What is the relationship between brain dysmorphology and functional outcomes? - Chapter 6

During gestation, the immature brain is very vulnerable. Genetic influences and other biological and environmental risk factors contribute to structural changes and functional reorganisation of the brain in utero as well as early post-natal life, which in turn affect all subsequent neurodevelopmental processes. Even small variations in brain structure and neural organisation can, over time, lead to significant changes in cognitive functioning, academic achievement, and adaptive skills. Disorders of the CNS, such as early-onset-hydrochephalus (HYD), and structural disorders of embryogenesis, such as agenesis of the corpus callosum (CC) and non-syndromal craniosynostosis, give a unique opportunity to examine relationships between brain dysmorphology and functional outcomes. The relationship between biological risk and functional outcome is moderated by the compensatory effects of brain plasticity and other distal factors, such as the timing and adequacy of treatment, access to early intervention, family resources, and time of assessment. Hence, early occurring brain insults that occur in structural brain disorders are not single events. Instead, they form a complex set of processes and potential secondary insults or protective influences that together determine the outcomes. 

What are the characteristics of hydrocephalus?

Epidemiology

Hydrocephalus (HYD) refers to a disturbance of the formation, flow or absorption of cerebrospinal fluid (CSF), that is secondary to some other pathological event or structural brain anomaly. To put it differently, HYD is the final common pathway of several neurodevelopmental disorders or peri- or post-natal events, rather than a disease entity in itself. HYD occurs in around one case per 1000 births. CSF can be seen as a protection mechanism; it protects the cortex from injury, provides a barrier between brain and blood, and plays a role in the removal of waste products from the CNS. HYD manifests itself in infants by enlargement of the head at an abnormal rate, resulting in a bulging anterior fontanelle and downward deviation of the eyes, also called sunset gaze. Other symptoms are: irritability, lethargy, poor feeding, headaches, vomiting, declining school performance, motor incoordination and incontinence. Yet, some infants are surprisingly asymptomatic. Further, HYD is associated with visuo-perceptual and visuo-motor deficits. This can be explained by the neuropathological correlates of HYD: as the ventricles enlarge, optic nerves may be damaged, resulting in a high incidence of ophthalmic abnormalities. Another consistent finding in children with HYD concerns deficits in focused and selective attention, in particular in those skills that are dependent upon the arousal activation attention systems (orientation, focus, and shift) mediated by the midbrain and posterior attention system. Children with HYD manifest high rates of learning difficulties that persist into adolescence, as well as limited occupational choice and impaired quality of life in adulthood. 

Aetiology 

There are multiple causes of HYD. There is a comprehensive list of 73 causes of HYD, such as agenesis of the corpus callosum, brainstem glioma, achondroplasia, haemorrhage, and congenital syphilis. These 73 causes are subdivided into the following categories:

1. congenital malformations;
2. infectious causes;
3. traumatic causes;
4. neoplasms;
5. syndromes;
6. vascular causes; 
7. syndromes.  

Classification

There are different ways to classify HYD; it can be classified according to type (obstructive or communicating), aetiology (congenital or acquired) and/or the presence of comorbidities. Obstructive HYD occurs when there is a barrier to the CSF flow, either within the ventricles or cerebral aqueduct or at the outlet of the fourth ventricle, preventing free flow of CSF between the ventricles and the subarachnoid space. Communicating HYD occurs when there is free flow of the CSF within the ventricular system, but the absorption of CSF is disrupted within the subarachnoid space. Congenital forms of HYD are usually of the obstructive type and occur in disorders of embryogenesis, such as spina bifida, Arnold-Chiari malformations, aqueduct stenosis (AS), and the Dandy-Walker syndrome (DWS). Approximately 55-70% of all cases of HYD are congenital. 

Treatment

Progressive HYD is treated by surgery with insertion of a mechanical shunt, typically into one of the lateral ventricles that drains excess CSF into another body space, commonly the peritoneal cavity. Shunting has played an important role in reducing the mortality and morbidity that has been associated with HYD, although shunts may block periodically, requiring surgical revision, with each procedure being associated with risk of haemorrhage and infection. Unlike many forms of CNS disorder, children who are successfully treated (excluding those with comorbid spina bifida myelomeningocele (SMB) or comorbid cerebral palsy) may have no evidence of physical disability or permanent neurological signs or symptoms and may not need ongoing treatment or medication. 

What are the characteristics of agenesis of the corpus callosum?

Epidemiology

Agenesis of the corpus callosum is a birth defect in which there is complete or partial absence of the corpus callosum. The prevalence is 18 in every 10,000 live births, with higher rates associated with PT birth, higher maternal age, and in children with developmental delay. In healthy embryrogenesis, formation of the corpus callosum occurs prenatally from 11 to 15 weeks' gestational age. Disruptions during embryogenesis may result in either complete absence or agenesis of the CC (AgCC) or partial forms of the anomaly. Because the development of the corpus callosum is caudally (with the genu forming first, followed by the body, splenium, and rostrum), partial defects always involve the posterior segments of the CC. 

