. Timing of the surgery is also important – early intervention after symptom development is necessary for recovery or at least improval of neurological functions. Early surgical intervention as a prevention of further neurological damage requires early diagnostics [12].
Infants with open neural tube defects can experience meningitis – inflammation of brain and spinal cord surrounding meninges. Meningitis could develop as a consequence of open defect, as a complication of surgical procedures as well as a complication of shunting procedures. In case of bacterial meningitis there is a need for massive antibiotic therapy.
Most of the patients with severe spinal dysraphism suffer from neuropathic bladder impairment [24]. As the nerve damage causes urological complication by means of neurgenic bladder, this situation also brings specific possible complications. Usual problem is urinary retention that could lead to overflow incontinence, renal damage and urinary tract infections, that could be repeated or chronic and often requires antibiotic treatment.
It is necessary to maintain proper urine derivation with no residual urine left. These patients require long time follow up by urologist. Urological complications and renal disease as a consequence is very common cause of higher morbidity mainly in older children and adults with open spinal defect. Severe bladder mortality is most frequently present in patients with huge spinal defects without covering membrane. This verifies the theory of increased damage of nerve roots from direct exposure to amniotic fluid [34].
One of the most common problems of patient with spina bifida in adulthood is neuropathic bowel dysfunction with constipation and incontinence, but these patients also often suffer from dysphagia – mainly patients with brain stem compression.
Brain and spinal cord nerves modulate activity of enteric nervous system. Patients with severe and highly located forms of open spina bifida and resulting Chiari II malformation have impaired function of nerves leading to dysfunction of gastrointestinal tract mobility. Gastrointestinal problem that these patients suffer from is diminished bowel movements causing obstipation or opposite also diarrhea. Patients often suffer from anal incontinence from mild to severe degree [19].
Patients with large and high located myelomeningocele often suffer from dysphagia. Development of dysphagia in children with myelomeningocele is caused by cervicomedulary kinking and brainstem compression due to crowding in the posterior fossa in Chiari II malformation. Dysphagia leads to swallowing difficulties, feeding difficulties, failure to thrive, bronchopulmonary complications and later to peptic ulcer disease [34, 35].
Children with large and high located myelomeningocele display also other complications such as Chiari II malformation that often leads to dysfagia. Severe dysphagia causes swallowing and feeding problems that might cause complications as aspiration pneumonia, pulmonary disease, reactive airway disease, bronchiectasis, stridor or apnoea [35]. Although almost all children with open spina bifida live into adulthood, patient suffering with brainstem dysfunction leading to such bronchopulmonary complications are at higher risk of fatal complications [34].
Children with thoracic and thoracolumbar levels of defect might in some cases also have impaired function of the accessory respiratory muscles. They also often have scoliosis that could lead to reduced forced vital capacity of the lungs [36].
Orthopedics deal in patients with spina bifida with congenital and acquired deformities. Because of weak muscles of spine and lower extremities, these patients with open spinal defects can present with variety of orthopedic problems. Most frequently occuring problems are: scoliosis, kyphosis, muscle contractions, bone and joints deformities, hip dislocation, abnormal growth and talipes (club foot) [37].
Scoliosis is present in almost all children with severe and highly located myelomeningocele. Children born without covering membrane of the defect tend to have neuromuscular imbalance and spinal cord tethering which are conditions leading to scoliosis. Severe paraparesis leading to full-time use of wheelchair also enables occurrence of scoliosis [34]. Scoliosis also leads to pelvic obliquity with subsequent changes in sitting balance and contributes to unequal pressure during sitting. This factor together with lack of sensitivity leads to skin breakdowns [36]. One of the most important factors for maintaining ambulation in adulthood is strength of quadriceps and hamstring muscles [11].
Many patients with open spinal defects are at higher risk of latex allergy. This means allergic reaction to natural rubber and latex products. Symptoms could be mild – such as rush, sneezing, itching, conjunctivitis and rhinitis, as well as very severe condition – anaphylaxis, that is potentially life threatening situation. This is a potential reason for using latex-free gloves at labor and also at giving care to these patients. Latex allergy could also lead to perioperative complications [11].
Children and adults with open neural tube defects often suffer from sleep disorders, from which sleep apnoea is the most severe one potentially affecting life quality. These patients should undergo evaluation of sleep disorders.
Because of lack of skin sensitivity below the level of open spinal defect, patients do not properly feel small wounds or sores on their lower extremities, buttocks and back region. That is reason that these small wounds may develop into more severe wounds that are more difficult to heal and may sometimes cause generalized infection. Skin breakdowns are also consequence of friction and pressure related to the use of orthotic aids that assist in positioning and ambulation as well as constant pressure on insensitive skin due to immobility, especially with increasing body size and weight [38].
Many patients with open spinal defect have altered sitting balance due to paralysis of abdominal, thoracic and lumbar extensor musculature. Due to this imbalance together with insensate skin leads to frequent skin breakdowns [36].
Many children with severe forms of spina bifida suffer from specific learning disabilities, such as dyslexia, dyscalculia, problems with paying attention. Patients with less severe forms of spinal dysraphism and with lower levels of defect have higher chance to obtain higher education and better employment and insurance status [19].
Patients with open spinal defect prone more to develop depression or suffer from anxiety. Attaining early ambulation provides psychological benefits even if the child later becomes sitter [11].
Early diagnosis of spina bifida is crucial. This applies to open forms. It is known that closed spinal defect that affects only vertebral arch is often just incidental finding without clinical correlate. Early diagnose of open spinal defect gives better chances for better prognosis and for fetal surgery. In some sever cases it could lead to decision of termination of pregnancy.
Screening of neural tube defect is part of routine prenatal screening. Each pregnant women is offered to undergo screening tests. Widely used screening tests during pregnancy are blood tests fetal ultrasonography. In special cases can also amniocentesis be indicated. Fetal MR imaging is used to verified neural tube defect in cases when fetal surgery is planned.
Initial wide screening for neural tube defects is made by blood tests. It is important to know that this test can have false positive as well as false negative results.
A sample of maternal blood is taken for this test. Test determines the level of alpha-fetoprotein (AFP) in maternal serum. This protein is produced by fetal tissues and in normal production only small levels of this protein reaches mother’s bloodstream. In abnormally high production of AFP, higher level of MSAFP can be detected.
Normal MSAFP level does not absolutely exclude diagnosis of spina bifida. On the other hand high MSAFP levels could be caused by miscalculation of fetal age or multifetus gravidity. In case of positive MSAFP test it is usually repeated. If the level remains high there is an indication for further evaluation, usually by ultrasonography. AFP test can be a part of triple screen test that is used for screening of neural tube defects but also other organs abnormalities.
This diagnostic tool is widely and successfully used screening imaging tool. It is also accurate tool for early diagnostics of open spina bifida. Morphological ultrasound is made three time during pregnancy in each trimester. The first two ultrasounds are most important for early diagnostics. First examination by ultrasonography is performed usually between 11th to 14th gestational week. Second trimester examination is usual between 18th to 22nd week and this imaging is most important for assessment of correct fetal morphology and evaluation of signs of present spina bifida or hydrocephalus [2]. More advanced ultrasonograph could detect also milder forms of spina bifida and in experienced hands could be also useful in evaluation of severity of defect. Children with higher spinal lesions on prenatal ultrasound have more serious motor impairment [20].
Amnicentesis could be indicated after positive ultrasonography. This test is performed by needle inserted transabdominally under ultrasound control to amniotic cavity to take a sample from amniotic fluid. Amniotic fluid can be tested for AFP levels. Cells from amniotic fluid are used for genetic examination to rule out genetic abnormalities causing spina bifida, although genetically associated spina bifida is rare. This needs to be taken into account in decision making as the procedure of amniocentesis caries also risks.
Fetal MR imaging is a powerful diagnostic tool for evaluation of neuroaxis. It plays an important role in prenatal diagnosis, treatment planning and follow up [39]. Fetal MRI is used for determining the level of spinal defect and for selection of candidates for fetal surgery [34]. Fetal MRI is used in cases where prenatal screening and ultrasonography is positive. Open spinal defect in higher levels of spine is more often connected with increased fetal ventricular size [40]. Morphological evaluation by fetal MR imaging provides valuable information for prognosis and possible complications. Higher defects are frequently associated with dysfagia and absence of membrane covering defect is commonly associated with scoliosis and high risk of severe bladder dysfunction. Location and size of defect correlates with severity of motor deficiency, patients with higher and larger defects are predicated for full-time wheelchair use. Lenght and width of defect of the body defect are measured as segment span and interpediculate distance [34].
