What are the dimensions of theory and practice in the neuropsychology of children? - Chapter 1

The neuropsychology of children is defined as the study of brain-behavior relationships within the dynamic context of a developing brain. The focus of this branch of psychology is early childhood brain injury which happens in a developing system; consequently it may impact normal neurological and cognitive development. There is an existing debate with regard to possible advantages and disadvantages of brain insult occurring early in life. One extreme argues that when the younger brain is insulted, there is still great flexibility and capability for functions to be transferred. The other side argues for vulnerability following early insult, especially regarding attention, memory and learning which are essential for future skill acquisition. When studying children, it is crucial to regard its “totality”, namely all dimensions influencing development and recovery. Traditionally most knowledge of child neurodevelopment is based on adult models, which are now considered inadequate as they cannot accommodate the dynamic nature of a child’s brain. Other models are needed to account for complex cognitive, psychosocial and neurological consequences following early insult. Recently, to understand changes within the central nervous system (CNS) from gestation to full maturation, researchers started to draw on the disciplines of developmental neurology and cognitive psychology. Despite these developments, it remains difficult to grasp the interaction of cognitive, social, neurological and developmental factors affecting the child and how this manifests itself in observed outcomes.

The neurological dimension

The neurological dimension is present from early on in gestation throughout development. In the prenatal period it is mainly concerned with structural formation establishing the basic hardware of the central nervous system. Disruptions at this stage are most likely to result in overt structural abnormalities. The postnatal period deals with the extension of the central nervous system by establishing connectivity. On one hand there is evidence for a hierarchical manner of development with anterior regions maturing last, and a stepwise model of development involving growth spurts on the other hand. The processes of development can be influenced by a number of environmental variables including sensory deprivation or malnutrition for example. In addition, cerebral injury and infections are further variables which place high risk on ongoing development. Children as well as adults show a dose-response relationship between degree of impact and consequences. As opposed to adults which suffer from more localized damages and associated specific deficits, children are likelier to suffer from more diffuse damage leading to global deficits. Children tend to show global disturbances in their information processing systems (attention, memory, etc.) and executive functions. The acute phases of recovery after brain insult are similar across ages, whereas long-term recovery patterns differ greatly between the immature and mature brain. General findings indicate little advantage of the immature brain in terms of positive outcome after insult. The assumption underlying the transfer of knowledge arguing for better plasticity and recovery for children is most likely more complicated than previously believed; with factors such as timing and damage nature having a crucial impact on such transfer.

In case of prenatal injury transfer of function is unlikely to occur resulting in ineffectively developed skills and developmental delay. Even when transfer occurs after postnatal damage, it is not optimal and general depression of neuropsychological function might nevertheless be present.

One specific focus of child neuropsychology is to investigate the ongoing effect of injury on central nervous system development. Childhood cerebral injury is not static as in the case of adult injury, but likely interrupts ongoing maturation of the brain resulting in serious long-term consequences. The study of child brain development has become more efficient with technological innovations. The rate and localization of myelination in children over time can be investigated by magnetic resonance imagining (MRI), whereas functional imagining techniques like single-photon emission tomography (SEPCT) and positron emission tomography (PET) are utilized to map cerebral activation. These techniques can be used even in very young children. The possibility of functional transfer has recently been investigated by functional magnetic resonance imagining (fMRI) as opposed to more invasive methods in the past. The information gained by this technique have clinical implications with regard to cerebral surgery (e.g. minimize removal of functional tissue). Moreover, Electroencephalograms (EEG) are especially involved in diagnosing epilepsy and specific sleep disturbances, and event-related potentials (ERP) investigate abnormalities in information-processing and sensory systems. It is important to interpret findings of all the measures together in the context of age-appropriate norms.

Neurological correlates after early cerebral insult. Brain dysfunction directly impacts psychosocial and behavioral functioning. Research found that the prevalence of psychiatric disorders is much greater for children with brain damage compared to children with physical disabilities. Manifestations of behavioral disturbances depend on the nature and localization of damage. A study with children suffering from traumatic brain injury indicated a dose-response relationship, namely more severe injury was associated with greater emotional and behavioral problems. In addition, right-sided, more frontal injury resulted in generalized problems suggesting a direct effect of damage. Reports of depression and anxiety were independent of focus of damage, indicating that psychological factors (hospitalization, family separation) play a role in their development.

The cognitive dimension

Early cognitive development models have their roots in the hierarchical, stage-like theories of Piaget. Accordingly, all children invariably pass through a number of stages; with quality and level of thinking as key features to change and move forward in hierarchy. The first stage is the sensorimotor stage (birth-2 years), it is characterized by simple sensory and motor activities with slow emergence of first signs of their working memories. The second stage is the preoperational stage (2-7 years), in which children develop early abilities of communication, mental imagery and language. At this stage there is only very limited higher-order capacity. The next stage is the operational stage (7-12 years) with advances in reasoning, problem-solving skills and mental transformations. Finally, executive skills emerge in the formal operational stage by early adolescence.

Generally, there is persistent controversy at which exact ages changes are supposed to occur. There is evidence that the stage-like processes of cognitive development are in line with cerebral development, especially with regard to growth spurts in myelination.

Traditional cognitive models focus on specific skills, whereas cognitive-developmental theories argue for a more generalized progression throughout childhood. In a similar vein, in addition to individual variability stage progression, there are different rates of progression within different cognitive domains. This does not mean that the development of a specific cognitive skill is independent from other domains. So how do such theories contribute to neuropsychology? Most importantly, interpretation of neuropsychological deficits in children needs to be considered within an age-appropriate framework. Thereby the neuropsychologist can map the cognitive development of a child in order to identify deviations, formulate diagnosis and develop an appropriate treatment plan. A prerequisite is the understanding of normal developmental trajectories of children. Furthermore, it is problematic to utilize adult-based tests in assessments (Rey complex figures).

Reported deviations on these tests can reflect normal developmental processes or imply impairment in lower-order skills (e.g. visual perception) as well as age-appropriate immaturity of higher-order functions, such as executive functions. Therefore, reliable assessment of deficits is only possible at an age where the child is expected to show certain capabilities. It follows that children may not present impairments at the time of injury, but appear to grow into deficits when the emergence of new skills is delayed or does not occur at all. Progression of deficits does not necessarily imply deterioration or underlying deteriorating pathology. It is better seen as related to the early brain insult interfering with normal skill acquisition and associated slowed cognitive development.

The psychosocial domain

Children live within a social network, namely their families. This network is responsible for a number of issues including access to resources and provision of appropriate learning contexts. When children display chronic illnesses or disability this does not only impact the child’s quality of life, but also affects parental and familial adjustments. Normally, the child learns social skills over time in a stage-like manner consistent with cognitive and cerebral development. As an infant, one depends on the family to support and structure social interactions. Thereby learning rules and behaviors accepted within this system. In the preschool years children’s egocentricity diminishes and allows for more cooperation with others; subsequently leading to more independence from their families. It is argued that biological characteristics, the immediate home environment and broader social contacts are essential to social development. These can interact in many ways suggesting a dynamic interplay between the environment and child. If problems occur this might affect the child as well as its environment. Turning to childhood central nervous system insult, impairments will interact with their environment; affecting the child and the family. For instance, early injury may disrupt the child’s ability to learn appropriate social rules. With increasing age and associated decrease of familial support, social interactions may become increasingly problematic.

Generally, there are two possible ways through which insult can impact social outcomes. First, there can be a direct effect of cerebral insult or secondary effects on psychosocial factors. The second option is that the two are believed to interact and thereby result in more behavioral problems after injury.

Psychosocial correlates. It is obvious that a child’s behavioral development is influenced by social factors. In face of central nervous system insult, a child is confronted with many difficulties like accepting and adjusting to the condition, behavioral deficits as result of injury and possible restriction in social interactions due to the illness. Similar changes are also apparent for the family. Older research has identified several predictive factors related to poor long-term outcomes, namely low socioeconomic status, low maternal education, family stress and previous psychosocial problems. Taken together, children from disadvantaged backgrounds may be more vulnerable to effects of early injury, which supports the double-hazard hypothesis. Other findings point in the opposite direction, namely that if an individual is already disadvantaged due to social background, biological risk factors are less likely to influence recovery. The impact of specific risk factors change with time since disorder onset. For instance, for children with meningitis early outcome is mainly predicted by disease severity, whereas long-term outcomes depend more heavily on psychosocial factors. So far most approaches are unidimensional and by far too simplistic. The need of multidimensional approaches arises in order to assess many potential risk factors and their interactions simultaneously. Moreover, to account for dynamic processes of development, more longitudinal studies are needed to gain better understanding of long-term consequences following early childhood insult. There is huge variation on the individual level that is best conceptualized by viewing the child in terms of vulnerability. This is assessed by considering potential risk factors like severity of insult and its location. Unfortunately it is still hard to investigate the interactions between all possible variables. Up until now, some unfounded assumptions regarding child neuropsychology exist.

First, it is assumed that brain disorders of children are similar in symptoms to adult brain disorders. Second, assessment techniques utilized for adults can be used for children as they map the same skills. Finally, specific behavioral disturbances after brain insult are in direct relation to one another. Generally, it is recommended not to overemphasize biological influences on outcome and to better advocate for a dynamic nature of development, which acknowledges potential influences of moderator variables.

Overall, the general principles of adult neuropsychology also apply to children. The knowledge about adult neuropsychology is largely based on research from brain-damaged populations correlating the brain lesion with observed and assessed cognitive dysfunction. Recently the notion of functional systems was introduced with the premise that no single and isolated brain region is sufficient to mediate cognitive abilities; rather they depend on an integrated neural system. Consequently, damage to any part of a system can lead to a range of consequences.

At a conceptual level of the central nervous system, it is assumed that adults and children have similar patterns of functional systems and localization of function. Considering neuropsychological assessment and principles for children, these too are based on adult practices. Unfortunately, adult models cannot accommodate the immature and developing central nervous system of children; therefore development-specific principles are needed. Up until today, the development of neuropsychological assessment practices looked at three stages. First, it focused mainly on detention and localization of damage which is largely irrelevant to children with more generalized damage. Secondly, principles reflected an increased awareness of functional implications in assessment. For adults, this included considerations of injury severity, pattern of deficits and underlying components of disturbed functions. The last stage is most useful also to child neuropsychology, as it focuses on the detection of cognitive weaknesses as well as strengths in relation to demands of an individual’s environment. This last approach can be generalized across all ages as the dynamic and ever-changing child and its environment are accounted for.

Most recently, functional analysis for daily living performance has been focused on. Fine-tuned task analysis is being done and an effort is made to better relate test performance to relevant everyday activities. The earliest contributions to childhood neuropsychology were made by looking at recovery of functioning after early insult and plasticity. Some researchers argue for sparing of certain functions after early injury, which is not observed in equivalent injuries in adults. This is summarized by the Kennard principle stating that it is better to have brain insult early in life. Plasticity research is mainly based on studies of children suffering from aphasia and hemispherectomy, who showed remarkable recovery of functions not anticipated regarding the consequences following adult brain insult. Such findings are interpreted to be in line with the theory of function which regards a child’s brain as less differentiated and therefore more capable of transferring functions as opposed to the more mature brain of adults. Up until today, there is considerable debate about the advantages of an immature brain regarding good recovery. Critical periods of development have been described as a limited time period in which external factors have a significant effect on central nervous system development. This led to the suggestion that injury is likely to result in different outcomes depending on its timing. If a cerebral region is dysfunctional or damaged during such a period it can lead to irreversible changes of cognitive skills mediated by the affected region. It has been suggested that even if plasticity does exist, its effect are likely very time-limited and not linearly-related to age. Evidence against plasticity comes from the observation that lesions during the prenatal development or in the first year of life result in especially severe impairments. Studies of critical period are mainly based on environmental deprivation models. Concerning the visual system, there is a sensitive time in which sufficient sensory experience is needed for normal development. The same deprivation of stimuli at later stages has a comparably little effect.

It has been argued that the visual system is pre-programmed to establish normal connections, but depend on exercise within the first months of life. A similar critical period has been established for language development.

There are some requirements needed to establish a developmental neuropsychological model that is unified and complete. First, such a model should be able to account for the spectrum of neurobehavioral disabilities and abilities of children. Secondly, it should account for development and interaction of brain connection axes (up-down, right-left, anterior-posterior). In addition, an ideal model would also consider interactions among neurological, psychosocial and cognitive variables within a dynamic developmental context.

The theory of non-verbal learning disability

This theory combines the knowledge of central nervous system developments with certain cognitive profiles. Central characteristics of the learning disability include:

1. Bilateral tactile-perceptual problems, which tend to be more pronounced on the left side of the body.

2. Visual recognition deficits as well as organizational and discriminatory problems.

3. Bilateral psychomotor disturbances, which also tend to be more pronounced on the left side of the body.

4. Severe problems in dealing with novel information.

Despite these number of deficits, there is no global impairment in children with non-verbal learning disability. They show a number of intact functions like (1) word reading and spelling, (2) basic expressive and receptive language, (3) selective and sustained attention for auditory-verbal information, (4) rote learning, (5) auditory perception and (6) simple motor skills. In addition to the primary deficits listed above, a number of secondary and tertiary problems can evolve. At a cognitive level, these children present a reduction in exploratory behavior, poor visual attention and memory, as well as subtle language problems with regard to prosody and pragmatics. At a functional level, deficits cluster around psycho-emotional deficits reflected in poor ability to adapt to social situations and a general problem with social interactions. The emotional problems of children with non-verbal learning disability (NVLD) are likely internalizing in nature. The children show deficits in skills that are essential for general skill acquisition. There is a dynamic interaction between a child and its environment: their reduced tendency of exploratory behavior due to visual, psychomotor and tactile problems limits their exposure to experiences necessary to learn. Such experiences also include social interactions, with a lack of it resulting in impoverished learning of social skills and eventual social isolation later in life. The model contributes to neuropsychological understanding by linking cognitive-developmental characteristics to possible underlying neurological causes. The white matter hypothesis has been adopted to account for NVLD with several factors impacting symptom presentation, namely amount of white matter damage, age at lesion and nature of lesion. A core point of the theory is the importance of the functional white matter in the central nervous system to develop normally. This goes in line with myelination processes which occur from the prenatal stage throughout childhood, leaving the white matter vulnerable during this time until it is fully matured.

There are three principle classes of white matter within the central nervous system:

1. The commissural fibers, which link the left and right hemisphere including the corpus callosum, hippocampal, posterior and anterior commissures.