Corpus callosum

The corpus callosum (CC) is the largest cerebral commissure in the brain, spanning much of the frontal and parietal lobes from the anterior commissure to the hippocampal commissure posteriorly. The CC offers neuronal connections between the two hemispheres of the human brain in order to facilitate transfer of information and to coordinate activity between contralateral areas. The CC can be divided in three components: (i) the genu or anterior part that connects frontal and premotor brain regions across the hemispheres; (ii) a middle section or body that connects motor, somatosensory, and parietal areas; and; (iii) the splenium or posterior section that connects homotopic areas of the temporal and occipital cortices. 

Comorbidities

AgCC may occur as an isolated condition, but is also associated with other disorders of the central nervous system, including malformations of cortical development such as SBM, DWS, interhemispheric cyst, neurofibromatosis type 1, and macro- or micro-cephaly. AgCC is also associated with higher rates of malformations in other organ systems, such as eyes, kidney, and hart. Another common comorbidity of AgCC is epilepsy. Commonly noted behavioural and social difficulties that have been observed in children with AgCC are labile mood and conduct problems. Several researchers have drawn attention to an overlap between the social deficits manifested in AgCC and those evident in neurodevelopmental disorders such as autism spectrum disorder (ASD) and Tourette syndrome (TS). Given the heterogeneous nature of AgCC in terms of comorbidities, clinical symptoms, and neuropathological findings, and the methodological limitations of present research (in particular small samples, many single-case reports), it is not surprising that there has not yet been identified a characteristic neuropsychological profile. 

What are the characteristics of craniosynostosis?

Epidemiology

Craniosynostosis refers to a premature fusion of one or more of the sutures that normally separate the bony plates of the skull to accommodate rapid brain growth during early development of the brain. It affects around 1 in every 2000 children. Fusion of multiple sutures usually occurs in genetic disorders such as Apert, Crouson, Pfeiffer, and Carpenter syndromes, and typically involves elevated rates of intellectual disability. In this chapter, however, the focus is on single-suture craniosynostosis (SSC) which involves isolated, non-syndromic fusions of the sagittal, coronal, metopic, or lambdoid sutures. Skull phenotype is dependent upon the particular suture that is fused. 

• Sagittal synostosis hinders lateral (bi-temporal) growth of the skull, redirecting brain growth towards the frontal and occipital lobes; this condition is also known as scaphocephaly. 
• Coronal synostosis comprises forward growth of the anterior cranial vault and may yield a hypoplastic frontal lobe on the affected side, with compensatory prominence of the frontal bone on the unaffected side; this condition is also known as anterior plagiocephaly. 
• Metopic synostosis hinders growth of the frontal cranial vault with compensatory increased parietal and occipatal width, producing a triangular head shape; this condition is also known as trigonocephaly.
• Lambdoid synostosis is characterised by flattening of the occipital and parietal regions of the unaffected side, causing posterior plagiocephaly. 

Sagittal synostosis is the most common form of the condition, accounting for approximately half of the total number of cases, followed by coronal (20-29%), metopic (20%), and lambdoid (2-4%) synostosis. 

Neuropsychological findings

Despite IQ usually being within the average range, SSC is associated with a range of more subtle neurodevelopmental problems, reported in 25-50% of children with SSC. Commonly reported problems are persisting speech and language impairments, as well as deficits in memory, learning, attention, and executive skills. The commonly reported language deficits in SSD may be attributed to reduced short-term auditory memory capacity compromising early acquisition of both receptive and expressive language skills. In addition, a range of functional difficulties have been identified in children with SSC, including academic difficulties (repeated grades, increased need for remedial support, difficulties in math, but in particular impaired literacy and writing difficulties) and behavioural difficulties, as shown by elevated scores in the clinical range of the Internalising and Externalising scales of the Child Behavior Checklist (CLC) at age 3. Important contributors to outcome are: family resources, SES, family functioning, and parental mental health. Research has found high levels of stress and poor mother-child bonding in infants with early medical problems.

Treatment

In addition to medical interventions, early intervention should support parenting practices that encourage autonomy and explorative and contingent play, while organisational tools may compensate for executive deficits. In addition, social skills training may be helpful to approve appreciation of peri-personal space and to foster a capacity for intimacy, appropriate self-disclosure, and empathic listening skills, as well as to encourage opportunities for peer interactions. For the interventions for children with structural brain disorders the following twelve key issues have been listed:

1. Follow normal progressions in cognitive development, that is from surface to depth, from concrete to more abstract.
2. Build a knowledge base by aiding the child to acquire meaningful new content.
3. Target the efficiency of cognitive processes.
4. Teach organising strategies to increase memory capacity in real-life settings, until they become habituated.
5. Use an approach that is balanced among targeted cognitive activities, compensation strategies, and environmental structuring, based on the short- and long-term goals of the child.
6. Support generalisation of new learning to real life situations.
7. Provide services in a meaningful context to support daily living, school, social, vocational, and leisure goals.
8. Consider the role of motivation and executive functioning and actively teach strategies to enhance performance as well as learning.
9. Integrate and organise training activities over time and avoid setting multiple goals simultaneously.
10. Teach adults that are involved with the child to be cognitive coaches and to engage in effective behaviour management.
11. Provide a high level of support initially and reduce it as the child consolidates necessary skills.
12. Teach adults the links between cognitive impairment and behavioural problems in children with brain insults.