Ultrasonography is a safe and effective screening method that is commonly used in screening system of the newborns. It is noninvasive imaging method that does not require sedation of newborn without exposure to radiation [12]. Newborns with physiological finding on ultrasonography do not require any further imaging evaluation. On the other hand, positive finding on ultrasonography require more detailed imaging performed by MR imaging [41].
Ultrasonography is the first-line survey for the assessment of spinal cord abnormalities. During the first six months of life non-ossificated vertebral arches and cartilagineous posterior elements provide acoustic window for detained imaging of spinal canal with its content and surrounding soft tissues [17].
Ultrasonography of the spinal cord in infants is very effective tool for imaging of spine and spinal cord compared to postossification [3, 12]. Major indication of spinal ultrasonography in selected group of newborns is possible detection of tethered cord syndrome. Progress of ossification in time makes ultrasonography more difficult [12].
Indications for spinal ultrasonography in newborns are: cutaneous lesions on the back (such as hypertrichosis, subcuteaneous lipoma, sacral sinus, sacral dimple), spinal deformity, neurological abnormality (paraparesis, neurogenic bladder or bowel dysfunction), spinal trauma during delivery and syndromes with associated compression of spinal cord [41].
Spinal ultrasonography is performed in infant in lying prone position with the upper body higher than lower and in flexed spine (curved over pillow). This position offers better acoustic window. Imaging is performed with linear transducer through longitudinal and axial plane scans from craniocervical junction to coccyx [3].
The main structures that must be identified are: conus medularis, filum terminale, cauda equina and spinal roots, central echo complex and subarachnoid spaces. Tip of conus medularis is in newborns usually located L1 and L2 interspace, occasionally on the level of superior end plate of L3. Filum terminale is a band of fibrous tissue that extends from the conus to the caudal end of spinal canal. At the level of L5 and S1 it should be less than 2 mm thick and should be predominantly hypoechoic with a bright hyperechoic periphery. Cauda equina and spinal roots must move according to the pulsatile production of cerebrospinal fluid, as the ultrasonography provides live image of the structures. Central echo-complex is train-line hyperechogenicity provided by the interface of the two margins of spinal canal. It needs to be detectable at all levels of spine and the space must be regular along entire extension. The subarachnoid space is anechoic and does not contain structures except spinal cord and nerve roots [3].
In order to avoid unnecessary further imagings it is important to know some anatomical variations that are considered physiological. Some of them are: mild thickening of the epidural fat, mild thickening of the filum terminale (between 1 and 2 mm), malformation of the coccyx with palpable prominence in the sacral region, transient dilatation of the central canal (usually disappears during the first weeks).
Also known as fifth ventricle. It refers to mild cystic dilatation of the terminal part of spinal cord canal due to incomplete regression of embryonic ventriculus terminalis in the conus medularis. This condition is usually asymptomatic, but in some patients could cause low back pain, sciatica or urinary bladder dysfunction [3].
As ultrasonography of the brain and spine is quick and good available it is the bet diagnostic first-line tool. But for proper imaging of brain, spine and supporting structures for evaluation of extent of the defect, treatment planning and estimation of prognosis there is a need for use of other diagnostic methods. After detailed ultrasonography newborns with more severe spinal defects undergo MR imaging of spine. In open spinal defects with a risk of hydrocephalus newborns undergo CT or MR imaging of the brain according to clinical need with a detection of serious neuroimaging findings, such as ventriculomegally, tonsilar descent, hind brain abnormalities, nodular heterotopia of gray matter and corpus callosum abnormalities – such as aplasia, hypoplasia/partial aplasia with or without dysplasia [23].
Termination of pregnancy with severe fetal anomalies is a controversal issue with many moral and ethical controversies. Indication for termination of such pregnancy is a medical decision but as well moral choice of mother or parents. This moral choice is affected by religion beliefs, legislation, cultural values and socio-economical status [42]. Around 40% of mothers decide to continue with pregnancy after diagnose of severe open spinal dysraphism [23].
Treatment of spina bifida depends on severity of primary defect. Occult forms of spina bifida usually do not require any treatment. All other forms are indicated for surgical repair.
There has been a significant improval of patient outcomes in the past 50 years because of multidisciplinary approach with an increased life quality of patients and prolonged life expectancy [43]. But though survival has changed significantly within past decades, there has not been significant improval of neurological outcome [44]. In struggle to ameliorate the neurological outcome fetal surgery seems to be a promise. If fetal surgery is not indicated newborn needs to be operated soon after birth.
As the spina bifida is a complex problem, also treatment needs to be complex and include also treatment of complications.
Neurological deficit in patients with spina bifida is thought to be result of two circumstances – the primary insult is the congenital anomaly and the second is from direct exposure of spinal cord to amniotic fluid and intrauterine trauma. This hypothesis is the rationale for preventing secondary damage to spinal cord by fetal surgery [21].
Fetal surgery in fetus with open type of spina bifida, though risky, is a promising procedure in improval of neurological outome. This procedure has to take place before completed 26th week of gestation. Indication for fetal surgery is a result of multidisciplinary decision. Fetal surgery should be performed only in centres experienced with fetal surgery equipped by neonatology intensive care unit. It requires cooperation of more specialists: pediatric neurosurgeon, gynecologist, fetal surgeon, fetal cardiologist and neonatologist. During this procedure uterus needs to be surgically exposed, opened and spinal cord and meninges of the fetus are closed and covered by skin. In some cases this procedure can be performed less invasively by means of fetoscope.
Prenatal surgery of fetuses with open spina bifida – myelomeningocele before 26th weeks of gestation leads to lower incidence of postnatal presence of Chiari II malformation or its lower severity and less amount of infants with myelomeningocele requiring ventriculo-peritoneal drainage for hydrocephalus. Other abnormalities accompanying Chiari II malformation – such as kinking of brainstem and dislocation of forth ventricle are less frequent in infants who underwent prenatal repair of myelomeningocele [30]. Children after fetal surgery are less likely to need mobility aids, such as crutches. But fetal surgery still remains a risky procedure with possible pregnancy complications such as preterm rupture of membranes and premature delivery before 34th week of gestation in almost half of the cases that underwent fetal surgery [30]. Persistence of Chiari II malformation with descendent herniation on MR imaging 6 weeks after prenatal repair is a predictor of need for postnatal surgical hydrocephalus treatment [45].
Since prenatal surgery might bring more favorable results but carries risk of premature birth, parents facing decision about prenatal versus postnatal repair, need to get reliable and up-to-date information to make this difficult and necessary choice [23].
Myelomeningicele and meningicele if not treated prenataly, need to be surgically treated as soon as possible within the first days after delivery [46]. Early surgery gives better chances for good outcome. Another reason for early surgery is diminishing the risk of infection of exposed neural structures. During surgical procedure surgeon closes spinal cord a creates a meningeal layer around spinal cord and covers defect with muscular and skin layer. In case of newborn with symptoms of intracranial hypertension, ventriculoperitoneal shunt can be immediately implanted to treat hydrocephalus.
A meta-analysis of two prospective studies showed no significant difference in neurological outcome between prenatal and postnatal surgical repair, but suggested improved independent ambulation at 30 months of age in children following prenatal repair [47]. Surgical complications are cerebro-spinal fluid leakage, infection and wound healing complications [23].
As the irreparable nerve damage has already occurred during abnormal development all treatment modalities aim to minimize resulting neurological deficit and to treat complications and to exclude them form having impact on life quality and overall survival. Treatment of complications usually begins right after birth. Some patients require repeated surgeries.
Although advances in treatment of spinal defect, such as fetal surgery and active screening and early treatment of complications have rapidly changed survival of these patients, complications are main cause of mortality of myelomeningocele patients. Most severe complications with possible impact on survival are brain stem dysfunction, hydrocephalus, shunt related complications and ventriculitis in children and renal disease in later life.
Hydrocephalus may be present at birth with symptoms of active hydrocephalus leading to raised intracranial pressure. In such conditions hydrocephalus needs to be treated immediately. In cases without acute symptomatic hydrocephalus could be initial decision of observation. In case of rising symptoms of hydrocephalus it needs to be treated. Typical procedure is insertion of ventriculoperitoneal shunt, in which cerebrospinal fluid is being drained to peritoneal cavity where it is resorbed. This shunt system consists of ventricular catheter, ventil with chamber and distal peritoneal catether. This type of drainage is most common. If there is a contraindication for drainage of cerebrospinal fluid to peritoneal cavity, it can be rarely drained to pleural cavity, right atrium of heart through venous system and very occasionally to gall bladder. Newer method is endoscopical procedure – third ventriculostomy in cases with stenosis of Sylvian aqueduct with cauterisation of choroid plexus to minimize production of cerebrospinal fluid. Possible complications of shunt systems, such as malfunction or infection usually require shunt revision. During growth children usually require revision with prolongation at least once [23].