2. The association fibers, which interconnect cortical regions within one hemisphere.

3. The projection fibers, which link the cortical regions with the subcortical regions.

Disruption in stages of myelination will impact the formation of such connecting fibers. With regard to the NVLD, there is a distinction between right and left white matter functions. The right hemisphere white matter is believed to be essential in developing and subsequently maintaining skills, whereas the left is only essential to development. Consequently, the right white matter depends more on functional integrity within the brain and the left functions act more in isolation. The left functions are thereby maintained even without right hemisphere input. Injury to the right hemisphere is sufficient to cause NVLD, with the underlying etiology being neuronal damage to white matter tracts that disrupt intermodal integration. There is no evidence indicating at which age insult to the right side of the brain is likely to result in NVDL, but it is commonly believed that earlier injury carries greater risk. The right-left axis is emphasized to play a role in the latter explanation of NVDL development. An alternative neurological explanation for the disability is to focus on the anterior-posterior axis, as the immaturity of the anterior region makes it vulnerable to insult. The resulting symptoms would be the same, but the underlying disturbance would focus on executive capabilities. This is not to argue against NVLD, but simply stresses the possibility that different axes may be important to specific deficit patterns at different developmental stages. In light of this information, the left-right axis may be more involved in early development of NVLD and the anterior-posterior axis only plays a role later. Indirect evidence comes from intracranial radiation studies, indicating that treating children under age of five years yield much poorer outcomes than those older than five.

There is a common notion which is yet to be proven, namely that early lesions impact all three axes leading to global deficits and later lesions having more specific impact, similar as to that in adults. The second influential theory is heuristic concentrating on cognitive development and changes with time. The focus is on age of injury and cognitive development since time of injury, but it makes no attempt to find neurological explanations. The model focuses on language development, but can be generalized to other cognitive domains. Within the heuristic model, language development is seen dynamically and interprets impairments after brain insult in an age-appropriate context. There are three crucial age-related variables in the model:

1. Age at lesion determining the nature of cognitive impairments. Similar insults will lead to different outcomes at different ages.

2. Age of lesion or time since injury, with increasing time since injury there can be worsening in age-related performance.

3. Age at testing, being crucial since even healthy children vary in performance on cognitive tasks at different ages.

It is assumed that after injury in very young children there are little or no deficits, but with ongoing development they seem to grow into their problems (do not acquire new skills). Also, the model divides skill development into 3 distinct stages, with different outcomes after injury depending on acquired level of a certain skill.

1. Emerging skills, these are in an early phase of skill acquisition and not yet functional. Brain dysfunction at this stage is likeliest to result in developmental delay of skill onset or changes in normal sequence of skill acquisition.

2. Developing skills, these have been partially acquired, but are not yet fully functional. Brain dysfunction at this stage will result in a delayed rate of skill acquisition or even shortfall in the final establishment of the skill.

3. Established skills, these are fully functional; but only few of these exist in young children. Brain dysfunction at this stage will have less serious consequences.
   Mostly it will disrupt skill control with subsequent transient loss of it, or deficits in maintaining the skill may occur.

Obviously, this theory is in direct contrast to earlier plasticity theories; according to the earlier approach earlier insults result in more serious consequences. One implication of the model is that the full impact of early insult can only be fully assessed when the cognitive skill has completely developed. Unfortunately, validation of many underlying principles is problematic. First, chronological age is mostly employed as an arbitrary indication for the developmental stage. Secondly, the core concepts of onset and order rate have not yet been effectively operationalized.

How does the brain develop throughout the pre- and postnatal period? - Chapter 2

The development of the central nervous systems consists of a variety of complicated and overlapping processes. Development starts in gestation and continues well into adulthood, with the central nervous system developing in genetically predetermined stages. With increasing knowledge about biological processes underlying CNS development and timing of maturation, it might be possible to find parallels between this development and cognitive progresses. Moreover, knowledge about certain events taking place within the CNS and their timing might lead to better understanding of cognitive deficits in prenatal and postnatal stages as well as possible recovery. In the prenatal stages of development the most rapid brain growth occurs, with about 250,000 brain cells being formed every minute. The development at this stage is mainly genetically predetermined with little influence of environmental factors. Disruption of structural development likely results in abnormal morphology even at a gross level. At time of birth, the structural morphology is already mature with ongoing growth. Reaching adulthood the brain mass has quadruplet in size with its peak in young adulthood and gradual decline thereafter. Postnatal brain development is mainly concerned with elaboration of dendrites and synapses which are responsible for several processes. At this stage development is still largely based on biological factors, but environmental variables also gain in influence; with external damage interfering with ongoing cerebral elaboration.

The CNS starts to develop in gestation and is visible by the 100^th day of it. There are two major developmental processes at work in the CNS. First, there is simple additive development in which continuous growth processes add up. Myelination is one such example with ongoing increase in dendritic elaboration throughout the CNS. Second processes involve periods of regression in which there is first an overproduction followed by elimination of redundant elements. As an example, prenatally there is an excess in neuron development which is later reduced by processes of differentiation. Nowadays it has been established that cerebral development is not a gradual process but involves several growth spurts. The earliest growth spurt occurs around week 24-25 of gestation which coincides with neuronal generation completion. Another one is seen in the first year of life due to myelination, synaptic and dendritic development. Later spurts are around age seven and the last one in early adolescence. If disruption occurs in any of these growth spurts consequences are especially serious leading to delay or irreversible changes to future development. The notion of sensitive periods is closely associated with these spurts. Another central issue to CNS development is the sequences of maturation of several brain regions. It is believed to follow a hierarchical progress with anterior regions maturing the latest. There are some processes that are exceptions to this like synaptogenesis which happens simultaneously in several brain regions. In general, the cerebral development follows a fairly fixed, biological way. Most common factors impacting prenatal development are genetic factors and infections as well as environmental factors like maternal malnutrition. After birth, the infant is also susceptible to external traumas and deprivation. Other social factors that are likely to influence development include the mother-child relationship and level of stimulation.

Prenatal cerebral development

The prenatal cerebral development is focused on structural features of the CNS. It starts right after a cell is fertilized, then begins to divide and eventually forms the embryonic disc. This disc consists of three different layers, which further develop to build specific organic systems of the body. The CNS develops out of the outer layer (ectoderm) through a process called neurolation. Initial stages of neurolation emerge around the second week of gestation which lead to the emergence of a neural plate by the third week.

In a gradual process a neural grove emerges and is flanked by two edges (neural folds) which eventually fuse together to form a tube by week four. Early disruption to development of this will result in serious changes of structure and especially likely are disorders of neural tube closure including the condition of spina bifida. The tube further develops along three different dimensions with each impacting different aspects of the CNS.

1. The dimension of length is concerned with formation of major structural aspects of the brain (forebrain, midbrain and spinal cord). Disruption at this dimension is likely to result in failure to form structural division such as failure to form two hemispheres.

2. The dimension of circumference is important for the differentiation between sensory and motor systems.

3. The dimension of radius results in the various cell types and layers within the brain. Along this dimension vesicles start to form in which cells later are generated and differentiated into certain neuronal systems.

At a cellular basis of development, neurolation progresses through the fast generation of new cells. There are two main classes of cells that develop within the CNS. First, there are neurons which derive from the division of neuroblasts. They are the functional units of the brain responsible for transporting impulses within complex interrelated networks of brain cells. The neuron consists of several body parts: cell body, axon, dendrites and presynaptic terminals. Depending on a neuron’s location, the characteristics of its axon and dendrites can vary. Neurons with longer axons and more dendritic branches form major connections throughout the nervous system and neurons with shorter axons and less dendritic branching are responsible for higher cortical functioning within the cortex. Generally, neurons have a very active role within the nervous system. The second class of cells is glial cells which are concerned with nurturing and supporting neurons. These cells emerge from the division of glioblasts. Some of their many tasks are supporting neurons and enabling regeneration of damaged neurons. There are nine times more glial cells than neurons within the system. They are very similar to neurons but do not have axons.

There are three subtypes of glial cells, each presenting with different tasks.

1. Astrocytes form the blood-brain-barrier and are involved in directing migration, supporting the cellular structure of the brain and cleaning up injury sites.

2. Oligodendrocytes are responsible for coating neural axons with myelin and thereby increasing the speed of information transfer.

3. Microglias primarily operate within the grey matter and clean up areas of injury.

Similar to neurons, glial cells are relatively immature early in cerebral development and continue to generate until maturity. Formation of both classes of cells involves three mechanisms.

Cell proliferation is the first of these mechanisms. After rapid cell divisions, groups of proliferating cells emerge which are further differentiated into the layers of the embryonic disc. The inner layer (endoderm) will further evolve to form the body’s inner organs, whereas the middle layer (mesoderm) forms the muscular and skeletal system. The outer layer forms the CNS as well as the skin surface. The cortical neurogenesis takes place within the neural tube starting around the 40^th day of gestation and is nearly complete within the sixth month of gestation. The only exceptions are within the cerebellum and hippocampus.

After sufficient neuron generation, but not before the sixth week of gestation, the process of migration takes place. Groups of young neurons generated at similar times migrate towards the outer layers of the neural tube and eventually form the cortex and subcortical structures. Most of it occurs between the eighth and 16^th week of gestation with only little migration following thereafter. Commonly there are two different types of migration within the nervous system. The first process is passive migration or cell displacement in which cells are merely pushed away by younger cells and consequently move toward the outer brain. This process is thought to result in midline structures. The other process is that of active migration in which younger cells move passed older cells and move towards external regions of the brain. The laminar structure emerges with different layers of neurons having different migration times. The underlying processes of migration are a topic of controversy. One prominent hypothesis states that radiating glial cells direct such migrational processes with neurons migrating along these to genetically predetermined regions. When migration is completed these directing glial cells evolve to become astrocytes. It is a rapid process resulting in visible layers of the cortex by the fifth week of gestation. Disruption to migration can cause cells to migrate to wrong places and to form inefficient synaptic connections.

After completion of this stage of development the process of differentiation begins. Compared to the other two it is a rather complicated process involving four different and distinct processes simultaneously. These are the development of cell bodies, formation of synaptic connections, dendritic and axonal growth and selective cell death. Similar to neurons, also glial cells differentiate to increase functionality. With formation of relevant connections, cells become integrated into specialized systems. Within the process cells become rather unique with regard to their structure and function. Half of all generated neurons will die due to selective cell death if they are redundant. Unlike the other processes, differentiation continues after birth. In case of axonal development, pioneer axons with high concentrations of chemical markers are supposed to trace a path that other axons recognize and can follow. These markers are only present for a limited time period in gestation. Some suggest that axons do not necessarily grow directly to a predetermined location, but rather grow to a number of sites with later elimination of redundant ones.

There exist two extremes with regard to axonal movement within the nervous system. On the one hand, there are preformists arguing for the sole influence of genetic factors, and on the other hand there are empiricist arguing for environmental influences (experiences) on which connections will be eliminated. Dendritic development does also start after migration and continues until early childhood, but it is regarded to be under more environmental influences. In case of synaptic development, it begins around the fifth month of gestation and elaboration of synapses continues postnatally in accordance with increased dendritic branching. The infant starts with an excess of synapses which are latter selectively reduced in order to maximize functional connectivity.

Interruptions to prenatal development can result in many consequences mostly dependent on the timing of insult as opposed to severity and nature of it. With very early disruption of development impacting the gross morphology of the brain, disruption later in gestation will impact migrational activity and neuronal differentiation. The general finding is that damage is more global and likely to involve frontal structures as these are the last to mature and are therefore especially vulnerable to disruptions.

The postnatal development

The postnatal development is mainly concerned with further elaboration of the brain. Before the introduction of more noninvasive techniques, the study of postnatal development was mainly based on animal research and on fetal autopsies. The size of the brain gradually increases throughout childhood due to three major processes at work.

Dendritic arborisation is one such process. It is additive in nature with no signs of regression in dendrites. The investigation of it mostly employs staining techniques on isolated neuronal tissue. Most research has focused on processes within the visual cortex. Dendritic branching starts to emerge between the 23^th and 30^th week of gestation continuing after birth. Postnatally, major changes happen with regard to dendritic length and branching, with most dramatic developments between 5 to 21 weeks after birth. Adult levels are reached after about six months. Cerebral regions differ in their dendritic development. Most regions reach maturation as mentioned before, but more frontal regions continue to branch up until the age of seven. Moreover, the process is very susceptible to environmental influences reflected in findings of increased dendritic branching in stimulus-rich environments; consequently deprivation of stimuli may hinder such developments. The capacity to develop specific branches in response to external experiences is likely to come at the cost of fewer non-specific branches. The occurrence of abnormal or stunted growth has been associated with several intellectual disabilities.

Another process in postnatal development is synaptogenesis, generally investigated by utilizing electron microscopy with post-mortem tissue. Synaptic connections increase from birth on with several bursts at various stages with ultimate maturity achieved at variable levels. The process starts in the second trimester of pregnancy which is close to the completion of the migrational phase, but most development occurs after birth.

Initially synapses seem to appear in a random fashion and most early connections are unspecified. The postnatal development is marked by an overproduction of synapses and redundancy and only gradually neural circuits develop and synaptic connections become more specified. If connections are not being used these are eliminated starting after the first year of life and this progresses at different rates according to regions. In contrast to dendritic branching, this process is relatively immune to environmental stimulation as well as deprivation. The auditory and visual cortex have a similar time schedule of development with an initial burst around three to four months of age and relative maturity by one year; completion is not before age seven though. The prefrontal cortex development starts at around the same time, but does not reach its peak before the first year, with maturity occurring only in early adolescence. Turning towards functional plasticity, it might be possible that non-specified synapses become integrated into a damaged system before elimination occurs and thereby might compensate for lost connections.

The last process is that of myelination. For efficient neurobehavioral functioning, adequate myelination of axons is necessary to increase conduction velocity of neurons. This is mostly studied with magnetic resonance imagining. Most progress in myelination occurs within the first three years of life and continues at a slower rate well into the second decade of life. There are several rules of myelination:

• posterior regions are myelinated before anterior regions

• central areas are myelinated before poles ones

• projections areas are myelinated before association ones

• sensory pathways are myelinated before motor ones

• proximal pathways are myelinated before distal ones

The general pattern of myelination is consistent with the hierarchical sequences of CNS development. Vestibular and spinal tracts are the earliest to be myelinated already starting around the 40^th week of gestation, with most other regions starting postnatally and the prefrontal cortex showing myelination well into early adolescence. Myelination is not to be seen as an all-or none process, but rather as a gradual thickening of the myelin cover.

The rate of myelination varies according to different brain regions. Cerebral trauma and environmental toxins can interrupt myelination processes resulting in reduced attention, slowed response speed and a more general impairment of the information-processing system. The most vulnerable period is the first eight month of life in which myelination is initiated and completion is most active.

