Inge Cuppen

Chapter 1 provides the general introduction to this thesis, starting with basic information about the prevalence, features and definition of spinal dysraphism, followed by preventive measures and their consequences. Spinal dysraphism can be detected prenatally by an ultrasound scan, which may lead to termination of the pregnancy. Counselling of the prospective parents on this decision, however, is extremely difficult as no reliable individual prognosis for the child with spinal dysraphism can be given in the majority of cases. Nowadays, the option of foetal surgery of the defect may also be considered, but postnatal prediction of long-term outcome remains a big challenge. The chapter concludes with the aim and outline of this thesis.

Chapter 2 describes a retrospective study to assess foetal biparietal diameter (BPD) and head circumference (HC) in the second trimester of pregnancy in foetuses with open spinal dysraphism as possible prognostic markers for cognitive outcome. BPD and HC were measured at 16-26 weeks in 74 foetuses with open spinal dysraphism and compared to reference values. Of all cases with open spinal dysraphism, 62.2% had a BPD < 3rd centile and 79.7% had a BPD < 10th centile. Of all patients, 54.1% had a HC < 3rd centile and 74.3% had a HC < 10th centile. Almost all foetuses with open neural tube defects have a smaller BPD and HC at 16-26 weeks compared with reference values, which implicates that these are part of the phenotype of children with open spinal dysraphism instead of independent prognostic markers for a poor cognitive outcome. Chapter 3 provides the description of a retrospective cohort study, including 95 neonates with myelomeningoceles born between 1990 and 2006, to assess the effect of delivery mode on early neurologic outcome. This effect was assessed as the difference between functional neurological level and X-ray level (ΔFAX). Early neurological outcome was better in the vaginally delivered infants than in those delivered by cesarean section. Multivariable linear regression analysis with correction for confounding demonstrated that vaginal delivery was associated with better early neurological outcome as compared to cesarean section (β=1.21; 95% CI 0.16; 2.27; P=0.03) for infants in vertex and breech position combined. Subgroup analysis revealed a non-significant trend towards better outcome after vaginal delivery, which was more pronounced in infants in breech position than in vertex position. In infants with myelomeningocele, born in either vertex or breech position, there is no clinical evidence that early neurological outcome is improved by cesarean section. Electroencephalography (EEG) is described for infants born with spina bifida. Thirty-one infants born between 2002 and 2007 were evaluated and followed up for 2 and a half years to assess their cognitive development and physical disabilities. All EEG recordings were within normal limits, but 3 out of the 31 children showed a mild mental disability and major physical disabilities. We concluded that single EEG recordings are of limited prognostic value for infants born with spina bifida. Serial EEG recordings in combination with other neurophysiologic investigations, such as MEPs and CMAPs, might show better prognostic value. In the study described in Chapter 5, lumbar motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were assessed to determine their prognostic value in comparison to clinical neurologic examination in infants with spina bifida. Thirty-six neonates born between 2002 and 2007 were evaluated and followed for 2 years. MEPs were recorded from the quadriceps femoris, tibialis anterior, and gastrocnemius muscles and CMAPs from the latter two muscles before surgical closure of the spinal anomaly. Better clinical neurologic outcome at the age of 2 years, defined by better Muscle Function Classes and ambulation status, was associated with larger MEP and CMAP areas of the gastrocnemius and tibialis anterior muscles at neonatal age. In spina bifida, MEPs and CMAPS of these two muscles are of prognostic value for clinical neurological outcome and might be useful to assess residual motor function. Chapter 6 reviews the progress made in understanding the pathogenesis of spina bifida. We aimed to disentangle the proportional contribution of upper and lower motor neuron dysfunction to motor impairment in children with spina bifida. We enrolled 42 school-aged children with spina bifida and 36 control children of similar age. Motor impairment was graded to severity scales in children with spina bifida. We recorded MEPs after transcranial and lumbosacral magnetic stimulation and CMAPs after electric nerve stimulation. Regarding lower motor neuron function, severely impaired children with spina bifida demonstrated smaller CMAP areas and lumbosacral MEP areas than control children; mildly impaired children hardly differed from control children. CMAP and MEP latencies did not differ between children with spina bifida and control children. Regarding upper motor neuron function, children with spina bifida demonstrated smaller transcranial MEP areas and longer central motor conduction times than control children. The smallest MEP areas and longest central motor conduction times were observed in severely impaired children. We concluded that the contribution of upper motor neuron dysfunction to motor impairment in children with spina bifida is more considerable than expected from clinical neurologic examination. Chapter 7 contains the general discussion, in which we put the results of the studies described in the previous chapters into perspective in light of the aim of this thesis and the current context, after addressing a number of methodological considerations pertaining to study designs and measurements used. The complex process of counselling and decision making surrounding prenatal detection of spinal dysraphism, may be aided by advanced diagnostic techniques, but it is still impossible to provide an adequate individual prognosis for the majority of cases, especially taking into account the differences in valuation of quality of life between prospective parents and patients. Prenatally assessed biparietal diameter and head circumference do not contribute to the prognosis and neither does mode of delivery. Foetal surgery, however, may greatly increase the prognosis of children with spinal dysraphism, despite the risks for mother and child involved in the procedure. Advanced imaging techniques may be used to evaluate the impact of foetal surgery and learn more about the pathophysiologic processes involved in spinal dysraphism. In addition, future perspectives should include aetiologic studies, primary prevention, and centralized care of children with spinal dysraphism.