Patients with open spina bifida need to be regularly evaluated for bladder and bowel functions to minimize the risk of complications and organ damage. Regular blood tests, ultrasound, kidney function tests, urodynamic assessment and X-rays need to be performed.
Urinary and bowel complications are associated with diminished life quality of patients [25]. Degree of continence and management techniques differ by type of spina bifida and age of patient.
Urinary management also changes with age of these patients. Chance for spontaneous voiding decreases with age. Daily use of antibiotics as a prophylaxis is rare, but more common in adults. Almost half of patients uses antimuscarinic medication and this is more frequent in children and younger age groups. Alpha adrenergic receptor agonist and antagonist medication to improve continence and voiding is rare [24]. One fourth of adults have undergone bladder augmentation. Creation of continent cathetrizable channel (Mitrofanoff or Monti), cutaneous vesicostomy and bladder outlet operation are more common in adults compared to school children and adults. History of surgery for urinary stones is more prevalent in adult age group. Use of CIC is less frequent in school children than in older age groups and is more common in patients with severe open spinal dysraphism. Management by indwelling catheter, condom catheter, Credé maneuver or urostomy bag (incontinent diversion) is overall less frequent but from age groups is more common in adults. Patients with spina bifida are more likely to develop urinary stones and this risk increases with age, so higher rate of urinary stone removal in adults is not unexpected [24].
Bladder continence is reported to increase by age. Around one third of patients is continent in school age but almost half of the patients in adult age [24]. Though urinary incontinence affects life quality, it has lower impact than bowel incontinence [48].
Dramatic improvement of life quality of patients with severe anal incontinence, severe constipation and no anal control can experience with antegrade continence enema – ACE, that is minimally invasive surgical procedure [23].
Other surgical procedures for treatment of neurogenic bowel dysfunction are: cecostomy button or tube, cecostomy button closure, colostomy and ileostomy [19].
Type of used bowel management tool may also differ by age. Use of oral medication is low or insufficient in all age groups. Timed evacuation and suppositories are more used in small children and their use decreases with age. Standard rectal enemas are more used in school children and adults and less by adolescents. Cone and mini enemas are more used in school children and less by adolescents and adults. Antegrade enemas through a surgically created chanel or a cecostomy button and tube are more used in adolescent age than in childhood and adulthood. Digital stimulation and disimpaction is used by small number of patients and mostly used in adults. Higher prevalence of colostomy is in adults. Ileostomy is less frequently performed [19]. Degree of continence and sufficiency of incontinence control has great impact on life quality of patients with spina bifida [19].
The mail goal of orthopedic treatment in patients with spina bifida is to correct deformities that may prevent the patient from using orthoses to ambulate during childhood [11]. Orthopedic complications are common in patients with spinal defects, mostly congenital and acquired deformities. Frequent congenital defermities are kyphosis, hemivertebra, teratologic hip dislocation, clubfoot and vertical talus. Acquired developmental deformities are related to the level of defect and are caused by muscle imbalance, paralysis and lack of sensitivity in lower extremities, such as contractures, calcaneus and cavovarus. Orthopedical complications may also be a consequence of surgical intervention – for example in postoperative tethered cord syndrome [11].
Orthopedical surgical interventions are most common within first 5 years of life, especially within the first year of life – mostly due to presence of congenital deformities that require surgical correction [38].
Deformities of
Extension contractures are much less common and occurs secondary to unopposed quadriceps function in weak hamstrings, extensive bracing in extension or surgical treatment for flexion contracture, but most of the cases are congenital and often also with teratogenic hip dislocation or clubfoot. Initial treatment is usually serial casting attempting to achieve satisfactory knee flexion that is around 90 degree. If the contraction interferes with gait and is persistent, usually VY plasty of quadriceps is performed with good results. In non-ambulatory patients in whom the contraction causes difficulties with sitting, tenotomy of patellar tendon is an option.
Deformity of the knee joint is a result of static forces of positioning, fibrosis of the surrounding muscles, muscle imbalance around knee joint and fracture malunion. Valgus knee deformity is more common in patients with low-lumbar or sacral dysraphism and leads to instability, pain and acceleration of arthrosis in adulthood.
Torsional deformities of femur and tibia are frequent in patients with severe spinal dysraphims and presents more severe problem for ambulatory patients. Femoral torsion is present normally in all newborns initially, but in children with severe spina bifida does not decrease with growth due to abnormal gait and activity. Tibial torsion is more common. Internal torsion is congenital and frequently associated with clubfoot and external torsion is acquired secondary to muscle imbalance. Initial treatment is usually ankle-foot orthosis with twister cables. If not successful, internal torsion of tibia can be treated by rotational osteotomy and severe cases of external torsion by internal rotational osteotomy of the tibia.
Clubfoot is the most common foot deformity in spina bifida patients [50]. Factors that contributes to development of clubfoot are spasticity, intrauterine positioning, contractures and muscle imbalance. Treatment methods that could be used are: serial manipulations and long-leg casting to gradually correct deformity and tenotomy of the Achilles tendon followed by foot abduction bracing for several years. If this treatment is ineffective there is an indication for double osteotomy – closing wedge osteotomy of the cuboid with an opening wedge osteotomy of the medial cuneiform.
Equinus is also frequent deformity. Spasticity probably plays the most important role in it etiology. In prevention regular routine of passive stretching with a night-time ankle-foot orthosis is used. Surgical treatment is indicated in patients with unbraceable foot with skin breakdowns. Mild deformities respond to Achilles tendon excision, severe contractures require radical posterior release in the posterior tibiotalar and talocalcaneal joints.
Another contracures occuring in spina bifida patients are vertical talus, calcaneus or calcaneovalgus, ankle valgus, hindfoot valgus, cavus, varus and cavovarus [49].
More severe cases may require surgical repair – correction of ankle or foot deformity, correction of congenital foot deformity, correction of equinus contracture, tendon excisions, correction of scoliosis, osteotomy for correction of bony deformity, osteotomy of femur, pelvic osteotomy, reduction of hip dislocation, release of contracture of hip or knee joint, spinal fusion and corrective osteotomies for scoliosis. Spina bifida patients are at higher risk of postoperative complications such as wound infection, delayed union or malunion, skin breakdowns and post-immobilization fractires. For post-surgical imobilisation custom-molded total body splint should be used and spica total body cast should be avoided [11].
Measures of muscle strenght are key for surgical management of orthopedic patients [38]. Better functional effect in patients with spina bifida is a result of better understanding of impact of radiologically diagnosed deformities on functional effect within last decades and their earlier treatment as a prevention of deterioration [11].
Due to present paraparesis in almost all cases, patient usually need mobility aids, such as: crutches, braces, walkers or even wheelchair at least for some time during growth. These mobility aids together with regular physiotherapy can help the child to become more independent. For daily functioning some aids could be used such as walking frames, commode chairs and bath chairs.
According to functional mobility ambulatory outcome could be:
Various factors affect ability to ambulate, most important of those are: level of neurological impairment, hip deformity, scoliosis, foot and ankle deformity, age and presence of obesity [11].
Almost all patients with severe forms of spinal dysraphism with exception of some patients with low sacral lesions will require use of orthoses in ambulation from indications, such as maintanance of alignment, prevention of deformity, correction of flexible deformity, facilitation of independent mobility and protection of insensitive limb.
In children with defect in thoracic and high-lumbar regions around age of 12 months if child controls head and neck position, usually standing frame is prescribed, later hip-knee-ankle-foot orthosis and reciprocating gait orthosis.
Patients with low-lumbar and sacral spinal dysrahpism usually require solid ankle-foot orthosis as it substitues for weak or absent ankle plantar flexors and dorsiflexors. Use of forearm crutches should be considered as well, as these patients often display weakness of hip extensors and abductors. Patients with internal or external rotational deformity can benefit from ankle-foot orthosis with twister cables. Also knee-ankle-foot orthosis can be used in patients with excessive valgus stress at the knee joint who are too young for correctional osteotomy.
Skin problems are very common in patients suffering from spina bifida [50]. As the skin sensitivity is affected in children and adults born with open spina bifida they are more likely to develop various skin problems. Blisters, soles, calluses and burns on lower extremities are frequent. When found late this skin problems can lead to serious problems of complicated healing.
The most common site of pressure sores are sacrum, ischial tuberosity, greater trochanter and feet. Severe complication of skin breakdown and pressure sores is osteomyelitis of the underlying bone. When wound does not heal with appropriate soft tissue care, underlying deep infection must be suspected and diagnosed by laboratory and radiograph findings. Antibiotic treatment is indicated, in more severe cases also surgical debridement. Last therapeutical opportunity in severe non-healing deep wounds causing sepsis is amputation with preservation as much lenght of the extremity as possible [49].