Research on cerebral metabolism has indicated an overdevelopment similar to that observed in synaptogenesis. There is a rise in metabolism within the first year of life, but it presents itself at different levels across the CNS. Peak in activation has been observed in children around the age of four and this level, which surpasses adult levels, is maintained until nine years of age. Thereafter follows a gradual decline to adult levels reached in the second decade.

Other techniques revealed that the cerebral blood flow patterns are also consistent with synaptic elimination and development. Also, EEG patterns change throughout childhood independent of external influences. The immature brain presents itself with long latencies linked to longer times of transmission, which again relates back to immature synaptic connections and unmyelinated axons. The pattern shows peaks and falls well into adolescence consistent with general growth spurts.

In addition, patterns differ according to regions with simultaneous completion of maturation. In general, the immature brain shows non-specific electrical activity whereas the mature brain displays more localized and functional activity.

The frontal lobe development takes relatively long and is the last cerebral region in the hierarchy to reach maturation, and this does not happen before early adolescence. This is not surprising though, as frontal lobe development depends on input from posterior and subcortical regions to function appropriately. Especially the prefrontal cortex depends on input from literally all areas of the frontal areas and neocortex. Regarding this, efficient functioning depends on the quality of input received from other areas. In the past, it was believed that the frontal region is silent during infancy. In contrast recent findings indicate that frontal lobe activity in infants happens as young as six months. The lobe is organized in a hierarchical manner with myelination progressing from the primary and sensory areas towards association areas and finally to the frontal regions including the prefrontal cortex. There are specific growth spurts within the frontal cortex, the first around the age of six, the second around age ten and the final one in early adolescence. This is supported by behavioral research which holds that improvements in executive functioning occurs according to these spurts.

The localizationists’s approach

The localizationist’s approach owards specialization of the cerebral cortex states that certain behavioral functions can be linked to certain cortical regions. This approach is mainly based on lesion studies of adult patients presenting similar deficits after lesions in the same location. This localization of function may apply to the mature CNS, but it is not yet clear with regard to the immature, developing brain of children. It is not known whether such localization is apparent early in gestation or if it occurs gradually during development. In the prenatal stages there is some pre-specified functional organization with regard to processes of proliferation and migration of neurons. Nevertheless, other related issues like the impact of functional aspects on development and environmental influences are less well understood. There are two fairly contrasting views of specialization within the CNS. On the one hand, there is the notion of a “tabula rasa” where specialization is assumed to depend on environmental factors. On the other hand, there is the view of innate specialization in which biological factors are assumed to underlie specialization. It presents a protomap model in which differentiation begins in the prenatal stages (proliferation& migration) when neurons follow predetermined pathways to final destination and then become integrated parts of a functional system. According to this view, structures and functions are established before birth and therefore before any environmental influences can take place.

Support comes from studies of structural asymmetry. Furthermore, it is incompatible with the earlier notion of plasticity. Recently, the concept of transfer of function is regarded as more complicated than initially believed. Rather than a simple transfer to healthy tissue, it is seen as a process of recruitment. This means that additional skills are utilized in order to compensate for lost or disrupted ones. The alternative view is very well compatible with plasticity. In line with this view, the cortex is initially undifferentiated and only starts to differentiate after birth with external input in terms of sensory and motor stimuli. It is postulated that cortical regions can take on a variety of functions depending on early input. The latter approach is more likely, but the precise processes remain unclear. In case of cerebral insult taking place before specialization is complete, irreversible changes to functional location may follow.

There are certain gender differences in cerebral development and presentation. On average, men have about ten percent more brain volume which is already apparent in early development. Additionally, the male brain presents with greater neuronal density within the cortical grey matter. In contrast, the female brain shows more cortical density in specific layers of the cortex (posterior temporal region) and has an increased amount of dendritic material within the pyramidal region. This raises the possibility of more synapses, despite fewer neurons for women. Generally, there are no gender differences with regard to cerebral asymmetry. The two sexes show differences in their developmental pathways of the CNS which might be related to hormonal differences. Women show more rapid development of their left hemisphere in early childhood, whereas men have faster development of their right hemisphere. This pattern later reverses, as there are no differences in asymmetry later.

How do information-processing and executive skills develop along with cognition? - Chapter 3

The focus of the chapter is on information-processing and executive skills as these two skills are most often impaired as a consequence of early childhood injury. Some parallels can be found between cognitive advances and cerebral growth spurts. In the past, most cognitive models supported the hierarchical view of development with Piaget’s four stage model, which is compatible with patterns of CNS development. In the early approaches, focus was on global cognitive development, whereas in more recent approaches the focus shifted towards more localized developments. Several cerebral regions of the CNS show phase-like advances occurring at different times, which in itself is compatible with the idea of crucial periods. However, the different timetables of development do not exclude the possibility of interaction between systems. This shift away from stage-like and rather restricted progression entails several implications. For one, it raises the possibility that different pathways can be utilized next to the normal one for a skill acquisition. Secondly, it expands the concept of abnormal development to include deficits next to the known simple delay of reaching subsequent levels. Finally, it allows accounting for individual variability among children that choose different routs but in the end achieve same level of outcome. This further implies that children may establish certain skills at different times and at different rates. Instead of a set of fixed stages every child goes through, it is seen as a more individualized process. However, some aspects of development depend on other cognitive skill developments. This suggests that there is an overall rough guideline that development follows, with variations within this development.

The information-processing

The information-processing system is subdivided into several interrelated components, namely memory, attention, central executives and output. The general process within this system is as follows: first the individual attends to external information which is then registered, encoded and stored so that it can later be retrieved and used for output. If disruption of development affects any part of the system, it impacts effective information-processing.

The first component is attention; it is represented by an integrative neuronal system consisting of posterior and anterior cerebral regions, the brain stem and the reticular activating system. Two attentional systems have been proposed to be present within the CNS.

1. The reflexive or environmentally triggered attention system, which mostly reacts to biologically meaningful and novel stimuli. It is characterized by fast habituation to new stimuli and is not dependent on higher-order cognitive processes for adequate functioning.

2. The volitional attentional system, which involves an individual’s interpretation of encountered stimuli and is mediated by higher-order cognitive processes.

Both are believed to work in a parallel manner within the mature brain, but there is little known about their development; only that the more primitive system develops first and the volitional system with increasing experience and maturity. A second attentional model has been presented which is consistent with the first model.

1. The posterior system which mainly involves the thalamus, midbrain and parietal lobes. It is responsible for selective attention and attention shifting, and it is functional in infants starting as young as four months.

2. The anterior system relies on the anterior cingulate cortex and the prefrontal cortex. It is responsible for directing and intensifying attention towards cognitive tasks. It develops after the posterior system as it depends on these for effective functioning.

Recently, attempts have been proposed to separate the attentional system into different, interrelated subcomponents. Damage to any part of this integrated system results in several attentional consequences.

1. Sustained attention, which refers to the ability to maintain attention over a prolonged period of time. The reticular formation is likely to mediate this attentional component.

2. Focused attention, which is the ability to identify relevant stimuli while suppressing attention directed towards irrelevant stimuli, allowing for appropriate motor responses. This ability is mediated by temporal and parietal regions.

3. Shifting of the attentional focus, which describes the ability to efficiently and flexibly shift attentional resources from one aspect to another. It is mediated by the prefrontal cortex.

4. Stability of attentional effort, which is associated to brain stem and midline structure activity

5. Divided attention, which allows for processing two stimuli at the same time and is mediated by frontal regions.

6. Inhibition/impulsivity, which is also mediated by frontal regions and refers to the ability to inhibit impulsive responses.

The immature CNS of children shows a very limited capacity of attention, which is linked to unmyelinated axons and the still developing of frontal regions. With advances in the attentional system, children become increasingly better in overriding innate responses in favor of more appropriate and advantageous responses. These increases underlie neuronal development which leads to faster information transmission within the CNS. As with other cerebral systems, the single elements of attention progress at different rates and mature at different times. This is partly linked to progression of other cognitive domains as well as social development which impact attention. There is existing evidence in support of interactional processes between biological and environmental factors impacting attentional development. The potential of development is dependent on neural substrates underlying each component, whereas environmental variables influence to what extend development approximates its full potential. Most research on attention in children focuses on the school-aged population, which established a rough sequence concerning the different developmental timetables of attentional subcomponents. The earliest subcomponent to establish full maturation is selective attention, which reaches adult levels in very young children. For sustained attention performance is fairly stable throughout childhood until a growth spurt at around eleven brings it up to approaching adult level. Response speed makes gradual increments in childhood until relative maturity at around the age of eleven. The Test of Everyday Attention for children (TEA-ch) was developed to assess several attentional processes across a variety of modalities (auditory-verbal and visual-spatial).

Generally these tests found that, between the ages of six and twelve, children advance tremendously in several attentional domains and across different modalities. The paradigm for auditory selective attention revealed an age effect with increments in performance related to older ages. Regarding the capacity of divided attention, there appears to be a growth spurt at around age nine, when performance increases tremendously. Similar findings have been made for visual and spatial attentional tasks.

Abnormalities in attentional processes have been linked to a number of different disorders, including attention deficit hyperactivity disorder (ADHD), autism and traumatic brain injury. Yet, the manifestations of attentional deficits differ according to each condition, indicating different underlying brain pathologies or, alternatively, different onset times of the disorder. Such deficits, even if only mild, are likely to greatly impact the young child in terms of ongoing development, as limited attention impacts future learning of new skills and knowledge. Eventually, this may manifest in deterioration on tests because of cumulative deficits and delays. Another component of the information-processing system is memory. Many different models have been proposed with only some consistency regarding its major components (sensory store).

Memory

For most components little consistency exists, including concepts of short-term memory, long-term memory, working memory as well as processes of encoding, storing and retrieval. Commonly, the central executive is understood to control voluntary attention and retrieval of stored information. Furthermore, there is a division of memory types; between declarative (explicit) memory and procedural (implicit) memories. The maturation of underlying neural regions parallels advances in memory capabilities of children. At the process level, the young CNS contains more unmyelinated and therefore inefficient axons resulting in longer transmission rates of information. Moreover, the frontal lobe mediates effective organization of information which facilitates later retrieval as well as strategies to optimize information-processing. Overall, the central executive is less efficient in younger children. At the level of memory structure, the basal ganglia and brain stem are two of the first regions that fully mature, these regions mediate implicit memories and conditioned responses that can already be seen in infants. The ability to store and encode explicit information is mediated by the temporal lobes and the hippocampus which both take longer to reach maturation. In this hierarchy of memory development, the frontal regions are again the last to mature. These control voluntary action, the central executive and selective attention, of which some are still immature in children. Memory and learning processes start right after birth. Even though it is tricky to elicit reactions indicative of learning in infants, some paradigms have been developed. Test of object permanence and preference of novelty have shown efficient recognition memory in very young children. As within other cognitive domains, there is great variability concerning the development of certain memory aspects. So recognition abilities mature first with adult level performance reached already by age four. Immediate recall capacities increase throughout childhood until early adolescence where the standard plus/minus seven digit recall is reached. The young child displays different patterns of recall and repletion compared to adults. Young children demonstrate a recency effect, but primacy effects seem to emerge with age. The cognitive psychologist attributes advances of memory to improvements in expanded storage capacities, less distractibility, better selective retrieval of relevant pieces of information, increased speed of information-processing and better ability to acquire new information. Alternatively, memory advances could be accounted for by increasingly more functional memory strategies. The concept of metacognition (one’s knowledge about personal cognitive preferences) is another source of improved memory performance. With greater understanding of the personal memory system, older children are able to adjust their memory strategies and allocation of resources accordingly in order to optimize performance. The task of child neuropsychologists is to establish accurate assessment and interpretation of memory functions for children with neuropsychological disorders and create appropriate and tailored intervention programs. To establish an appropriate diagnosis the psychologists needs to meet three requirements:

1. Make use of a model of memory which allows assessment and interpretation of all memory subcomponents.

2. Usage of standardized test which provide age-appropriate norms against which test results can be compared.

3. Knowledge about how specific memory deficits will impact the child’s daily functioning.

In practice, this is often difficult for infants and very young children as it is nearly impossible to elicit sufficient responses from which different memory components can be differentiated. This lack of reliable assessment methods led to a general omission of this age group in research as well as clinical settings. With regard to school-aged children, age-appropriate norms have been established for a number of adult memory tests and recently test batteries have been developed especially for children. Overall, memory and learning capacities improve over time. These age-related changes may reflect simultaneous advances in immediate memory or may reflect implementation of more successful memory strategies and better capacities to organize incoming information. Research supports the latter explanation.

Older children seem to benefit from familiarity of tasks, which indicates potential utilization of prior knowledge to maximize performance. Additionally, the trend of reduced discrepancies between scores of spontaneous recall and recognition is believed to underlie better organizational skills. Some argue that the ability of delayed recall is highly dependent on other earlier processes of the memory system. In contrast to age-related increases in registration and memory skills, the capacity to hold information over time is fairly stable across different ages. Many CNS disorders show deficits in memory functions; with behavioral manifestations varying according to developmental variables and the range of injury. Disorders involving frontal or temporal regions are most likely to experience specific memory deficits. Children with left-sided hippocampal sclerosis display problems with material-specific recall and recognition in verbal memory tasks. Disorders involving local frontal lesions often show deficits in retrieving information across various modalities, but exhibit intact recognition. Other conditions lead to more generalized impacts on memory capabilities, including ADHD and traumatic brain injury. These deficits are associated with more generalized information-processing dysfunctions of attention and processing speed. It follows that emerging memory processes are particularly vulnerable to insult impact. Early childhood damage is more likely to interfere with subsequent skill acquisition and, at a functional level, to result in difficulties in learning of social rules and behaviors. For successful interventions, the neuropsychologist has to identify deficits and establish a detailed performance profile while also accounting for other neurobehavioral abilities. The last component of the information processing systems is speed of processing.

Overall, the speed of information transmission over the entire system reflects the system’s level of efficiency. Faster processes allow for faster task completion with minimal chances of exceeding attentional capacities, thus enabling to move forward to the next task. In a similar vein, the increased processing speed minimizes potential loss or decay of information material. There are age-related increases in speed across a number of activities. Studies using the Trail-Making task (dot-to-dot connections) and Contingency Naming task (rapidly name characteristic of a presented stimuli), both with increasingly complex rules to follow, have shown faster completion across difficulty levels with increased age. From a neurological perspective, the advances in processing speed are related to increased myelination of axons within the CNS. Support comes from children and adults with axonal damage disturbing myelination, who exhibit significantly slower response rates compared to healthy controls. There are many conditions which result in slowed responding including hydrocephalus and cranial radiation which affects primarily the white matter fibers. At a functional level, slow responding, especially if it involves language abilities, will interfere with social interaction opportunities.