Parents and caregives need to prevent bed sores – avoid lying on one side too long, prevent sun burns and regularly control skin of back and lower extremities at least once a day. In case of new orthosis even more often. In older children it is necessary to control if the shoes fit properly. Barefoot walking should be avoided, especially on rough and hot surfaces. Self-adhesive foam pads can be used over pressure points [49].
Interventions of plastic surgeon within first year of life are mostly skin flaps and skin grafts associated with spinal closure. Need for surgery due to complications of wound healing is increasing with age.
In case of more severe bad healing wounds there is sometimes necessary to perform surgical debridement of skin wound, incision and drainage of abscess, skin flap operations, flap grafts, skin grafting, reduction of callus and revisions of skin scars [38].
Because of nerve damage patients born with open spina bifida defect suffer from sexual dysfunction in adolescence and adulthood. This might affect their sexual life. But most of spina bifida patients are fertile and are able to have children. Women born with open spina bifida should plan their pregnancy and are recommended to take 4 mg of folic acid a day (normal dose is 400 mcg) a month prior to conception and during early stages of pregnancy.
Patients with spina bifida affecting mobility have higher risk of developing components of metabolic syndrome in younger age due to low physical activity. They often suffer from abdominal obesity, insulin resistance or dyslipidemia with its metabolic and vascular complications [51]. People with physical disabilities spend less time performing physical activities compared to their nondisabled peers [52]. Consequences of a sedentary lifestyle include physical deconditioning [53]. Physical exercise can improve metabolic dysfunction [51].
Overweight, obesity, high BMI, high waist circumference and percentage of body fat are more prevalent in patients with spina bifida and they also have reduced aerobic fitness and muscle strenght [54]. Metabolic syndrome is more prevalent in spina bifida patients compared to nondisabled controls. They often display high levels of VLDL and overall cholesterol, triglycerides and low HDL, suffer from hypertension and insulin resistance [55].
Arterial diameters in these patients are reduced and sheer stress on the vascular wall is increased what predicts endothelial dysfunction [51].
Patients with spina bifida often have post-operative complications, mainly infectious complications – wound and urinary infections, that require antibiotic therapy. According to frequent latex allergy in these patients, they should be operated and treated only in latex-free gloves in order to avoid severe anaphylactic reaction [11].
Special care must be taken to avoid pressure sores as due to lack of sensitivity and frequent hypomobility these patients are at higher risk of developing pressure sores and other wounds. All skin lesions in spina bifida have higher risk of getting infected.
Children with spina bifida often display precocious puberty and need to be examined by endocrinologist.
Due to frequent joint contractions, post-surgical immobilization and worse mobility these patients often suffer from osteoporosis and they are at higher risk of pathologic fractures. These fractures are more common in patients with higher level of neurological impairment due to more severe neurological deficit and this risk rises with age [11].
As the effect of folic acid intake is known for its role in decreasing incidence of neural tube defects it has a great potential in prevention. Mandatory folic acid fortification has significantly higher effect on increasing serum folate levels that just recommendation [56]. Supplementation of folic acid starting at least one month prior conception and continuing through the first trimester of gravidity reduces the risk of neural tube defects. Because of the fact that many women discover their pregnancy within second months, what is late for prevention it is recommended for women in childbearing age to have long time daily supplement of 400 mcg of folic acid. Some foods such as: enriched bread, rice, cereals and pasta are fortified with 400 mcg of folic acid per serving. Except this also consumption of foods that are naturally rich in folate is recommended, such as: milk, egg yolks, avocado, citrus fruits and juices, beans and peas and dark green vegetables, as broccoli and spinach are.
Because of only available prevention of neural tube defects, that is also cheap and accessible, planned pregnancy is the best option. It is advised for women who plan pregnancy or are likely to get pregnant to have daily intake of 400 to 800 mcg of folic acid.
Fetal absorption of folic acid from mothers intake is better than absorption of folate from food. Combined with fact that most of the people do not have recommended intake of folate from diet rationale for intake of synthetic folic acid is high. There is an evidence, that proper intake of folic acid could lead to diminishing risk of also other developmental disorders – such as cleft lip, cleft palate and also congenital cardial defects. Women who were born with neural tube defect themselves or have anamnesis of birth or pregnancy with fetus with neural tube defect should take higher doses of folic acid. The same applies for women with anti-seizure medication.
Management of treatment of severe forms of spina bifida that require surgical intervention begins just after diagnose. Prenatally diagnosed cases need to be referred to tertiary unit for further management. Usually first more detailed imagings are performed, genetic examination and screening for other congenital anomalies. Mothers with fetuses with spina bifida are referred to multidisciplinary team for pregnancy follow up, choosing the therapeutical strategy and timing of treatment in consensus with decision of instructed parents [23].
All pregnancies with fetuses with more severe form of spina bifida are followed up in tertiary centres. Birth is usually scheduled from 38th week of gestation [23]. Babies with myelomeningocele tend to be in breech position. Breech position, cystic form of spinal defect or big sac are indications for ceasarian section. This type of delivery is also performed for its timing during the day when all specialists are available and newborn can be immediately treated.
Directly after the birth newborn with open spinal defect is admitted to newborn intensive care unit and strictly monitored and stabilized. Newborns need to be properly examined for presence of other congenital defects or birth trauma, as well as evaluation of severity of spina bifida symptoms.
Examination of the newborn should include identification of level of paralysis of each extremity, presence of visible signs of spinal defect (skin lesion, visible sac), deformities of extremities (such a clubfoot, hip or knee contraction or dislocation) [11].
If newborn with open spinal defect did not underwent fetal surgery, postnatal surgery is indicated as soon as possible – just after stabilization of vital functions within the first days after delivery [46, 57]. Usually closure of spinal defect is indicated first with subsequent monitoring of ventricle size and symptoms of intracranial hypertension or symptoms of decompensation of Chiari malformation. Newborns who present with severe symptoms of intracranial hypertension at birth require shunt placement immediately.
Infants with stable slight ventricullomegaly with normal neurological status who are indicated for observation for hydrocephalus need to be routinely controlled. Clinical examination consists of evaluation of neurological status as well as regular frequent measurements of head circumference, palpation of fontanelle and cranial sutures. Also radiological controls are necessary. Best accessible is routine imaging of brain ventricles via head ultrasound and in special circumstances also use of magnetic resonance imaging.
After stabile postsurgical course with stable slight ventriculomegally and physiological neurological status with no symptoms of active hydrocephalus and decompensated Chiari II malformation, infant can be discharged to home with indication for frequent outpatient multidisciplinary evaluations. Weekly, later biweekly evaluations by neurosurgeon are necessary with active detection of symptoms of active hydrocephalus and decompensation of Chiari malformation. In some cases growth of head circumference will stabilize and follow normal growth curve and mild to moderate ventriculomegally will be stable.
Criteria for later indication of ventriculo-peritoneal shunting are onset of symptoms of intracranial hypertension (irritability, headache, somnolency, troubles with feeding, vomiting, bulging fontanelle, fixed downward gaze, „sun-setting “eye movements, bradycardia and sudden progress of head circumference), radiological finding of rapidly enlarged ventricles (via ultrasonography or MR imaging) and also worsening of Chiari II symptoms (abnormal eye movements, swallowing problems, apnoea or stridor). If these symptoms are present, infant should be immediately indicated for ventriculo-peritoneal drainage [58].
Children with spina bifida, mostly open forms require very close follow up and observation for all possible problems. Most of the complications could be solved or at least properly managed to maintain adequate life quality. According to study with 50 years follow up 50% of patients born with myelomeningocele and surgically treated after birth were able to walk 50 m at the age of 9 years and 27% at the age of 50 years. Mobility decreases in time partially due to obesity and deterioration of general health conditions [22].
The role of
As most of patients with spina bifida thanks to advances in treatment reach adulthood there is a need for transition of health care to adult specialists [19]. Because the prevalence of obesity and metabolic syndrome is higher in these patients there is a need for careful monitoring of metabolic complications also in young patients [51].
Children and later also adult patients with diagnosis of open spina bifida after initial treatment need special treatment and follow up from various specialists:
This specialist should be part of the multidisciplinary team and survey the overall development of the child and indicate further examination of specialist when needed.
Child needs to be regularly controlled by neurosurgeon to evaluate proper function of ventriculoperitoneal drainage. Especially children with mild ventriculomegaly without symptoms of active hydrocephalus need regular controls so that in case symptoms develop could child immediately undergo surgery. Around half of the patients with open spinal defect undergoes other neurosurgical intervention in addition to initial spinal closure and half of these additional surgeries occur before 1 year of age – most common procedures are spinal closure, ventriculo-peritoneal shunt placement or shunt revision [38].