The executive functions

The executive functions are one of the last cognitive functions to mature and are therefore particularly prone to become dysfunctional after childhood brain injury. They can be seen as part of the information-processing system that coordinates and integrates information as well as activities, and directs attention.

Other approaches regarding conceptualization of the executive functions propose four subcomponents: effective performance, purposeful behavior, planning and volition. Besides, executive skills are regarded as more global as opposed to other domain-specific cognitive abilities. Another more integrative model of executive functions describes it as a set of related skills which enable an individual to define personal goals and achieve these by mentally holding them, monitoring performance and controlling for influences of interfering factors. For others it is an umbrella term for various capabilities, including generation and implementation of strategies, monitoring, focusing and sustaining attention and making use of feedback. In general, there is agreement that executive skills are not employed in routine actions, but rather become active in novel and unfamiliar situations.

All these approaches indicate three distinct but interrelated components of executive functions.

1. Attentional control, including sustained and selective attentional processes.

2. Cognitive flexibility, including self-monitoring, conceptual transfer, shifting attention and working memory

3. Goal setting, including strategic behaviors, problem-solving abilities, planning and initiatin

Interruption to any component will result in executive dysfunction, which is characterized by impulsiveness and poor self-control. These functions are mediated by frontal regions which do not mature until early adolescence. Therefore, it is important to consider age-appropriate expectations before diagnosing a dysfunction. The sequential advances in executive abilities are in line with observed growth spurts in the frontal lobes. As mentioned previously, the frontal regions depend on input from other cortical areas and therefore, it is hard to isolate frontal involvement in executive task performances. In a similar vein, advances in executive skills are closely tied to advances of other cognitive abilities. There seems to be an association between executive abilities and advances in memory capacity, processing speed, attention and language abilities. In contrast to past beliefs that the frontal regions remain silent during infancy, recent findings established frontal activation in infants as young as 6 months. Indirect evidence comes from increments in the understanding of object permanence, and planning and organizational skills during early childhood, as seen lacking in baby monkeys with frontal lobe damage. This indicates that even in very young children the frontal lobe is already active. Different components of executive functions develop and mature at different times and rates. There is evidence of three stages concerning executive function development.

1. At age six, the child reaches maturity in resisting distractions.

2. At age ten, the child reaches maturity of skills of impulse control, hypothesis testing and organized search.

3. In early adolescence, maturity of planning, motor sequencing and verbal fluency takes place, but not yet at around age twelve.

Research has shown that most development in planning occurs between years nine and thirteen with relative stability thereafter. This is consistent with cerebral growth development spurts. Recently, it was found that during growth spurts performance actually declines. Studies using the Tower of London test provide evidence, that performance shows clear improvement until ten and after twelve, but at age eleven there is a steep decrease. This decrease becomes evident with an increased rate of errors being made. This might reflect greater mental flexibility and increases in new strategy development and implementation. Accordingly, the child is able to try out many possible ways of solutions which later leads to selection of the most beneficial ones.

Overall, the different developmental timetables of executive subcomponents are associated with the different rates of maturation of their mediating brain regions. From a biological perspective, it is possible that advances in performance are associated with ongoing maturation of posterior regions. From a cognitive point of view, maturation in other cognitive domains may account for advances in executive functioning. Investigation of executive development needs to look at further aspects besides the frontal lobe maturation. The specific impacts of executive functions on ongoing development are yet to be established.

Case studies provided evidence that after early cerebral insult of the frontal lobes in childhood, these children grow up to be adults that display some typical characteristics of executive dysfunction (e.g. poor planning). In accordance with the early vulnerability theory, even focal damage to the frontal lobes early in life can have serious and global effects on further development in children. In contrast, later acquired damage is more aligned to adult patterns of specific deficits. Caution is needed when diagnosing executive dysfunction. Executive dysfunction is reported in many CNS conditions like ADHD and autistic children. The dysfunction can be identified and carefully documented; the etiology however, is hard to establish. It is very important to consider age-appropriate expectations when assessing for potential executive disturbances.

Overall, factors like time of injury, developmental stage of skill establishment and the child’s context interact in determining cognitive consequences after CNS injuries.

The younger a child is at time of injury, the fewer well-established skills it possesses, which increases the risk for more global impairment. The impact of insult is especially detrimental in sensitive periods of development, most likely resulting in irreversible damage. As development occurs within a dynamic context, deficits in one cognitive domain can impact normal development of another related domain. Eventually, primary and secondary impairments add up which might provide an explanation for the global impairments often encountered in children with early CNS damage.

What are the neural bases of plasticity and early vulnerability? Recovering from early brain injury - Chapter 4

Common pathological conditions like localized ischemic strokes will certainly result in specific cognitive deficits for adults, whereas children show a very different pattern of consequences. Childhood outcome is more dependent on the nature of injury. Early CNS insult that is localized leads to a more beneficial outcome in children compared to adults, but in the case of more diffuse damage, poorer rates of recovery become evident. There are two contrasting views on childhood cerebral injury and consequent recovery.

Views on childhood cerebral injury and consequent recovery

On the one side, there are so called plasticity theorists that argue for an advantage of the immature and undifferentiated brain over the mature brain experiencing CNS injury. As synapses and dendritic branches have not yet been completely specified and the overall functional system of the brain is not as determined yet, there is a higher possibility of transferring functions in response to injury in the younger brain. This reorganization underlying better recovery outcome for children can either be within or between the two cerebral hemispheres. Traditionally, research population for plasticity research relies on children with unilateral, local lesions acquired in prenatal stages. Early findings of children after hemispherectomy and aphasic children pointed towards more favorable recovery rates compared to that of adults with similar conditions. However, these early studies are confounded and constrained by several methodological flaws. More recent and better-controlled studies still support that there is a better outcome when localized damage occurs in the immature CNS compared to the mature CNS. These findings are not universally applicable. The theory cannot account for children that exhibit serious consequences following early damage, especially in the case of generalized damage or damage in prenatal stages. Plasticity might reflect an oversimplification of cerebral processes taking place after early cerebral injury.

On the other side of the extreme are early vulnerability theorists who claim that early CNS disturbances are more serious than later ones with respect to ongoing developmental processes. They argue that the theory of plasticity ignores the fact that brain injury results in different consequences according to time of occurrence in development. Put differently, early insult can have more serious consequences for the child because some cognitive skills critically dependent on the integrity of brain systems at a particular time. So if this integrity is not given due to insult, the cognitive skill may be severely delayed or may not occur at all. The possibility of plasticity is not fully refused; rather it is seen as very time limited and as having a nonlinear relationship with age. Even if plasticity and associated reorganization of functions occur, this might not necessarily lead to an optimal outcome. The danger of crowding exists when functions normally mediated by two hemispheres are crowded within one hemisphere after damage. This may result in a general depression of all functions. Most likely cognitive deficits affect skills essential to subsequent learning and skill acquisition, which then lead to accumulation of deficits with increasing age. Nowadays, the two extremes are regarded as two ends of a continuum an individual can fall in between. The eventual outcome of a child is dependent on the interaction of several factors including injury-related, environmental and developmental factors.

Recovery

Two biological mechanisms underlying recovery present an advantage of the immature CNS over the mature one. After cerebral injuries, a number of brain tissue changes may occur depending on the nature of insult. With occurring lesions, degeneration takes place in a number of ways, including cell death and axonal shrinkages which limit related neural systems. Further, glial cells take action in repairing as much damage as possible and cleaning the injury site. Most degeneration happens in acute phases of recovery in children as well as adults.

In cases of diffuse damage after TBI or cranial radiation, some degeneration and associated collection of pathology may continue. Recovery involves the neurological and function level of CNS. One class of recovery mechanisms is called restitution of function.

It proposes that some time after the damage, spontaneous recovery occurs in which healing processes start, neuronal pathways are restored and functions are reinstated. There are four stages associated with functional reinstitution.

1. The theory of diaschisis, which provides an explanation for the generalized pattern of deficits right after an injury. Within the first days or weeks after the insult, rapid improvement of neurological and conscious state takes place. This quick recovery is related to the reinstatement of spared tissue that has been disrupted but not completely destroyed. Diaschisis can be described as a state of general inertia which temporarily inhibits overall brain activation by means of increased intracranial pressure and excessive release of neurotransmitters throughout the brain. This theory enables a distinction between transient disorders of the CNS which disappear after some time and more permanent consequences. The early stages of recovery show no age-related differences in outcomes. After completion of this stage, other processes for further recovery take place.

2. The process of regeneration, which enables the re-establishment of previous connections when axons, terminals and neurons start to re-grow. The successful regeneration is often complicated by resultant scar tissues or bleeding. In the end, only a small subset of axons will reach its former destination with the majority reaching incomplete or even maladaptive recovery.

3. The process of sprouting, whereby remaining fibers develop branches in order to occupy sides that are empty after brain damage. This re-usage of areas takes place early after the injury and progresses fast, which might account for some neurobehavioral improvements within the first weeks of recovery.

4. The process of denervation supersensitivity, in which postsynaptic processes within an injury site become supersensitive to released neurotransmitters of other neurons. This may allow for new pathways to emerge and thereby allow reinstatement of previous functioning.

All of these later mechanisms are equally effective in the immature and mature CNS. Nevertheless, the immature brain carries a higher risk for abnormal re-growth of neurons as its organization is not as static as it is in adult brains. One possible explanation comes from mechanisms of neural competition. Accordingly, the immature CNS damages lead to relocation of functions which consequently reduces the number of available synapses for other neurobehaviors. Eventually, this may result in a crowding effect with associated overall depression of functions as only few synapses are left for subsequent skill acquisition. The second class of biological mechanisms is substitution of function, in which healthy tissue takes over functions previously mediated by damaged tissues. It provides some evidence in favor of plasticity theories. The immature CNS is not yet specified, allowing for a transfer of functions with little resultant residuals. Substitution can involve two processes.

1. Anatomical reorganization, stating that in the young brain a great deal of area is still equipotential and has the capability of taking on functions after damage occurred. This capability diminishes with age, arguing for an advantage of early brain injury. But more recent findings of especially dramatic effects after prenatal disruptions are inconsistent with plasticity theories.

2. Behavioral or functional compensation, refer to the development of alternative strategies for cognitive functions that previously depended on damaged areas. Alternatively, external strategies can be employed to compensate for deficits. For instance, calendars can be a great help for patients with memory problems. Therefore, rehabilitation interventions should target behavioral compensation by suggesting strategies and adjusting the environment according to the patient’s needs.

The final outcome

The final outcome after cerebral insult depends on a wide range of factors. Among these are: injury severity and natur, age at time of injury, gender, the psychosocial context of the child.

1. Injury severity and nature. Earlier findings of better outcome after early injury have been mainly based on research of patients with localized lesions. With respect to severity and site of local damage, there is no linear relationship. Small lesions, as well as larger, but unilateral lesions tend to show favorable recovery patterns. This might partly be explained by some transfer of function within the hemisphere and as usually carries the risk of crowding effects. For moderate and bilateral damage, plasticity is unlikely to compensate for it and generally recovery is poor. For more diffuse damage after TBI, recovery is also poor and indicates dysfunction at a more global level. Overall, there is a dose-response relationship between outcome and injury severity regardless of age.

2. Age or developmental level at time of injury. The younger the child, the less mature is their CNS with only few well-established cognitive functions. A complicated relationship exists between age and plasticity, evident in poorest recovery from postnatal disruptions of development. Nevertheless, early injury may be compensated for by creation of abnormal cortical connections which spare functions. Times at which this is possible appear to be very limited and also depend on specific cognitive domains. Additionally, periods of very fast development have been shown to be particularly vulnerable to interferences from cerebral injuries. Another issue, which is important to research, concerns the interval between damage and subsequent assessment of functions with regard to age at which assessments are done.Immediately after an injury a child might present with little or no residuals, but as time passes they might not be able to learn new skills at normal rate. These children seem to grow into their deficits with time.

3. Gender. The issue of gender-specific outcomes after early CNS injury is controversial. Functional imagining techniques revealed that the male brain shows more lateralization of functions and the female brain exhibits more bilateral activation. Nevertheless, this is not universal as no such differences are reported in language functions. It can be argued that structural differences within male and female brains impact CNS recovery. One possibility is that, with the female brain appearing to me more diffusely organized, it might have greater potential for functional transfers. There is some evidence supporting this, stating better recovery for girls after early brain damage. This might account for higher prevalence rates of boys with developmental disorders such as ADHD and specific learning disabilities.

4. The psychosocial context of the child. Factors like family functioning, socioeconomic status and access to rehabilitation resources are impacting a child’s recovery. The influence of these impacts increases with time. Initially, outcome is predicted by lesion-related variables and in the long-term, psychosocial variables become more predictive of good outcome. Children from socially disadvantaged families who sustained brain injuries present poorer recovery and outcome with time, in contrast to children from more appropriate social resources. Animal research indicates that the post-injury environment greatly impacts later learning.

The effect of early brain injury on language lateralization has been subject to great debate with two contrasting theories about it. One theory is concerned with equipotentiality and postulates that after birth the two hemispheres are both capable of taking on language functions. The left hemisphere becomes increasingly important with increasing age and eventually language functions are fixed within the left hemisphere by middle childhood. Most support for this theory stems from studies of children having undergone hemispherectomy, in which language functions can be spared even after removal of the left hemisphere. This immense transfer of function is limited to early childhood, namely to a period of rapid language development between the ages of two and five. After this period, such transfer is no longer possible.

Additional evidence comes from early childhood epilepsy with seizures in the left hemisphere: these children can display transfer of language localization into their right hemisphere. Another approach is that of innate specialization, which is compatible with the localizationists’ approach mentioned earlier. This theory argues for genetically predetermined parts within the cortex essential for later language functions and are believed to have an innate representation of language. Up until recently, it has been very difficult to establish direct evidence for such lateralization of language. With technological advances, including noninvasive methods like fMRI and PET technologies, it became possible to find evidence for or against lateralization. There is convergent evidence against equipotentiality and evidence for left hemisphere specialization of language functions. In addition, even early injury to the left side of the brain can result in serious residuals of language disabilities later in life.

Most of these early studies can be put into one of three categories. The first category is IQ differences related to one-sided cerebral damage. Most studies used clinical samples of children with unilateral vascular damage and hemispherectomy. Commonly, the IQ performance is reported in relation to age at injury; with increasingly lower IQ scores with increasing age. Main focus lies on relative differences between Verbal IQ (VIQ) scores and Performance IQ (PIQ) scores on the Wechsler IQ test. There is evidence from a number of studies which show that intellectual outcome depends on timing of damage and its side. Findings are incompatible with early plasticity and functional reorganization theories which are supposed to be greatest within the first year of life. Lesions acquired after the first year show only little impact on intellectual performance if lesion occur only in the left side (with more damage before age one); lesions to the right hemisphere result in specific impairments of non-verbal skills (with more global impairment before age one). These results have to be interpreted with caution, as measures of IQ are relatively insensitive to more subtle neurobehavioral deficits. A more sophisticated approach to IQ measure focuses on three factors: freedom from distractibility, perceptual organization and verbal comprehension. Studies with this measure showed that all children who suffered from CNS insult performed poorly on the freedom of distractibility factor. This was independent of age and localization of injury and is indicative of a more general effect on processing capabilities and attention. General findings suggest some sparing of language abilities of lesions occurring after age one, regardless of side, with only little impact on it. This argues for more functional transfer after the age of one, which is contrary to the original notion of plasticity (with better outcome prognosis before age one). All these findings need to be interpreted with caution due to methodological flaws. For one, the studies assume a simple dichotomy with PIQ representing right hemisphere functions and VIQ representing left hemisphere functions; which is untenable nowadays. Furthermore, IQ scores are unlikely to reflect the full range of impairments. Some patients can perform within a normal IQ range, despite severe cognitive deficits.

The second category is sodium amytal ablation studies. Here patients are studied who suffer from intractable epilepsy and undergo this procedure before temporal lobectomy. The name of this procedure is WADA and is mainly concerned with helping to identify which hemisphere mediates language functions. Some studies with children contained subgroups that showed abnormal localization of language functions. Considering left-handed children only, 28 percent had left-sided speech locus, 53 percent hat right-sided speech locus and 19 percent showed bilateral locus of language. Several factors are likely to influence such reorganization, namely focus, severity and age of lesion onset. Transfer of language function only takes place if the language cortex is damaged. Similar studies have been conducted using fMRI to investigate brain activation patterns in children. The underlying idea is that with language-based activation paradigms it should be possible to precisely determine the location of language areas. Furthermore, this enables the exploration of possible functional reorganization. Early findings support the idea that with early injury there is greater potential for relocation to the non-dominant hemisphere- this is not a universal finding though. An alternative hypothesis states that other healthy areas might be recruited in order to support language functions; rather than taking them over.

The third category is studies with normal children and infants. These studies provide some evidence in favor of innate specialization. Postmortem studies of fetuses and infants showed that left areas within the left hemisphere are larger than their counterparts in the right hemisphere. Such asymmetry is in line with language lateralization. Additional research employing electrophysiological measures also support anatomical asymmetries. It follows that some language specialization is innate within normally developing children, but with damage occurring early there is some potential to spare language functions by means of functional reorganization. It has been postulated that some primary system to mediate language function exists and another back-up system in case of disruption to the first. This possibility diminishes with increasing age, reflecting maturation and associated specification of the CNS.

There are three potential mechanisms that might underlie cerebral reorganization after brain damage.

1. Intra-hemispheric maintenance is one such mechanism and refers to an absence of functional transfer. Consequently, skills mediated by the disrupted system stay within it and manifest itself as maximum dysfunction. This mechanism is mostly occurring in adult cerebral injuries. With regard to the immature CNS, this mechanism is most likely to take place following disruption in prenatal and perinatal stages. In these cases, severe developmental impairments result from it (e.g. mental retardation). One-sided lesions at these vulnerable stages will affect speech and language development (delay); with general lesions resulting in more general cognitive impairment. Such recovery patterns are also common in adolescents approaching adult levels of brain development. Furthermore, intra-hemispheric maintenance mechanisms tend to occur following small local lesions and little associated residuals, such as in generalized early cerebral injury. This leaves the children with only little healthy tissue that can take over these functions.

2. Inter-hemispheric transfer most often results from rather small damage or larger one-sided lesions, leading to major deficits within that hemisphere. Research points in the direction of possible language and also some non-language based (memory functions) transfer of function to the other hemisphere. An alternative approach argues for a less dramatic process in which healthy areas are only recruited to compensate for damage. Regardless of which specific mechanism is at work, there is an age-related limit to them. So inter-hemispheric transfer of language is most likely to occur within the first two years of life. Outcome for children is then impacted by a crowding effect leading to global depression of functions as opposed to more specific impairments after similar injury in adults.

3. Intra-hemispheric transfer refers to functional reorganization within the damaged hemisphere. There has been little research investigating this mechanism with limited availability of appropriate measures. It probably occurs after one-sided and local damage and more so in older children between the ages of two and eight. Support comes from a case study of a girl with a focal tumor in the Broca’s area, where adjacent brain areas were recruited in language-based tasks.

Overall, neither plasticity nor early vulnerability theories can account for the wide range of consequences following early CNS injury. Most likely the two form a continuum on which individuals fall depending on several factors. In the end it is the interaction between environmental and biological factors that determine possible plasticity and its functional effectiveness.

What is the cause and effect of traumatic brain injuries during childhood? - Chapter 5

Traumatic brain injuries

TBI are the most common cause of disability for children. It is estimated that one in about 30 children will have sustained a TBI before the age of 16.The majority of these are mild resulting in little or no impairment, with only a small proportion sustaining more severe brain injuries with permanent cognitive and behavioral disturbances.

Of all TBI incidents in childhood, about five to ten percent will display either temporary or permanent deficits and another five to ten percent of these injuries will result in death. As with other brain insults, also for TBI there exists a dose-response relationship between outcome and severity of force impacting the skull.

On a more superficial level, about a third of severe injuries will be fatal and the chances of good recovery are much smaller as opposed to mild or moderate TBI accidents. The impairments commonly observed after TBI limit the child’s ability to effectively interact with the environment, which interferes with subsequent skill acquisition and eventually results in an increasing gap between age peers and the affected child.

In addition, secondary problems are often related to traumatic brain injuries, affecting the whole family of an injured child. The neuropsychologist plays a critical and continuous role especially in cases of severe TBI. The tasks include understanding the individual difficulties faced by a child and their families after TBI, provide information about the child’s condition to the family, teacher and collaborate with other workers involved in the child’s rehabilitation, as well as providing individually tailored academic interventions, behavioral management strategies and counseling opportunities.

Reported prevalence rates of TBI suggest that incidents as well as nature and cause of the injury vary according to three likely interacting factors. For one there is age, with children younger than about three years of age having the highest incidents rates. Infantile TBI mainly results from falls or physical abuse, with a majority of non-accident causes leading to particularly severe patterns of deficits and are associated with much higher morbidity and mortality rates. As the child gets older and reaches preschool age, the main cause of TBI is related to falls, but also an increase in pedestrian accidents due to a child’s advances in mobility combined with insufficient awareness of danger. Once in school, most accidents result from sporting, pedestrian and bicycling accidents. Different causes of TBI will affect the resultant cerebral damages and changes. In general, the fatality rates are negatively related to age, so that with increasing ages the fatality probability after TBI decreases. Furthermore, recovery tends to be better with older ages of injury which is in line with greater vulnerability early in life with regard to diffuse cerebral insults.

Gender differences

Over the whole life span, boys and men are more likely to experience TBIs than their sexual counterparts. At school age boys are about twice as likely to get injured. Obviously, gender plays a role in incident rates of TBI, but also in TBI severity. Boys not only tend to have a higher probability of brain injury, they also tend to sustain more severe injuries with a mortality rate of about four to one when compared to female injuries.

It has been suggested that higher levels of activity and exploratory behaviors in boys are closely related to these rates. In particular, whereas incidents rates for girls show a gradual decline throughout childhood, boys show an increase well into adolescence. Detailed investigation of TBI accidents revealed that most accidents happen in the afternoon, on weekends or holidays. This emphasizes the notion that many TBIs stem from reckless behaviors within an environment that is marked by poor supervision. Other psychosocial factors are likely to impact TBI incidents. Research provided evidence that TBIs are more common in families with the following characteristics: poor supervision and neglect of the child. Furthermore families from socially disadvantaged backgrounds with emotional disturbances and unemployment issues pose a risk factor for TBI. In addition, child characteristics are also influential, with premorbid behavioral issues and learning disabilities increasing the risk of TBI accidents.

Causes

Traumatic brain injuries commonly involve either a wound to the head or a physical blow, accompanied by an altered state of consciousness and might leave the child with permanent neurobehavioral deficits. The level of change in consciousness is routinely examined to differentiate true TBI from more mild forms of head injuries.

It should not be regarded as a unitary unit because outcomes can differ greatly depending on underlying mechanisms and resultant brain pathology. Among other factors, outcome is influenced by factors related to the injury itself, namely the force of impact, injury site, if fractures accompany the injury, thickness of skull and scalp, as well as vectors of transmitted force within the skull. In general, consequent injuries can be categorized into two distinct ways.

1. Primary injuries include contusion, laceration, diffuse axonal damage and at times fractures as well. These injuries are the direct result of impacting forces on the brain. Damage due to these injuries is mostly nonresponsive to treatment and leaves the victim with permanent damage.

2. Secondary injuries include hemorrhage, edema, hypoxia and raised intracranial pressure among others. These stem from primary injuries and are responsive to treatment if timely and appropriately provided.

If death does not occur right at the time of impact, most common causes of death in children are increased intracranial pressure (ICP), ischemia, and subarachnoid hemorrhage as well as diffuse white matter damage. What injuries and resultant residuals manifest within a child also depends on the nature of sustained TBI.

Classification

TBI is classified according to nature of injury; either it does or does not involve direct brain penetration.

In case of penetrating head injuries, as the name suggest, some kind of missile like a bullet or knife penetrates the skull and underlying brain structures. Primary injuries are rather localized with more wide spread damage stemming from fracture fragments and shattered fragments of the missile that go right into the brain. Only the minority of childhood TBI involves skull penetration (ten percent). Due to the nature of injury secondary consequences of penetrating head injuries likely involve some kind of infection as well as brain swelling, bleeding and increased ICP. Consequent deficits are rather specified and consistent with lesion location.

Overall, loss of consciousness is uncommon after these injuries, but epileptic fits are most often observed after closed head injuries. Even though, resultant residuals are likely to persist with permanently damaged brain tissue, recovery tends to be good when compensatory strategies can be employed.

The majority of TBI fall into the category of closed head injuries. Here the brain is shaken within the skull leading to more global damage due to multiple lesion sides. The damage results from deformation and compression of the skull at insult site, with severity depending on the impacting force. Most often these accidents involve high velocity deceleration forces as can be seen in motor accidents, as one example. Primary injuries are first of all contusions (bruising) at the site of impact leading to coup injuries and at the opposite site leading to contre-coup injuries. Contre-coup injuries tend to be worse. Regions in the frontal and temporal lobe as well as the basal ganglia have an especially high risk of contusion. Depending on the kind and force of impact the brain is shaking back and forth, and might even rotate. Nature of consequent pathology depends on these brain movements. Localized damage can be expected with linear injuries, whereas swirling and gliding of the brain (rotation) mostly causes more diffuse damage. Underlying more generalized injuries is the shearing and tearing of axons, particularly those connecting the brain stem with other cortical areas. Secondary injuries like hematoma formation, edema and increased ICP are most predictive of later recovery and outcome. Some of these might be caused by disturbed neurochemical processes.

It has been shown that elevated levels of excitatory amino acids disturb cell functioning and might lead to cell death. This excess persists for several days after the injury. Also, the amount of it correlated with computerized tomography (CT) findings of brain damage. Disruptions to the blood system might result in bleeding which can result in hematoma. Depending on size and location, surgery might be in need to prevent further damage. One indication of hemorrhage is a change in conscious state a while after TBI that cannot be accounted for by the initial impact on the brain.

There are three subtypes of hematomas, classified according to their location.

1. Epidural hematomas: These occur as a consequence of bleeding just above the dura mater with no direct brain involvement. This is commonly seen after skull fracture when vessels in the meninges are damaged. If treatment occurs fast, the prognosis is good.

2. Subdural hematomas: If cortical blood vessels or the venous sinuses are damaged after massive cortical disruption, blood is collected between the subarachnoid and dura mater. These are more common and serious than other forms of hematoma. There is a high risk of edema calling for fast surgical treatment to prevent suppression of underlying brain tissue.

3. Intracerebral hematomas: These are commonly observed after penetrating head injuries and result in a blood clot formation within the brain. The prognosis depends on site and extent of the hematoma.

A number of secondary injuries are associated with hematoma formation. Edema (brain swelling) is a condition in which fluid volume within the brain increases. Among other causes, it can result from obstructions to the cerebral blood flow as it is the case with hematomas. Both increase the risk of subsequent elevations in intracranial pressure which impacts the brain either locally or the whole brain. As serious damage is expected with increased ICP, which is why it is crucial to monitor it and, if necessary, provide surgical treatment. Immediate consequences of high ICP include midline shift, ischemic damage due to reduced blood flow and herniation. At times, delayed consequences can follow TBI, especially after surgical interventions which carry their own additional risks. Even though only rarely observed after closed head injuries hydrocephalus, infections and cerebral abscess may occur in post-acute stages of injury. Hydrocephalus is a condition in which the cerebrospinal fluid system is disrupted and fluid accumulates within the skull resulting in diffuse cerebral damage. Post-injury epilepsy is quite common after penetrating head injuries, less so for closed head injury. Additional risk factors are brain trauma at younger ages that are severe and localized.

Overall, the specific outcomes after TBI are not only dependent on severity and mechanisms of the injury, but are also influenced by the age of the affected child. The impact of insult will lead to different outcomes according to a child’s developmental standing as well as its brain and skull development. Infants are particularly vulnerable to external forces since their skulls are still very thin and consequently easily deformed, and their neck muscles are not strong enough to sufficiently support head posture. One advantage concerning infantile TBI is that contusions and hematomas are very unlikely, as the open sutures can somewhat absorb the impacting forces. On the other side, about one third of TBIs result in fracture at this age. As the child gets older mass lesions like hematomas are more frequently observed. Throughout childhood contre-coup lesions are quite rare as opposed to in adult TBI. The immature CNS with its unmyelinated axons can absorb some of the forces, since the two hemispheres are rather soft and pliable. At the same time though, unmyelinated axons are more vulnerable to disruptions causing more diffuse axonal damage in children. In contrast to adults suffering from traumatic brain injuries, children and especially infants are far less likely to show a loss of consciousness after TBI, but have increased incident rates of post-injury epilepsy. In general, the consequent brain pathology, outcome, recovery and resultant residuals differ between childhood and adulthood TBI.

Diagnosis

Initial diagnosis of TBI starts right at the scene of the accident, where state of consciousness and neurological status are assessed for the first time. After admission to the hospital a number of data are needed to evaluate the extent of primary and secondary injury as well as severity and nature of the injury itself. At this acute stage the focus lies in an accurate identification of secondary injuries and adequate treatment to minimize further neuronal damage.