All children after open neural tube defect with subsequent lasting neurological impairment need to be under supervision of experienced pediatric neurologist who controls motor functions, indexes progression of motor functions. In case of worsening of neurological functions there is a need for imaging – usually MR imaging for active screening of possible complications, such as tethered cord syndrome or decompensation of hydrocephalus, malfunction of drainage.
Each child after open spina bifida repair needs to be regularly evaluated by pediatric urologist. This evaluation consists of examination of kidney functions and urine derivation. Blood tests together with ultrasound and X-rays are often used, also other imaging techniques and urodynamic evaluation. Aim of this follow up is active screening for urological complications to prevent further damage. Since the survival of spina bifida patients has changed during years and most of patients live into adulthood there is also a need for management and follow up subsequently by adult urologist [24].
Sexual health and education
Gastroenterologist controls
The role of orthopedics is to monitor and treat deformities, follow up after early treatment, also monitor spinal balance and deformity and help in evaluation of motor function. The follow-up periodic orthopedical examination should include assessment of motor functions, sensitivity, range of motion, spinal deformity and integrity of skin. Early treatment of deformity by casting, bracing and surgical treatment may prevent fixed bony deformity [49].
Orthotics should periodically control the motor and mobility aids to ensure that orthoses are appropriate, in good shape and do not cause any pressure points on the skin [11].
Special rehabilitations are necessary for children with open neural tube defect to increase movement, flexibility and muscle strenght. Skilled physical therapist plays an important role in the early detection of subtle muscle imbalance which could lead to severe deformity if left untreated. Therapist should perform serial manual muscle testing as a part of the routine at least annual examination [49].
There is a need for close cooperation between physical therapist and parents and caregivers to teach them basics of rehabilitation to practice it at home. For older children summer camps and recreational facilities for disabled are possibility to improve their physical activity. Some patients are also able to participate successfully in sports and should do so [51]. Basic physical strategies focus on muscle strengthening exercises, orthopedic supports and assistive devices meant to aid ambulation and posture control. Lifting weights is recommended for adolescents and adults to maintain condition of muscles. As patients have limited use of lower extremities, exercise has to rely on upper extremities and trunk. There is a potential for physical therapeutist to cooperate with local sport clubs and fitness centres to develop activity programs and supervise them [51]. Physical activities offer possibility to prevent other problems, such as obesity, metabolic problems or depression [52].
Spina bifida patients have to face a lot of barriers to lead conventional life. As a result of physical disability, life-style, their environment and combination of these factors these patients are at higher risk of depressive disorder [60]. Teenagers, adolescents and also adults might feel isolated from their peers and have low self-esteem. They might feel worried, stressed, anxious or sad. If the feelings last for long time they might lead to depression. Occupational therapy and psychotherapy might help, as well as physical exercise. Daily physical activity is positively correlated with quality of life [51]. In serious cases consultation of psychiatrist might be necessary.
Many of children affected by open spina bifida, mostly those with implanted shunts to treat hydrocephalus have problems with concentration, hyperactivity, work slowly.
Many children born with open spina bifida do not have problems at school. Children that present with some neurocognitive problems and special educational problems such as dyslexia or dyscalculia might profit from special education. Cognitive problems are more common in children who have hydrocephalus. Children at school need individualized educational plan with assistance. This plan is a result of cooperation of parents, teachers, school psychologist, school nurse and physical education teacher.
Patients with less severe forms of spinal dysraphism and lower level of spinal defect tend to reach higher educational effect. This is partially due to better mobility of these patients but very important factor is also bowel continence degree. Patients with bowel continence or sufficient incontinence control usually reach higher educational degrees, have higher employment and insurance status and are more likely to be independent, as educational status and employment are major determinants of health insurance status in adults [19]. Urinary incontinence does not have that impact on educational status as bowel incontinence. Bladder incontinence (particularly low-volume) has usually lower impact on overall life quality, educational status and employment than bowel incontinence [24, 48].
There is an urgent need for adequate social contact of these children. Participation in sports and physical activity with peers improves social contact and life quality. Families can also contact Intervention programs for patients with spina bifida that work in many countries. Children with spina bifida meet a lot of barriers in acces to various activities and have to rely on adults to organize and supervise activities [51].
Proper diet is important to avoid complications mainly according to bowel function. With a help of dietitian can parents and caregivers find the best dietetic tools for each individual child. Addition of dietary fiber can help to maintain regular stool. Enough water intake is important in prevention of obstipation and urinary infection. Proper dietary intake together with physical exercise helps to prevent overweight and obesity that could lead to metabolic syndrome and cause later metabolic and cardiovascular complications [51].
In the 1950s the survival rate of patients with most severe form of spina bifida – myelomeningocele was about 10% [61]. In the last decades, the multidisciplinary approach to care of spina bifida patients, has significantly improved patients outcomes. Recently, thanks to advances in medical and supporting treatment almost all children born with spina bifida survive into adulthood. There has been increase in life expectancy and gain in the quality of life of spina bifida patients but also of their caregiver’s life [43] But unfortunately, neurological outcomes of spina bifida patients did not change significantly over the years of medical progress [44]. That is mostly due to fact, that the neurological impairment is mostly caused by primary damage from congenital spinal abnormality and also secondary due to exposure of nervous tissue to amniotic fluid [21].
Important factor for prognosis is ability to attain early ambulation. It provides physiological and psychological benefits even if the child will later become a sitter. Also patients with high-level spina bifida who participated in walking program have lower risk of fractures, pressure sores are more independent than those who had been prescribed wheelchair early [11].
According to long term follow up study median survival of myelomeningocele patients was 50 years. 34% of patients had died before 5 years of age. Most common cause of death was cardiorespiratory, neurological and urological complications, then hydrocephalus and infections of central nervous system, other causes are significantly less frequent [22].
Most of the survivors had IQ over 80 points. Only one fifth was fully continent without need of incontinency aids. One third of patients recorded chronic back pain.
Percentage of patients living independently on their caregivers raises in time after age of 25. Independent living at the age of 50 years is more common in patients without anamnesis of intracranial hypertension and without cerebrospinal fluid shunt revisions [22]. Increase of independent living with age might be partially due to fact that longer survival is associated with less severe primary defect.
Spina bifida occulta is usually an incidental finding with no effect on life quality. On the other hand, the most severe form myelomeningocele is a complex problem. Due to many complications threatening patient with this complex health issue, there is an essential need for multidisciplinary approach to monitor, prevent and treat possible complications that have impact on functionality, life quality and survival. Parents and close caregivers have crucial role in whole mutidisciplinary team. They need to know how to manage child’s situation and give child social and emotional support. Raising the child in caring environment could help to develop into young adult who is able to fight basic life issues: to care about his own health issues, going to school, working, finding and using transportation, living in their own and having a healthy relationship and family.
Most newborn infants successfully transition from fetal to neonatal life without any help [1]. However, approximately 10–20% of newborns (13–26 million worldwide) need some degree of respiratory support at birth [2, 3, 4], which remains the most critical step of neonatal resuscitation. Furthermore, an estimated 0.1% of term infants and up to 15% of preterm infants (2–3 million worldwide) requires extensive cardiopulmonary resuscitation (CPR) at birth, which entails chest compressions (CC) and 100% oxygen with or without administration of epinephrine [5, 6, 7, 8, 9]. Despite receiving CPR, approximately 1 million newborns die annually worldwide. Even with successful resuscitation, infants receiving extensive CPR in the delivery room have a high incidence of mortality (40–80%) and neurologic morbidity (e.g. 57% hypoxic–ischemic encephalopathy and seizures) [5, 6, 9]. Therefore, resuscitation techniques require further refinement to provide better outcomes. The guidelines for neonatal resuscitation recommended by the American Academy of Pediatrics/American Heart Association Neonatal Resuscitation Program [2, 3, 4] are based, in part, on the recognition that the cause of cardiovascular collapse in most newborns is asphyxia. However, in many cases the guidelines rely on data from studies in the adult population and extrapolate it to the neonatal population. Such data may not be entirely applicable to the neonatal population, because the most common cause of cardiovascular collapse in the adult population is primary cardiac compromise/ventricular fibrillation, not asphyxia. Therefore it is imperative that pre-clinical studies with appropriate animal models are carried out to determine the optimal resuscitation techniques before they are translated into the delivery room for newborn infants.