The Glasgow Coma Scale is a common measure to assess severity of injury, which classifies the severity of TBI according to the level of consciousness that a patient presents. The scale measures a patient’s verbal and motor responses as well as his ability to open his eyes, depending on their response scores, with a given lower score indicating more impairment. Scores range from 3 to 15 and classify TBI into three according categories. Mild TBI, which is characterized by only slight conscious changes (drowsiness), falls between scores of 13 to 15; moderate TBI falls within a range of 9 to 12, and severe TBI is reflected by scores of 8 or lower. These cutoff scores are based on adult research and are not appropriate for infants and children.

Many of the verbal and motor responses require a level of performance that young children have not yet reached. It is generally accepted to use adult ratings with children around the age of five or older. The Pediatric Coma Scale is based on the Glasgow Coma Scale, with scores and severity adapted to the child’s age. Accordingly, infants younger than six months can only reach a maximum score of nine. Only the eye opening subscale can be readily used across all ages. Both scales provide a universal measure of severity of classification, which are widely accepted and used. Despite its wide usage, several limitations apply. Foremost, the reliability of the measure is highly dependent upon the rater himself. Many patients need painkillers and even surgery with anesthesia that disrupt the utility of the scales and there is no consensus about when to best use the measure. Far and beyond the scales usage as a severity indicator, it has also been used to predict recovery and screen for potential deterioration that might be indicative of underlying brain pathologies. There is some controversy with regard to its predictive value; some argue that the motor scale is most predictive of later outcome.

Another severity classification system relies on the duration of posttraumatic amnesia (PTA). It is defined as a state of confusion and disorientation often following TBI or after regaining consciousness. In the past, it was classified as a memory disturbance, but more recently it has been accepted to underlie attentional impairment rather than memory dysfunction per se. It is suggested to vanish, once the patient can successfully recall new pieces of information from their memory. There are several steps before reaching absolute resolution of amnesia, which are graded to indicate injury severity. Adoptions have been made to accommodate childhood TBI. It includes memory tasks that are specific to children, namely recall of personal information, some basic memory tasks and temporal orientation. The measure is administered repeatedly over the days following TBI, until a threshold level indicating functioning, is reached. If administered in a standardized manner, it is supposed to be more reliable and predictive than the Glasgow Coma Scale. In practice, this is rarely the case.

In order to assess brain pathology, several technological methods are available. This is especially crucial right after the accident to establish whether surgical interventions are needed. Structural imagining techniques like computer tomography (CT) and MRI scans are routinely used for radiological investigation of the damaged brain. In the context of skull fractures, suboptimal consciousness and/or neurological abnormalities, these techniques provide first information about primary and secondary injuries. Results of investigation fall within one of three categories:

1. No abnormalities are evident on scans,

2. intracranial mass lesions like hematomas are evident and might call for immediate surgical interventions,

3. There is indication of diffuse axonal damage which necessitates monitoring for increases in ICP and surgical treatment.

These techniques are important, as about half of all comatose TBI patients have intracranial bleeding which demands surgery. CT scans are not sensitive enough to show diffuse axonal damage. Some severely injured patients are known to show normal CT scans, therefore more sensitive scans of MRI are utilized to investigate more non-life threatening injuries during the course of recovery. In contrast to CT scans which have little predictive value, MRI scan taken after acute stages of recovery are highly related to later outcome. If structural findings suggest large lesions, other functional imagining techniques are employed. SPECT and PET scans can indicate more subtle injuries and provide valuable information on damaged regions regarding their metabolic activity. Nevertheless, their usage is limited, especially in children as they require radioactive agents. In general the utility of EEG findings in TBI patients is very limited. It has been shown that in combination with CT scans within acute stages of recovery, EEG show some predictive utility with regard to academic outcome. This only applies to moderate and mild TBI cases. Another electrophysiological measure has proven useful in establishing injury severity and predicting outcome. Evoked Potentials provide information about sensory systems in patients that are unresponsive (comatose). On a more functional level, impairments are assessed by neurological examinations. It is recommended to routinely employ these measures independent of injury severity. Information about sensation and coordination of a patient’s limbs as well as general motor power is indicative of underlying brain dysfunction. Regardless of findings, these do not exclude the possibility of more generalized dysfunctions which cannot be assessed by neurological methods. Overall, adequate and reliable assessment of injury severity depends on a combination of the presented methods. No single one provides sufficient information. The prognostic predictions about neuropsychological outcome in children after TBI are very limited so far. One challenge of childhood neuropsychology is to identify still unrecognized variables that might determine patient outcome.

Recovery

The acute recovery phases differ between mild and moderate/severe TBIs. In the case of mild TBI, patients display only brief episodes of altered consciousness and at times some posttraumatic amnesia. Most cases are not hospitalized and only observed for a limited time.

General behavioral symptoms are fatigue and irritability, which suggest that the patient most of all needs to rest. Initially, transient cognitive dysfunctions in attention, memory, language ability and psychomotor speed may occur, but these tend to vanish over some time. Children show good recovery and especially if no premorbid behavioral problems exist. Consequential behavioral changes have only been observed in cases of premorbid dysfunction, in which TBI is believed to exacerbate these pre-existing problems.

In cases of moderate or severe TBI, recovery takes much longer. In contrast to mild injuries, the child goes through multiple stages of recovery. The overall outcome depends on an interaction between a child’s physical recovery and level of development as well as reintegration of the child (family, school) and family responses toward the child. In acute phases of recovery, the severely injured child is probably unconscious, hospitalized and potentially in intensive care.

If the child is unresponsive, careful monitoring is crucial to detect worsening of the child’s condition, which might indicate underlying brain pathology. In these early stages, rehabilitation is mainly concerned with maintaining fundamental activities like feeding and strength. For the family, this time is marked by anxiety about the child’s survival with emotional fluctuations commonly observed. Additional stressors for families include care for other children. Possibly other relatives have been hurt as well and need support due to financial and employment problems. Once the child emerges from coma and survival is secured, the next stage of recovery follows.

In the early rehabilitation phase, the focus lies on identifying deficits and maximizing recovery. After awakening the child will still be in a state of confusion (PTA) which is marked by restlessness and for some even aggression and abusiveness. Thereafter, when functional deficits start to show, rehabilitation is implemented. The specific rehabilitation programs depend on the child’s profile, but most commonly contain physical and speech therapy throughout hospitalization. The general goal is to enable the child as soon as possible to return home. Even after successful discharge from the hospital, regular rehabilitation sessions are essential to further good recovery. Eventually, the child should gradually be reintegrated into its daily life, including return to school. At the beginning the child should only attend school for short periods of time, mainly to support socialization with friends and peers. With advances in physical strength, the child can increase school hours. During this phase constant communication and liaisons between the child neuropsychologist and the child, the family, teachers and other people involved in the child’s recovery are needed. It can be very stressful for families to find a balance between rehabilitation goals, social adjustment, and school and family resources. Moreover, not only the child, but also the family needs time to adjust to the new situation.

Families vary in their reactions and have their own coping styles; nevertheless, for some it may take years to adjust to their child’s permanent impairments.

The last phase of recovery is called the chronic phase. Here the focus is on helping the child and the families to accept and adjust to permanent deficits of the child. The majority of severely injured children will be in a life-long need of medical support and rehabilitation. Only some exceptions exist where children make good recovery with relatively little need of further support. As the child grows older, families will encounter special challenges related to transitional stages of development. At these times, they likely need additional support and input from the child neuropsychologist to face upcoming problems. One such transition is when the child starts school. With school entry some cognitive residuals become more apparent, for instance, poor motor coordination will reflect itself in sport, writing and drawing performance.

In addition, deficient communicative and attentional abilities will restrict a child’s academic and social interactions with others. Depending on the severity of impairments a child displays, the school might not be able to accommodate to the special needs of the child.

In these instances, it is up to the family to find additional needed resources, secure and also finance these. The child neurologist can alleviate some stress of the family, by contacting the school staff and educate them about the child’s condition and provide help in effectively managing the child. Above and beyond all these challenges, the child’s recovery also interacts with family stress and other variables. Particularly mothers report feelings of being trapped, angry and depressed. These feelings are often related to the child’s behavioral and emotional disturbances. In general, physical impairment appears to be much less stressful to families. In cases of moderate to severe TBI, the child will need ongoing professional support into adulthood and especially at points of transition.

Studies of neuropsychological outcomes

Early studies investigating the neuropsychological outcomes in children following TBI indicated that children’s CNS is more plastic and can handle much of the injury impact resulting in less severe consequences compared to adults. They also argued for a dose-response relation between severity and outcome. More recently, it has been established that earlier findings cannot be true since some children suffering from TBI show significant deficits in functionality. This initiated further investigation of injury severity as a potential predictor of outcome. With advances in more child-specific measurements, research identified many factors aside from severity that influence outcome, namely premorbid behavioral problems and specific learning disabilities, age at injury, time since injury and psychosocial factors. These were first studied in isolation, but now there is a shift towards a more multidimensional approach. Complex interactions as well as relative contribution of each factor alone are of interest.

The Klonoff study was the first attempt to systematically evaluate the effects of TBI on the immature CNS in children. It aimed to investigate the relationship between antecedent factors (age, sex), injury-related factors (nature, severity) and outcome (academic and neuropsychological). In a matched-pair design children were repeatedly assessed on a number of neuropsychological tests over the course of five years. Initial results showed that 40 percent of the children one year after the injury displayed some form of impairment, which decreased to 24 percent after five years. In adults about 31 percent report to suffer from persisting problems. The study revealed a common pattern of deficits including, among others, memory, attention and learning problems. The best predictors for long-term outcomes were injury severity, presence of premorbid problems and initial IQ scores. Despite limitations of the study, it provided important information on the natural course of childhood TBI.

Another important early study is the Rutter study which focused on social and cognitive functioning and aimed to identify recovery patterns for different functional domains. A major goal was concerned with the separation of the different effects on post-injury consequences; including effects of the injury itself, from pre-existing characteristics to secondary psychological stress factors. It was a longitudinal study that followed TBI children over the course of 2.25 years and assessed their neuropsychological performance on four occasions.

Results supported a relationship between injury severity and cognitive outcome, with more severe injury leading to poor initial performance on IQ testing. The duration of PTA has been associated with the persistence of intellectual problems, with longer PTA leading to more problems. In addition, even though severely injured children made good cognitive recovery, over half of them showed psychiatric problems. These behavioral and emotional problems appeared to worsen over time. Children with severe injury combined with premorbid issues were at greatest risk to develop psychiatric problems. They argued though that a sample of children with TBI is not representative of the general public. The typical victim was a boy stemming from socially disadvantaged backgrounds who had a higher likelihood of premorbid behavioral problems and/or learning disabilities.

These early approaches mainly focused on global cognitive outcomes. More recently, the interest in domain-specific neuropsychological outcomes in relation to severity of insult has grown.

IQ. Many studies utilize IQ either to describe their sample or as an outcome measure after cerebral accidents. With regard to mild TBI, studies consistently found little depression of overall intellectual functioning. This is not to say that in these cases there are no deficits, but rather that the IQ measures are insensitive to more subtle cognitive impairments. More severe cases of TBI result in general depression of IQ scores, which affects performance IQ scores more than verbal IQ scores. In the acute phases of recovery, VIQ is generally spared, indicating that already established skills and knowledge (crystallized) are more insensitive to cerebral disruptions. On the other hand, PIQ are likelier to be impaired in short- and long-term, which indicates more vulnerability of fluid skills. Most rapid recovery occurs within the first six months after the injury and levels off thereafter. Despite initial recovery, the score may drop again over time, when children fail to establish new age-appropriate skills. Overall, IQ scores are not sufficient to map the full range of possible impairments after sustained TBI. Even severely impaired children might initially perform within the normal range, when they can rely on already established skills. In addition, the well-structured format of IQ tests benefits the brain damaged child in mastering these tests adequately.

Language. Even though severe language disorders like aphasia are a rare consequence of TBI, other more subtle language deficits have been reported. Commonly documented impairments are evident in verbal fluency, speed of speech and logically sequencing words and sentences, thereby negatively impacting a child’s ability to communicate.

Research on four language aspects (naming, expressive and receptive language skills and writing capacity) has supported a dose-response relationship between all four of these and injury severity. Even with pre-injury well-established language skills, severely affected children suffered from global language impairments, which remain persistent beyond the first year post-injury. No such deficits have been found in children with mild or moderate TBI. Children are far more impacted by TBI than are adults with regard to language functioning. This is consistent with earlier mentioned sensitive periods of language development in children.

To assess children’s language abilities in a more natural manner, focus shifted towards the quality of discourse in children with TBI history. Discourse describes language in the contextual, narrative and conversational setting in which it is daily used and understood. More detailed investigation revealed, that even children performing adequately on standard language tests showed impairments in discourse (fewer sentences and words). Further, younger age at injury has been associated with more global language problems affecting discourse skills as well as formal language aspects. Within one year after injury, children improve their language skills and make fewer errors, but still do not reach age-expected levels.

Visual and motor skills. In acute stages of recovery, the child will usually exhibit severe visual and motor deficits, which undergo fast recovery within the first couple of months. Only in cases of severe TBI do these deficits persist. More subtle deficits can also persists after mild injuries, including reduced eye-hand coordination and general psychomotor slowness. Even very mild impairments can impact everyday functioning resulting in secondary complications in self-esteem, socialization and academic performance.

Generally, visual and motor impairments are equally likely to follow TBI in children and in adults. More detailed investigation aimed at separating the effect of psychomotor slowing from other motor and visual residuals. On these tests, even severely impaired patients showed no deficits in tasks of motor and visual ability one year post-injury. Once speed requirements rise, severely affected children showed most difficulty in task accomplishment. Apparently, recovery can take place up until five years after the injury, but in a nonlinear, systematic manner. In general, younger age at time of injury combined with greater severity is related to poorer visuospatial and motor development.

Memory and learning. Memory functioning is especially sensitive to effects of early childhood TBI. Converging evidence from a number of studies established four major findings. First, there is a dose-response relationship between the degree of resultant memory dysfunction and severity of insult. Second, another dose-response relationship exists between the pattern of recovery and injury severity. Third, recovery of memory abilities does not affect all subcomponents to the same extent; storage is relatively intact but memory retrieval is more disturbed. And finally, there is a relationship between the nature of memory deficits (verbal or visual) and the age of insult. This is thought to mirror the level of skill at time of injury. In more general terms, there is support for more global impairments of learning, storage and retrieval for severely injured children. In contrast, for children suffering from mild or moderate TBI findings are less clear cut, but the children tend to recover better with only mild retrieval problems. Overall, less severe cases of TBI show more variability in terms of final outcomes, whereas severe cases are likely to be accompanied by persistent problems.

Attention skills. Even mild disturbances in attention and information-processing capacities can impact subsequent learning and eventually may result in global dysfunction. In adult TBI, sustained attention and focused attention are usually intact; but there is psychomotor slowing that is a result of underlying attentional deficits. Children exhibit a wider range of deficits across various components to the attentional and information-processing system. A study with adolescents after moderate or severe TBI revealed no impairment of sustained or focused attention as opposed to in adults.

Deficits in adolescents focused more on tasks that required fast responding, complex processing or higher-order attentional processes. Taking together the findings of several studies, children exhibit more globalized disturbances in attentional abilities which are likely to persist beyond acute recovery. It has been suggested that these global problems reflect relative immaturity of attention development when TBI strikes. In children the injury interacts with further development leading to delay or deficient development. Attention plays a critical role in further skill acquisition as the child gets older. Therefore, in addition to initial injury and impairment, ongoing development may be hindered. Inadequate learning might result, producing an increasing gap between the TBI children and peers.

Executive functions. Following childhood TBI impairments of executive functions are commonly reported. This is related back to the relative immaturity of the prefrontal cortex that mediates these functions. The more severe the injury and the younger the child at time of impact, the poorer the performance tends to be on executive tasks. Common patterns of impairment in moderate and severe injuries are: reduced capacity for abstract thinking, poor planning and problem-solving and slowed response speed. The latter is especially vulnerable with younger ages at injury. Findings are less consistent for children suffering from mild TBI.

Most of the current literature deals with performance on standardized tests, but even a mildly affected child with normal performance on tests can experience significant problems in everyday life. One contributing factor is the good physical recovery most TBI children undergo. Superficially, TBI children appear normal to others which leads to unrealistically high expectations that they cannot live up to. Therefore, functional outcomes of children with TBI and predictive factors are of great interest.

Functional outcomes

Educational abilities. Academic failure is probably the most serious consequence following TBI. So far it has been difficult to assess the extent of educational deficits as no tests have been established for this purpose. Some argue that incidences of academic problems are higher in children who later sustain TBI, suggesting an overestimation of actual TBI effect on failure. In the past, standardized tests were the only means to measure educational performance. Nowadays, school placement is a better indication. One year after severe and moderate injuries, children are more likely to require special assistance to manage school demands. It follows, that need for special education is closely related to injury severity and neuropsychological performance. Generally, reading skills are more insensitive to TBI effects as opposed by arithmetic skills and comprehension abilities. Age of impact is especially relevant to academic outcomes. When injury occurs prior to a child’s acquisition of basic literacy skills, even very mild injuries can result in subsequent school failure.

Similar findings have been established concerning reading comprehension, which is severely impaired after mild impacts when the child is younger than nine. Taking all this together, the interaction between age and pre-injury level and complexity of skills best predicts academic outcomes.

Behavioral consequences. It is quite problematic to measure behavioral outcomes in an objective manner, as before the injury a baseline assessment cannot be done. In general, there is controversy regarding the underlying etiology of behavioral problems after TBI. On the one hand, it may be related to premorbid problems that are exacerbated after injury as well as family variables. On the other hand, it may be more closely tied to direct injury impact on cerebral functioning. In reality, it is probably a combination of multiple factors, including premorbid characteristics and family functions, the injury impact as well as secondary adjustment problems. Initially, behavioral manifestations after TBI are most commonly fatigue and irritability, which vanish over time. More permanent manifestations involve aggression, hyperactivity, lack of motivation and poor self-regulation. Secondary effects may be that children develop poor self-esteem and experience social difficulties.

Behavioral problems are most disabling to the child and their families, especially as these tend to increase over time. This increase over time may either be related to TBI effects or to depression and other adjustment-related factors. There exists a dose-response relationship between severity of insult and subsequent development of behavioral and psychiatric problems in the short and long term. The occurrence and persistence of these problems are not related to cognitive impairments. In a study with severely impaired children, only ten percent presented ongoing neurological deficits, whereas 46 percent of the same children reported emotional or behavioral problems. Most predictive of later behavioral manifestations was a premorbid condition. Adaptive functioning has been defined as the ability to successfully negotiate everyday functional activities which requires the integration of information, flexible thinking and organizational capabilities. Some researchers found severe deficits in adaptive functioning in children with severe TBI, despite adequate levels of intellectual, neuropsychological and academic functioning.

At an individual level it is very difficult to predict recovery. Overall findings indicate that neurological problems are the first to stabilize, with most transient symptoms vanishing within the first three months. In cases of severe TBI some residuals will persist. In terms of behavioral outcomes, findings are not as clear-cut. Initial reduction of manifestations underlies decreasing effect of brain injury. Later incidences rise again, most likely related to adjustment factors. Intellectual recovery has been shown to dependent of various variables, mostly of age of impact, with poorer prognosis for younger children in terms of recovery and developmental delays. From a more general perspective, limited access to resources, emerging psychiatric problems, need of special education as well as nature and degree of injury will impact recovery outcomes. Moreover, psychosocial factors accompanying TBI are influencing a child’s recovery. Recovery is a highly individualized and complex matter. The predictive value of variables on eventual outcome depends on the time after injury. Accordingly, injury severity is the best predictor in acute stages with decreasing influence thereafter. In order to predict long-term outcomes, variables like premorbid characteristics, degree of family burden and family functioning play a major role.

Predicting outcome

There are two injury-related factors especially useful in predicting outcome. The first is the severity of injury. Across all possible domains of impairment, moderate and severe TBI are related to poorer outcomes when compared to milder forms of TBI. Obviously, there is a dose-response relationship between severity and global outcome. In contrast to adults who show recovery progresses over the next two years following TBI, children have much shorter phases. Possibly, children differ in terms of pathophysiological processes as they show quicker neuron recovery. Another explanation about the early plateauing of recovery considers the possibility of continuous recovery in addition to cumulative effects of impaired subsequent development. Furthermore, the specific nature of injury is relevant to recovery and long-term outcomes. This does not only include characteristics of the primary injury, but also secondary injuries that complicated TBI (edema, hemorrhage, etc.). It is the severity of all injuries taken together that is predictive of later outcomes.

The second related factor is the age at which injury has been sustained. Younger age in combination with more general brain injury is most likely to result in permanent cognitive impairment. Most common areas of dysfunction are memory, executive functions and information-processing. All of these skills are mediated by neural substrates that are relatively immature throughout childhood and therefore vulnerable to disruption in development. These residuals limit a child’s ability to subsequently interact and learn from the environment, which negatively impacts the social and emotional development of the affected child.

Premorbid and psychosocial factors. Premorbid level of functioning is a strong predictor of later outcome, with most robust relations to behavioral and psychiatric outcomes.

It is generally believed that TBI exacerbates rather than initiates problematic behaviors. It has been difficult to assess pre-injury functioning in most children. Some studies use gross measure of prior functioning (e.g. presence of developmental disorder) and others estimate premorbid functions by using information provided by the child’s family. With respect to the latter approach, it is beneficial to gain information before a child awakens from coma. Thereby the resultant level of functioning does not influence recall of previous functions (halo effect). The quality of family functioning prior to a child’s injury is also predictive of behavioral outcomes of the child and family. As an example, families with chronic life stressors and poor coping strategies reported more family burden and parental problems after the injury. Overall, psychosocial factors are highly influential on recovery patterns, with above average social resources compensating for severe TBI impact and below average exacerbating impact on outcome.

Rehabilitation

Even though interest in childhood TBI and its differences to adult TBI have grown over the last couple of years, implementation of child-specific rehabilitation programs are lacking behind. This is partly explained by the initial goal of enabling the child to return home as soon as possible. Some inpatient rehabilitation programs have started to provide gradual reintegration into the school setting. In general, rehabilitation for children is multidisciplinary, including a variety of professionals depending on a child’s needs. Parents are an integral part of rehabilitation and are required to implement strategies at home to maximize recovery. The main goals are to maximize physical recovery and communicative skills, to work on cognitive and behavioral deficits, and to monitor the family and other social environments for potential interventions.

There are three general principles of rehabilitation with different approaches employed to support the brain damaged child.

1. The restoration of function, which targets the re-establishment of deficient functions. In early stages of recovery, rehabilitation is mainly concerned with physical and speech therapy.

2. The adaption of function, which makes use of intact abilities to find compensatory strategies for lost or impaired functions. It mainly employs behavioral training. And the last one is

3. The environmental modification, in which the environment is adjusted to accommodate a child’s needs. This is more relevant in post-acute stages when the child first returns home and later to school.

Rehabilitation centers usually use a combination of these three. During the acute stage of recovery, the neuropsychologist’s role is very limited. Once the child is able to deal with assessment the neuropsychologist becomes an essential part of the recovery process. Initial evaluation of neuropsychological abilities is used to guide ongoing rehabilitation, with repetitive assessments to monitor progress or deterioration. When school integration is considered, it is the task of the neuropsychologist to educate school staff about the child’s current state and its implication for the school context. It is important that continuous communication and collaboration between the family, teachers and the neuropsychologist exists. Initially, the neuropsychologist provides support in decisions such as the amount of time a child should spend in school. Once reintegration is completed, additional problems may emerge, which need careful assessment and treatment through interventions. The extent of support needed depends on the resources of the child, family and school. More frequent support is often needed in cases of limited resources or severe cognitive and behavioral problems. In general, regular assessment of recovery and current status is important to monitor the child’s needs for special services. Overall, rehabilitation and intervention goals should be realistic and measurable. As the child’s permanent impairments also impact the whole family aside from the child itself, family supportive interventions have been established.

The family of a TBI child should receive counseling and support in order to ensure good functioning and sufficient resources, which contribute to optimal recovery patterns. The child’s injury can be very demanding in terms of emotional, financial and physical resources a family has. The neuropsychologist is in a good position to support such a family in better understanding and managing their child. Clearly the well-being of the child depends on a functional family system; therefore the family needs support and monitoring as well.

What does hydrocephalus cause in children? - Chapter 6

Hydrocephalus (HYD) stems from an imbalance between production and absorption of cerebrospinal fluid (CSF). It is often a secondary consequence following other cerebral injuries or structural brain abnormalities. Within the normal brain the CSF is produced by the choroid plexus which is in the lateral ventricles. From there the fluid flows through the foramina of Monro into the third ventricle. In continues through the foramina of Luschka and Magendia in order to reach the subarachnoid space that surrounds the spinal cord and cortex. Eventually, the CSF is reabsorbed by the arachnoid villi into the venous circulation. The CSF acts as a cushion that protects the brain from external impacts. In addition, it is involved in the removal of waste products from the brain and separates the brain from blood. The specific condition of HYD is classified according to its etiology, type and presence of comorbid pathologies.

Types of HYD

One type of HYD is the obstructive hydrocephalus which results from obstruction to the CSF flow. This obstruction commonly occurs either within ventricles or at the outlet of the fourth ventricle. Consequently, the natural fluid flow between the ventricles and subarachnoid space is disrupted, which eventually leads to an excessive accumulation of fluid within the skull.

The second type is called communicative hydrocephalus. In this condition the fluid can flow freely, but reabsorption is dysfunctional. In some rare cases it might also stem from an excess in fluid production. An alternative classification system has also been proposed, which is based on the extent of CSF build up within the brain.

According to this classification system, excessive fluid is collected within the parenchyma of the brain (intraparenchymal) or within ventricles and subarachnoid space (extraparenchymal). In combination with cerebral atrophy, which is associated with some degenerative disorders, HYD can have compensatory effects in the absence of clinical problems. Within the normal brain, HYD increases the intracranial pressure which can lead to severe cerebral damage and, if left to run its course, death. In infantile HYD, the head enlarges at an abnormal rate and the child shows bulging of the anterior fontanelle as well as abnormal downward deviations of the eyes (also called sunset gaze). At this age children may be surprisingly asymptomatic, despite some non-specific general behavioral manifestations (irritability and lethargy). As the child grows older and the skull can no longer enlarge to compensate for increased ICP, the child exhibits more specific symptoms; such as headaches, vomiting, incontinence and poor motor coordination. Treatment usually involves inserting a shunt or piece of silastic tubing, which drains excessive amount of CSF into other body cavities (mostly the stomach or the heart). Over some time shunts might get blocked, calling for surgical revision. Each surgical intervention carries the risk of infections and hemorrhage.

Etiology

HYD can further be classified according to its etiology, which is either congenital or acquired. Congenital hydrocephalus is mostly associated with disorders of embryogenesis and is usually obstructive in nature. Spina bifida is a disorder that manifests itself at the end of the first month of gestation. It is characterized by a malformation of the neural tube that can occur at any point along the spinal cord. There exist three forms of graded severity.

1. Spina bifida occulta is the least serious form and mainly asymptomatic. About five percent of the general population is affected by this condition. It is characterized by an incomplete formation of the vertebrae, but the spinal cord and CNS develop normally. Usually some form of skin or tissue anomaly is visible close to the malformation site.

2. Spina bifida cystica, is a condition that can take two different forms of severity. 2a. Meningoceles, is a malformation that is usually found in the lumbosacral

region. It is characterized by abnormal vertebral arches that externally form a skin-covered sac. Consequently, the CSF and meninges are pushed through that opening, but the spinal cord and CNS are unaffected. A slightly higher risk of HYD is associated with that condition.

2b. Myelomeningocele, is the most severe and also most common form of spina bifida. In this condition the spinal cord is pushed through an opening of the vertebrae. It is often accompanied by serious neurodevelopmental disorders. About 80 to 90 percent of cases involve progressive HYD that requires shunting.

Communicating hydrocephalus is more often a consequence of perinatal or postnatal cerebral damage. It is classified as acquired HYD, since the brain developed normally until the time of injury. The underlying pathology is usually a ventricular hemorrhage in premature and low birth-weight infants. At times it may also emerge after head trauma or infections. In the case of infantile hemorrhage, blood is collected within the germinal matrix and parenchyma which eventually blocks the arachnoid villi and therefore CSF reabsorption. In the long run such hemorrhages may lead to periventricular leukomalacia. Making a differential diagnosis between the two HYD classes is not easy. Secondary effects of communicating HYD might be the blockage of the aqueduct, as is the case in obstructive HYD. Respectively, the subarachnoid space might be blocked in obstructive HYD which is typically associated with the communicative type. Incidents rates are hard to establish, but it is generally believed that around 70 percent of HYD are obstructive and the remaining 30 percent communicative. After cerebral palsy, spina bifida cystic is the second most common birth defect and the most common congenital cause underlying HYD. Incidence rates vary from country to country, Ireland and England showing the highest and Japan the lowest incidence rates. With technical advances, it is now possible to test for spina bifida in fetuses. In the future these rates are estimated to increase with early detection and subsequent pregnancy termination and folic acid supplements as prophylactic means to prevent neural tube malformations. Many possible factors have been proposed that might result in spina bifida and subsequent HYD. Causative factors could be folic acid deficiency, maternal diabetes, environmental toxins, hereditary factors and a high core temperature of the mother during early stages of pregnancy. Etiology is hypothesized to be multifactorial, but mechanisms have yet to be discovered. Girls tend to have higher incidents of spina bifida and related HYD, whereas boys are more affected by HYD of other etiologies. The primary treatment in HYD is the insertion of a shunt to drain excessive fluid from the cortex. Before surgical interventions, only about a quarter of children survived into adulthood of which most were mentally retarded.