Asphyxia at birth, also known as perinatal asphyxia, is the most common reason that newborn infants fail to make a successful transition to ex-utero life [10]. Asphyxia may occur from several perinatal events, such as failure of placental gas exchange prior to delivery (e.g. placental abruption, uterine rupture, umbilical cord prolapse, chorioamnionitis), or deficient pulmonary gas exchange immediately after birth (e.g. apnea, airway obstruction, respiratory distress syndrome) [10]. Asphyxia is a condition of impaired gas exchange with simultaneous hypoxia and hypercapnia, leading to a mixed metabolic and respiratory acidosis [10]; it depresses myocardial function leading to cardiogenic shock, pulmonary hypertension, mesenteric reperfusion, acute renal failure, and ultimately cardiac arrest. The cascade of hypoxic–ischemic insults results in dysfunction of one or more organ systems in over 80% of asphyxiated newborn infants [11], leading to significant mortality and long-term morbidity. Newborns affected by perinatal asphyxia often present with an inadequate heart rate that does not respond to positive pressure ventilation (PPV). This is due to depressed myocardial function, vasodilation, and very low diastolic blood pressures through which the heart is unable to efficiently contract. Ineffective pumping of enough blood to the lungs inhibits the exchange and consumption of oxygen that is being delivered via PPV [10]. This inevitably leads to the need for CC to mechanically pump the blood through the heart until the myocardium is adequately oxygenated to resume spontaneous contraction and blood circulation [10].
Heart rate (HR) is the most important clinical indicator to evaluate the status of compromised newborns and to guide resuscitation efforts in the delivery room [3]. An increase in the newborn’s HR remains the most reliable indicator of adequate ventilation [3]. Until recently, HR assessment in the newborn was achieved via (i) palpation of the umbilical cord, (ii) auscultation of the precordium, and/or (iii) pulse oximetry [12]. In 2015, the neonatal resuscitation guidelines were updated to integrate the use of electrocardiography (ECG) as a tool for HR assessment immediately after birth [2, 3, 4]. This recommendation was based on observational data and small randomized controlled trials showing that ECG displays reliable HR faster than pulse oximetry [2, 3, 4]. However, the use of ECG does not replace the need for pulse oximetry, but rather compliment it.
The current neonatal resuscitation guidelines recommend initiation of PPV if the HR is below 100 beats per minute (bpm). If HR does not increase in response to PPV, several ventilation corrective steps are recommended: (i) check the seal of the face mask, (ii) reposition the neonate’s head in “sniffing” position, (iii) suction obstructing secretions, (iv) open the mouth to decrease resistance to gas flow, (v) increase the peak inflating pressure, and (vi) establish an advanced airway (intubate or use a laryngeal mask device). If the above ventilation corrective steps fail to improve HR and it decreases to below 60 bpm, CC and 100% oxygen are recommended. If HR persists below 60 bpm despite CC and 100% oxygen, administration of intravenous epinephrine is recommended at a dose of 0.01–0.03 mg/kg. If epinephrine administration is required prior to the establishment of intravenous access, it can be administered endotracheally at a higher dose of 0.05–0.1 mg/kg. The currently recommended technique of delivering CC to a neonate is using a coordinated 3:1 compression-to-ventilation ratio (3:1 C:V). This approach is comprised of 90 CC and 30 ventilation inflations per minute, with a pause after every third CC to deliver one effective ventilation. This technique achieves approximately 120 events per minute. The CC are delivered on the lower third of the sternum and to a depth of approximately one-third of the anterior–posterior chest diameter, and the 2-thumb-encircling hands technique is the preferred method. However the chest compression ratio recommendation is based more on expert opinion and consensus rather than strong scientific evidence, since there is currently very-low-quality evidence to suggest otherwise, according to the guidelines [4].
Pulseless electrical activity (PEA) is a form of cardiac arrest characterized by cardiac electrical activity, detected by ECG, but with the absence of a detectable pulse [13]. Although PEA is a commonly seen cardiac rhythm in adult and pediatric resuscitations (referred to as a “nonshockable rhythm”), occurring in approximately 32 and 24% of cardiac arrests, respectively [14], its occurrence in neonatal resuscitation is unusual and not widely recognized. In response to the inclusion of ECG in the 2015 neonatal resuscitation guidelines, there has been a rise in awareness of PEA in neonatal resuscitation. ECG displaying PEA could falsely mislead health care providers into overestimating the HR and delay necessary resuscitation techniques. It is possible that PEA may be common in asphyxiated newborns but has been undetected in the clinical setting prior to the recent use of ECG in the delivery room. Recent case reports have raised concerns over the reliability of ECG use during neonatal resuscitation, and the detection of PEA has been cited as a potential limitation of ECG use to guide delivery room resuscitation [15, 16]. Data from studies in the pediatric population indicate decreased survival following resuscitation with PEA events [17, 18], however this is inconsistent throughout the literature. Recent case studies in newborn infants presenting with cardiac arrest with PEA rhythm, as indicated on ECG [15, 16], suggest dire outcomes. Further studies (animal and prospective clinical) are needed to determine the cause and actual incidence of PEA in order to improve the survival of newborns experiencing PEA in the delivery room.
Herein we describe an experimental animal model from our research laboratory in newborn piglets that simulates neonatal hypoxia-asphyxia. Using this animal model, we are able to examine the systemic and regional hemodynamic changes during hypoxia-asphyxia, resuscitation interventions, reoxygenation, and the recovery process. The described experimental animal model is a non-survival acute procedure in neonatal pigs, aged between 1 and 3 days old and weighing approximately 1.5–2 kg. The approximate duration of the procedure is between six to eight hours and can be divided into the following sections: (i) anesthesia and surgical instrumentation, (ii) monitoring and stabilization, (iii) hypoxia and asphyxia, (iv) resuscitation intervention, and (v) reoxygenation and recovery.
Surgical procedures enable the establishment of mechanical ventilation, arterial and central venous access, and placement of catheters and flow probes for continuously monitoring intravascular pressures and blood flow across the common carotid artery, respectively. Anesthesia is induced using 5% inhaled isoflurane in 100% oxygen (delivered via a nose cone), and is then maintained at 2–3% with fine adjustment by 0.5% as appropriate, depending on the condition of the piglet.
Following induction of anesthesia, an incision is made in the right groin and the right femoral artery and vein are exposed. An area of approximately 1 cm is dissected around each of the vessels, which are then isolated by threading two lengths of suture ties under each vessel. The vessel is ligated distally using a suture tie, a small cut is made in the vessel wall, and then an Argyle catheter (3.5 or 5 French, Covidien, Mansfield, MA) is inserted into the vessel. A double-lumen catheter is used for the femoral vein and is inserted to 15 cm so it is placed close to the right atrium. The venous catheter can be used for medication and maintenance fluid infusions as well as continuous central venous pressure measurement. A single-lumen catheter is used for the femoral artery and is inserted to 5 cm so it is placed at the infra-renal aorta. The single-lumen arterial catheter can be used for continuous mean arterial pressure measurement and blood sampling. The groin incision is then sutured closed. Once vascular access has been established, the inhaled anesthesia can be switched to intravenous anesthesia using morphine and propofol infusions via the venous catheter. This is done after the piglet has been connected to the ventilator machine (see below).
The piglet is then intubated via tracheostomy. A horizontal incision is made at the neck, the trachea is dissected and exposed, and two lengths of suture ties are threaded around the trachea. An endotracheal tube (3.0 or 3.5) is inserted, connected to a ventilator and pressure-controlled ventilation (Acutronic Fabian HFO; Hirzel, Switzerland) is commenced at a respiratory rate of 16–20 breaths/min and pressures of 20/5 cm H2O. Oxygen saturation is kept within 90–100% by adjusting the fraction of inspired oxygen between 21 and 30%.
The right common carotid artery is dissected and exposed, and one length of suture tie is threaded around to isolate the artery. A real-time ultrasonic flow probe (2 mm; Transonic Systems, Ithaca, New York, USA) is placed around the artery and secured, and ultrasonic gel is placed between the flow probe and artery to allow for optimal signal transduction. The flow probe provides continuous carotid blood flow (CBF) measurement. The neck incision is sutured closed. Figure 1 shows the surgical instrumentation of the piglet.
Schematic of neonatal hypoxia-asphyxia porcine model (copyright
A pulse oximeter is placed on the piglet’s left hind limb for measuring percutaneous oxygen saturation. Continuous monitoring of the HR is achieved by attaching a 3-lead ECG to the piglet’s skin (continuously measured and recorded with Hewlett Packard 78833B monitor, Hewlett Packard, Palo Alto, California, USA). Generally, baseline HR is between 150 and 200 bpm. Glucose level and hydration is maintained with an intravenous infusion of 5% dextrose at 10 mL/kg/hour. The piglet’s body temperature is maintained at 38–40°C using an overhead warmer and a heating pad. During the experiment, anesthesia is maintained with intravenous propofol (5-10 mg/kg/hour) and morphine (0.1 mg/kg/hour). Additional doses of propofol (1–2 mg/kg) and morphine (0.05–0.1 mg/kg) are given as needed. The anesthetic state of the piglet is regularly monitored throughout the entire experiment using various criteria: neurological (body movements), behavioral (agitation), cardiovascular (tachycardia and hypertension), and respiratory (tachypnoea). The piglet is allowed to stabilize for 1 hour post surgery before the hypoxia-asphyxia protocol is commenced. Figure 1 shows the placement of the monitoring devices on the piglet’s body.
The piglet is exposed to severe hypoxemia, which is induced via 30–60 min of normocapnic alveolar hypoxia. The piglet is ventilated with low inspired oxygen concentration delivered by increasing the inhaled concentration of nitrogen gas to induce hypoxemia. The inspired oxygen concentration is adjusted between 10 and 15% to obtain arterial oxygen saturations (SaO2) of 30–40% and partial pressure of oxygen (PaO2) of 20–40 mmHg. Arterial blood sampling is conducted to assess the partial pressure of carbon dioxide (PaCO2) and the ventilator rate is then adjusted accordingly.
Hypoxia is followed by asphyxia, which is achieved by disconnecting the ventilator and clamping the endotracheal tube. Asphyxia can be conducted until either bradycardia, asystole or PEA (cardiac arrest). In this experimental animal model, bradycardia is defined as 25% of baseline heart rate, and asystole or PEA is defined as zero CBF and confirmed by auscultation of no HR. Following hypoxia-asphyxia, the resuscitation intervention protocol is commenced.
The primary goal of this experimental animal model is to provide a platform to investigate various resuscitation interventions in a pre-clinical scenario. Although the exact details of resuscitation interventions vary, they are predominantly comprised of the following elements: PPV (performed with a Neopuff T-Piece, Fisher and Paykel, Auckland, New Zealand), CC, ventilations, oxygen, and epinephrine administration. The ultimate outcome of the resuscitation intervention is to achieve return of spontaneous circulation (ROSC) in a timely manner, defined as an unassisted HR ≥100 bpm for at least 15 s. Section 8 summarizes the various resuscitation interventions published from our research group using this experimental animal model.
Following the resuscitation intervention and ROSC, the piglet is then reconnected to the ventilator with 100% oxygen briefly, and weaned down to 21% oxygen for the 4-hour post-resuscitation recovery period. At the end of the recovery period, the piglet is euthanized with an intravenous overdose of sodium pentobarbital (120 mg/kg). Tissue samples are collected as required.
Using our porcine model of neonatal hypoxia-asphyxia, we are able to describe an increasingly important clinical situation in the laboratory setting. Recent studies from our group have identified the presence of PEA rhythms in nearly half of neonatal pigs that were subjected to hypoxia-asphyxia in animal models of neonatal resuscitation [19, 20, 21]. In the study by Patel et al., 43% of piglets (23/54) had no CBF or HR on auscultation but had a HR of 15–80 bpm displayed on ECG, indicating PEA rhythm [20]. Luong et al. reported that 49% of piglets (22/45) presented with PEA rhythms, as indicated by no CBF or HR on auscultation but a HR of 17–75 bpm was displayed on ECG [19]. Solevag et al. also reported that 43% of piglets (9/21) presented with PEA rhythm on ECG, as confirmed by zero CBF and no audible HR/pulse; however, only 56% of piglets with PEA rhythms achieved ROSC compared to 100% of piglets with non-PEA rhythms (p = 0.02) [21]. Furthermore, survival to 4-hours post-ROSC occurred in only 33% of PEA piglets versus 58% of non-PEA piglets [21]. These studies indicate that cardiac arrest in the presence of a non-perfusing cardiac rhythm is common in asphyxiated neonatal piglets. Furthermore, this animal data is in agreeance with clinical observations of reduced CPR success in the presence of PEA in the delivery room in newborn infants [15, 16].
Studies from other research groups have also reported on the presence of PEA rhythms in their porcine model [22, 23]. It is important to note, however, that these studies were conducted in older piglets (2-month old “infant/pediatric” pigs) and were subjected to asphyxial cardiac arrest without the preceding hypoxia period. In the study by Lopez-Herce et al., 62% of piglets (44/71) had a PEA rhythm at the time of cardiac arrest [23]. However, there was no significant difference in the rate of ROSC between piglets with PEA rhythm (43%; 19/44) and piglets with non-PEA rhythm (30%; 7/23). Another study by the same research group, Gonzalez et al., also reported the presence of PEA rhythm at the time of cardiac arrest: 45% of piglets (22/49) [22]. Interestingly, the rate of ROSC was greater in piglets with PEA rhythm (45%; 10/22) versus non-PEA rhythm piglets (20%; 4/20) (p = 0.037).
The apparent discordance in the rate of ROSC post-PEA event between neonatal piglets [21] and pediatric piglets [22, 23] highlights the need for strong scientific evidence obtained from appropriate neonatal models to further our knowledge of delivery room resuscitation, rather than extrapolating data gained from the pediatric or adult populations. The percentages of PEA in our above-described neonatal model indicate relative consistency and can therefore be generalizable as a methodology. In this neonatal animal model, PEA is confirmed by electrical activity recorded on ECG in combination with no HR/pulse detected by auscultation and pulse oximetry and zero CBF. This animal model is beneficial for research directed at the management of PEA in newborns. Due to the increased awareness of PEA events in newborn infants, it is necessary to further investigate specifically tailored resuscitation techniques or changes in the resuscitation guideline algorithms to improve their survival. This translational model will therefore serve as a valuable tool to bridge the knowledge gap and improve the outcome of newborns that experience PEA in the delivery room.
Owing to its many advantages, the clinically relevant porcine model of neonatal hypoxia-asphyxia has provided a platform to extensively investigate neonatal resuscitation. The newborn piglet is equivalent to a human infant at 36–38 weeks of gestational age, and has a comparable size and weight (1.5–2 kg body weight). This allows for relatively easy instrumentation to invasively monitor hemodynamic and physiological measurements, such as blood pressure and blood gases, as well as the ability to monitor the degree of hypoxia-asphyxia and reoxygenation in the recovery phase. The large size of this animal model (compared to smaller rodent models) allows the repeated collection of biological samples (plasma, whole blood) during the experimental period for biochemical assays. The piglet’s cerebral metabolic data and many of the body systems, including cerebrovascular and cardiovascular systems, are also comparable to the human counterparts. This allows for better interpretation of the findings and makes it an exceptional animal model to study resuscitation interventions. The porcine model of neonatal hypoxia-asphyxia closely simulates delivery room events, with the gradual onset of severe hypoxia-asphyxia leading to cardiac arrest. Bradycardia or asystole (cardiac arrest) in newborn infants is usually caused by hypoxia/asphyxia, rather than primary cardiac compromise/ventricular fibrillation observed in adult patients. Furthermore, using our newborn piglet model, we are able to describe an increasingly important clinical situation in the laboratory setting – PEA, which is not well described in newborns in the delivery room. However, the asphyxia model uses piglets that have already undergone the transition from fetal to neonatal circulation and have cleared their lung fluid, which may present as a limitation. Furthermore, our model requires piglets to be intubated with a tightly sealed endotracheal tube to prevent any endotracheal tube leak. This may not occur in the delivery room where infants are either intubated (larynx bypassed, leak present) or receive respiratory support via a facemask, resulting in the possibility of airway obstruction or mask leaks. Nevertheless, many of its advantages make up for the few limitations of the model.
The porcine model of neonatal hypoxia-asphyxia has proven to be an invaluable tool through which new resuscitation techniques can be studied pre-clinically. It has also proven to be a crucial element in increasing our understanding of physiological and pharmacological changes surrounding neonatal resuscitation. Below is a summary of studies that have utilized the model to gain further knowledge in various aspects of neonatal resuscitation. Knowledge gained from the below described studies are key in shaping the future neonatal resuscitation guidelines [24, 25].
The current neonatal resuscitation guidelines and the previous guidelines in 2010 [2, 3, 4, 26] recommend using a 3:1 C:V ratio when CC are needed, however these recommendations are not based on strong scientific evidence and the most effective C:V ratio in newborns remains controversial. Using our porcine model, Schmölzer et al. investigated an alternative approach to providing ventilation during CPR in the means of sustained inflations (SI) [27]. Rather than the standard coordinated 3:1 C:V technique, Schmölzer et al. proposed that SI during CC would passively deliver an adequate tidal volume into the lungs and improve survival. SI was delivered with a peak inflating pressure of 30 cmH2O for duration of 30 s. During the SI, CC was delivered at a rate of 120/min; SI was interrupted after 30 s for 1 s before a further 30 s of SI was provided [27]. The results showed that piglets resuscitated with SI during CC not only achieved ROSC faster than piglets resuscitated with the standard 3:1 C:V technique, but also had improved hemodynamic recovery and survival [27]. Following that study, Li et al. investigated the optimal rate of CC during SI by comparing CC rates of 90/min and 120/min [28]. Both groups had a similar time to ROSC, survival rates, and hemodynamic and respiratory parameters during CPR, and the hemodynamic recovery in the subsequent 4-hours was also similar in both groups. This leads the authors to suggest that resuscitation with a CC rate of 120/min during SI did not show a significant advantage compared to 90/min and higher CC rates are not necessarily an advantage [28]. To assure this suggestion, another study by Li et al. compared SI with CC at a rate of 90/min to the standard 3:1 C:V technique [29]. Piglets resuscitated with SI during CC at 90/min had significantly improved time to ROSC and also a reduced requirement for 100% oxygen and improved respiratory parameters compared to piglets resuscitated with 3:1 C:V [29]. Mustofa et al. investigated the optimal length of SI during CC by comparing resuscitation with SI duration of either 20 s or 60 s [30]. Using SI duration of 60 s resulted in a similar time to ROSC as SI duration of 20 s, as well as similar survival rate and hemodynamic recovery [30]. Furthermore, Mustofa et al. showed no significant differences in lung and brain pro-inflammatory cytokine concentrations between the SI groups and the 3:1 C:V group, suggesting that the SI technique does not promote more acute brain and lung injuries that the currently practiced technique of 3:1 C:V [30].
Using the porcine model of neonatal hypoxia-asphyxia, Schmölzer et al. investigated a different approach to neonatal resuscitation with asynchronous ventilation during continuous CC; the rationale being that giving continuous CC without pausing for ventilation (as with 3:1 C:V) may avoid interruption in coronary perfusion and may improve minute ventilation during CPR [31]. Piglets were resuscitated with either the standard 3:1 C:V technique or the asynchronous ventilation technique, which delivered continuous CC at a rate of 90/min with asynchronous ventilation at a rate of 30 inflations/min [31]. Both groups had a similar time to ROSC, survival rates, epinephrine and oxygen administration, and hemodynamic and respiratory parameters during CPR; systemic and regional hemodynamic recovery in the subsequent 4-hour recovery period was also similar. This suggests that asynchronous ventilation during continuous CC is not more beneficial to the standard 3:1 C:V technique. In a following study, Patel et al. examined whether the outcome will improve by using different CC rates with asynchronous ventilation, namely 90/min, 100/min, and 120/min [32]. Even though rate and time to ROSC were similar between groups, increasing the CC rate to 120/min with asynchronous ventilation significantly improved hemodynamic recovery, as indicated by CBF, and cerebral and renal perfusion [32].
Current neonatal resuscitation guidelines recommend the use of 100% oxygen when CC are needed, however this is based on minimal evidence and 100% oxygen is also associated with increased oxidative stress [2, 3, 4, 33], and increased morbidity and mortality [34, 35]. Solevåg et al. examined the effect of using 21% oxygen (air) or 100% oxygen during resuscitation using either the 3:1 C:V technique or continuous CC with asynchronous ventilation (rate of 90/min) [36]. Time to achieve ROSC was similar between groups, however resuscitation with air was associated with a higher left ventricular stroke volume after ROSC and less myocardial oxidative stress compared to resuscitation with 100% oxygen [36]. This suggests that air during CC may reduce myocardial oxidative stress and improve cardiac function compared to 100% oxygen. However, the use of continuous CC with asynchronous ventilation in this study was less effective than the standard 3:1 C:V technique [36].
Pasquin et al. used the porcine model of neonatal hypoxia-asphyxia to examine different ratios of CC to ventilations; the standard 3:1 C:V technique was compared to a C:V ratio of 2:1 and 4:1 [37]. Time to ROSC, mortality, oxygen requirements, epinephrine administration, and hemodynamic recovery were similar between all groups, indicating no difference in the efficacy of various C:V ratios in asphyxial-induced cardiac arrest of neonatal piglets.
The purpose of inflations during CC is to deliver an adequate tidal volume to facilitate gas exchange [38], however limited information exists regarding tidal volume delivery during CC. Therefore, Li et al. examined the changes in tidal volume during CC and their effect on lung aeration in the porcine model of hypoxia-asphyxia [39]. Li et al. shows that when resuscitating using the SI with CC technique, passive lung ventilation/aeration can be achieved. In contrast, although use of the 3:1 C:V technique delivered tidal volume, it also resulted in a relative loss of tidal volume per 3:1 C:V cycle of up to 4.5 mL/kg [39]. This suggests that tidal volume delivery is greater when using SI with CC to resuscitate compared to the standard 3:1 C:V technique; this may lead to better alveolar oxygen delivery and lung aeration [39].
Using an objective method to evaluate recovery or predict the outcome of resuscitation may help decision-making during resuscitation. Therefore, Li et al. examined the temporal changes in end-tidal CO2 (ETCO2), volume of expired CO2 (VCO2), and the partial pressure of exhaled CO2 (PECO2) and their relationship with survivability and hemodynamic changes during CPR in the neonatal porcine model [40]. Li et al. reported that surviving piglets had significantly higher values of ETCO2, VCO2, and PECO2 during CPR compared to non-surviving piglets, suggesting that continuously monitoring ETCO2, VCO2, and PECO2 during CC has the potential to be a non-invasive method to indicate ROSC [40]. To further investigate if other parameters could be used as early outcome predictors after CPR, Solevåg et al. examined if cerebral and renal tissue oxygen saturation was different between surviving piglets and non-surviving piglets that were resuscitated after asphyxia-induced cardiac arrest [41]. The relationship of the tissue oxygen saturations with cardiac output, blood pressure, and biochemical variables was also examined [41]. No correlation between cardiac output or blood pressure and cerebral or renal tissue oxygen saturation was observed.
Espinoza et al. examined the changes in HR during adequate PPV following severe bradycardia in the porcine model of hypoxia-asphyxia [42]. The Neonatal Resuscitation Program (NRP) states that if adequate PPV is given for low HR, then the infant’s HR should increase within the first 15 s of PPV. However in contrast to the NRP, Espinoza et al. showed that adequate PPV does not increase HR within 15 s of ventilation in piglets with asphyxia-induced bradycardia; after 30 s of PPV only half of piglets had an increase in HR. This study challenges the current NRP statement and suggests that clinicians should not expect an increase in HR after 15 s of PPV if there is severe bradycardia [42].
Current neonatal resuscitation guidelines recommend the administration of intravenous epinephrine during if HR persists below 60 bpm despite CC and 100% oxygen [2, 3, 4]. However there is currently a lack of data evaluating the hemodynamic effects of epinephrine during neonatal resuscitation. Wagner et al. utilized the porcine model of hypoxia-asphyxia to examine hemodynamic changes after epinephrine administration during resuscitation and compare surviving and non-surviving piglets; epinephrine was administered at a dose of 0.01 mg/kg [43]. Epinephrine had no effect on either HR or cardiac output in survivors versus non-survivors during resuscitation; it did not increase survival rates or ROSC [43].
The abovementioned studies highlight the practicality of this neonatal animal model not only in driving progress in our understanding of neonatal resuscitation, but also in paving the way for new techniques into the delivery room.
Animal models that reliably reproduce the events surrounding neonatal resuscitation in the delivery room are imperative to improve the outcome of newborn infants requiring CPR and may also lead to benefits for the pediatric population. Due to its many advantages, the porcine model of neonatal hypoxia-asphyxia is one of the most commonly used large animal models for neonatal resuscitation studies. Not only has this model provided a further understanding of the effects of various resuscitation interventions, but it has also enabled the study of an increasingly important clinical situation in the laboratory setting – pulseless electrical activity. Using this animal model will further accelerate knowledge on neonatal resuscitation that will ultimately benefit patients.
We would like to thank the public for donating money to our funding agencies: GMS is a recipient of the Heart and Stroke Foundation/University of Alberta Professorship of Neonatal Resuscitation, a National New Investigator of the Heart and Stroke Foundation Canada and an Alberta New Investigator of the Heart and Stroke Foundation Alberta. The study was supported by a Grant from the SickKids Foundation in partnership with the Canadian Institutes of Health Research (CIHR - Institute of Human Development, Child and Youth Health (IHDCYH)), New Investigator Research Grant Program (Grant number - No. NI17-033) and a Grant-in-Aid from the Heart and Stroke Foundation Canada (Grant Number: G-15-0009284). We would like to acknowledge support from the Women and Children’s Health Research Institute, University of Alberta.
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He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. Gonzalez-Sanchez",slug:"juan-a.-gonzalez-sanchez",fullName:"Juan A. Gonzalez-Sanchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico System",country:{name:"United States of America"}}},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}}]}},subseries:{item:{id:"5",type:"subseries",title:"Parasitic Infectious Diseases",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. 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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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