Neurological changes

HYD is related to several neurological changes. Generally white matter is more affected by its effects than cortical grey matter, and only in very severe cases both are involved. The increasing ventricles damage connection fibers of the corpus callosum and projection fibers as well as the optic and olfactory tracts. In addition, ongoing myelination in the immature CNS is disrupted. If HYD is not treated, nerve cells become increasingly compromised and overall brain mass is reduced. Over the course of the condition (untreated), the cerebral blood flow will be disrupted which may result in ischemic damage. On a functional level, the frontal lobes are compromised, when connections between the prefrontal cortex and posterior and subcortical regions are disturbed. When HYD stems from disorders in embryogenesis, there is a high risk of comorbid abnormalities impacting CNS functioning. Besides, HYD increases the risk of subsequent seizure (10 percent). MRI studies found some cerebral abnormalities common to children with HYD. On average, their brains have a smaller corpus callosum and internal capsules as well as increased size of lateral ventricles.

Projection fibers close to the midline and therefore close to the ventricles are most likely to be affected by HYD. Furthermore, overall grey matter volume was smaller compared to controls, with more pronounced effects in posterior regions. An obvious consequence of CSF accumulation within the cranium is an increase in ICP, which causes delays in myelination and developmental progresses. These are partly reversible when pressure is elevated, but the degree of improvement depends on the overall duration of increased ICP. It turns out that duration is more predictive of recovery than the extent of ventricular enlargement itself. It is difficult to isolate the effect of HYD on brain pathology from other predisposing or comorbid conditions. As such, grey matter reduction can be caused by any.

An accumulation of damages has been proposed in cases of congenital, obstructive HYD. First malformations during embryogenesis with resultant HYD can cause additional damage, whereby it becomes hard to separate the single effects on the brain. Regarding acquired communicative HYD similar problems exist.

Before the introduction of surgical treatment, only 25 percent of affected children grew up to become adults, and only 40 percent performed within the normal range on intellectual tests. Nowadays, treated children fall within the lower bound of normal performance. All children with HYD perform more poorly on IQ tests than healthy children, but the prognosis is especially poor for children requiring shunting. With respect to underlying pathology, children with spina bifida have lower IQ scores, which is not surprising given the associated cerebral anomalies. No gender differences have been identified on intellectual measures. A study of demographic variables impacting neuropsychological outcomes, found that medical factors like the presence of comorbid seizures, are stronger predictors of later outcome than socioeconomic status and other family variables. Discrepancies between PIQ and VIQ scores in favor of the latter have been consistently reported in the HYD population. When tests did not depend on response times, these differences vanished. Therefore, it has been argued that the poorer performance on PIQ scale might actually be a result of motor deficits and reduced processing speed, rather than actual deficits in visuoperceptual performance.

Regardless of etiology, all children with an HYD condition showed a PIQ/VIQ discrepancy. However, it is more pronounced in some subtypes. If HYD is associated with aqueduct stenosis, performance on the PIQ scale was significantly worse than in other HYD conditions. Congenital causes are related to the greatest differences in verbal and non-verbal performance, in contrast to postnatal etiologies, in which performance is similarly poor in both. Neuroanatomical studies related the extent of discrepancy to the cerebral thinning of white matter, where larger differences were associated with more thinning of posterior fibers. In line with this finding, nonverbal test scores seem to correlate more strongly with the size of the corpus callosum than with HYD severity. In line with these findings, it has been hypothesized that children with obstructive HYD might be selectively depressed in nonverbal skills, since these children have the most white matter loss within the right side of the brain. Alternatively, callosal dysgenesis might block access to this information. Other research found these discrepancies in premature children with implemented shunts, which raises the possibility of additional damage due to the shunt itself.

Better VIQ scores fueled the idea that children with HYD possess normal language abilities. Despite the relative good performance on standardized language tests, children exhibit various language-related deficiencies. They present with problems of inferential language, meaning that it is difficult for them to extract meaning from non-literal and metaphoric discourse. Overall, children with HYD have impairments in language usage, rather than language content. The typical pattern involves intact abilities at the level of sentences and words, but shows marked difficulties in discourse and metalinguistic awareness. The latter is defined as the ability to monitor speech for completeness, form and semantics. A common phenomenon associated with HYD is the cocktail party syndrome, which is characterized by very superficial content and a tendency to talk too much.

Research with children suffering from spina bifida indicates that they have intact syntactical and vocabulary skills. However, their spontaneous speech is marked by preservations, exaggerated reliance on overlearned social phrases, expressed over-familiarity towards the conversation partner and poor shared-topic ability. Further, these features become less evident with age, but no universal pattern emerged from the study findings. Others found that the tendency to cocktail party language might be more strongly correlated to impairments of intellectual functioning and mobility, since only a small minority of children with HYD exhibits this phenomenon. Moreover, poor task persistence, visuoperceptual and abstraction abilities as well as increased distractibility contribute to abnormal speech patterns. Therefore it can be assumed that the cocktail party phenomenon might be caused by deficits in word-finding and sequencing. These deficits impact verbal fluency and may account for children’s overreliance on stereotypic phrases.

Alternatively, verbal dysfluency could be caused by slow processing speeds, which results from underlying white matter damages. Another common language alteration of HYD children is off topic, hyper-verbal language which might mirror dysfunctional selective attention. Again, others postulated that failures of executive functions explain language characteristics in HYD. Accordingly, compromised abilities in initiating, inhibiting and monitoring their speech results in excessive talkativeness. Overall, prenatal etiologies of HYD as opposed to perinatal and postnatal conditions with associated HYD were related to more severe language deficits. Also, deficit manifestation depends on underlying damage of CNS. For example, children with aqueduct stenosis exhibited isolated impairment on automatized naming tasks. This task depends on rapid inter-hemispheric information transfer at which these children are expected to perform poorly, since the main pathology in this condition is damage to the corpus callosum. Taken all the results together, it is apparent that children show great variation in language deficit manifestation. So, language is neither globally impaired nor preserved in HYD conditions. As the child grows older, deficits may either worsen or improve to some degree, but in either case they fall significantly behind age peers. Consequently, they experience problems in school and social interactions. In case of slowed skill acquisition, the prognostic value of early language ability is compromised.

With respect to perceptual motor abilities, research consistently proved existing impairments in visuomotor and visuoperceptual abilities in HYD children. Three possible explanations for those specific deficits have been proposed.

1. Children with HYD commonly exhibit deficits in motor and visual abilities, including oculomotor deficits.

2. The discrepancy between PIQ and VIQ scores is suggestive of greater deficits in nonverbal skills and might result from an overestimation of verbal skills. They perform above their actual ability due to the standardized nature of the test.

3. Executive dysfunctions in organization, attention, impulsivity, planning and self-monitoring interfere more with nonverbal skill performance.

In addition, motor deficits impact a child’s possibility to interact with the environment and reduce chances of experiential learning. From a biological perspective, the enlargement of ventricles most likely affects motor pathways and the optic nerve, contributing to visuomotor deficits. Some HYD forms affect the cerebellum which results in poor balance and limb coordination. Children with spina bifida exhibit additional sensory and motor impairments dependent on their lesion and degree of spinal cord involvement. Some research attempted to isolate effects of motor and visual abilities on poor test performance from other higher-order deficits. Children were assessed on tasks that place hardly any demand on motor capabilities, but still all relied on intact vision.

Results indicated poor performance on these tasks that cannot be accounted for by motor deficits. Generally, research results are mixed. Nevertheless one should not too readily accept simple motor explanations, but further investigate for other confounding skill deficits. Some neurological correlates with nonverbal problems have been found. Visuoperceptual impairments appear to correlate with increases in the right lateral ventricle and with bilateral increases of the internal capsules. These findings were interpreted as evidence that nonverbal skill acquisition depends on cerebral integrity across both hemispheres. In addition, disturbances of the corpus callosum and projection pathways result in deficient input-output as well as deficient integration of sensory and motor information, which behaviorally manifest itself in visuoperceptual and visuomotor problems.

Enlarged ventricles might also damage the brain regions associated with different memory and learning abilities. The hippocampus is one such structure that is likely affected by HYD and might result in deficient abilities to acquire new information. In contrast, problematic retrieval is associated with damage to subcortical white matter. Recent studies revealed specific verbal memory deficits, which cannot be due to language impairments. Children have great difficulties with delayed recall of stories, despite intact ability to immediately recall it. A growing body of evidence indicates deficits across many stages of memory.

Some commonly found impairments affect initial encoding, rate of learning, delayed recall and spontaneous retrieval. In contrast, recognition and cued recall are less affected. Test performance on simple memory tasks seem not to vary with age at testing, but as tasks become more complex discrepancies between normal and exhibited performance may appear. The general pattern for children with HYD is intact immediate recall of meaningful sentences and impairment in spontaneous retrieval and word list learning. This pattern indicates two potential problem areas.

1. Children with HYD have the tendency to excessively rely on rote recall and exhibit deficient higher-order organizational strategies; which are a perquisite for effective storage and retrieval of information. This accounts for strong recency effects that have consistently been found in these children.

2. They have been shown to exhibit great difficulties in retrieving information, unless cues are provided.

Retrieval problems correlate with the extend of white matter damage in subcortical areas. Word finding difficulties may underlie poor performance in recalling unrelated words; this also explains why meaningful items can be recalled. It is difficult to disentangle effects of fine motor and visual problems from pure memory deficits. Studies using face recognition paradigms which do not rely on any motor ability found no memory deficits. In a subsequent study, children exhibited problems with immediately recalling designs. Together with the previous findings it can be assumed that poor motor abilities may account at least for documented memory problems. Nevertheless, memory and learning deficits are also found on tests that place minimal demand on motor ability. When children with HYD are compared to their healthy siblings in recall performance, they perform significantly worse. More detailed investigation revealed that the poor performance is probably due to ineffective organization affecting encoding and retrieval.

Overall, there is little evidence that HYD impacts more strongly on visual than verbal memory. In absence of material-specific memory impairments, it is unlikely that poor performance in nonverbal tasks can be accounted for by visual disturbances alone. The severity of HYD conditions is related to the degree of memory and leaning impairments, which provides evidence that some illness-specific processes depress brain regions responsible for these cognitive skills.

Changes in level of arousal and alertness are commonly observed in the acute stages of HYD. Also, in asymptomatic and well treated children attentional deficits like poor concentration and increased distractibility have been reported. Direct investigation on attention is fairly limited, but often inference about it can be made based on other skill performances. For instance, deficient vocabulary skills probably reflect inefficient selective attention abilities. Overall, HYD is associated with poor sustained visual attention. On visual vigilance tasks children with HYD make more errors of omission and commission reflecting inattention and impulsivity of the child. A detailed study systematically evaluated attentional processes in children suffering from HYD. Results showed that selective and focused attention were primarily impaired in children with HYD. These deficits are hypothesized to result in poor performance on other executive tasks. In addition, these findings were related to posterior white matter damages. In contrast, other researchers found that simple focused attention was intact, but that impairments were present in divided and selective attention as well as in planning and inhibitory control. These attentional processes are mediated by anterior regions of the brain, suggesting more white matter damage in frontal regions of the brain.

With respect to executive functions, children with HYD tend to have difficulties in acquiring age-expected levels of higher-order organizational functions. Besides, they have greater problems to integrate new or complex information into overlearned schemas.

HYD associated with spina bifida results in specific depression of a child’s capacity to keep up behaviors in order to reach goals, in spite of sufficient task alertness and initiative. It has been very difficult to establish underlying reasons for poor performance on executive function tasks, since these depend on a variety of other cognitive skills.

Also, poor performance could stem from organic pathology or from experiential deficits. According to developmental theories, learning is a dynamic process which depends on early exploratory play and interaction with the environment. Children with limited mobility have only restricted opportunities which subsequently might negatively impact normal development of curiosity and goal directedness. A thorough investigation of children with HYD performing executive function tasks like the Tower of London and Wisconsin Card Sorting Task, points into the direction of more posterior-related problems underlying poor performance. Poor focused and selective attention prevented children from solving more problems compared to healthy controls. In contrast to pure profiles of pure executive dysfunction, the children did not break more rules or show signs of preservation.

Overall, tests of executive dysfunction are not able to reliably discriminate between HYD and non-HYD children, as opposed to measures of spatial cognitive skills. This raises the possibility of a more generalized spatial problem-solving deficit. This is in line with earlier findings that children sustaining white matter damage have difficulties on tasks of novel problem-solving, as these rely on the integrity of posterior right neuronal systems. HYD impairments on executive tasks can be accounted for by problems of activation and arousal which are mediated by the posterior right hemisphere. Alternatively, it could be a problem of full commitment to a task relating to HYD children’s deficits in goal directed behavior. Two recent investigations derived at two conclusions that are incompatible with the previously presented explanations.

1. Across different etiologies children with HYD exhibited poor abstraction abilities suggestive of anterior cortical damage.

2. Many children showed evidence of higher-order dysfunction in conceptual reasoning, mental flexibility and problem-solving abilities.

A unifying developmental theory has been postulated to better define brain-behavior relationships in HYD children. According to this theory frontal and executive functions are depressed due to damages of subcortical pathways which eventually leads to neuropsychological impairments. Frontal regions depend on efficient input from posterior regions and when these are damaged executive dysfunction may occur, despite healthy frontal lobes.

Children with HYD have slowed response speeds, independent of motor and visual demands of tasks. Poor and comparably slow performance on the Stroop task indicates that mental slowing also extends to autonomic responses. This finding is not surprising since this tasks requires cross-modal integrity and the HYD populations shows high incidences of callosal damage.

All of the neuropsychological deficits identifies so far will impact a child’s ability to succeed in school. In particular, intact word recognition combined with poor understanding of contextual information will place a burden on school achievements. In addition, deficits in visual memory and visuospatial skills will be reflected in poor writing, sporting and drawing abilities. Another interesting feature of the HYD population is the higher than normal incidence of left- and mixed-handedness, affecting about 20 to 40 percent. Lack of right hand dominance impacts writing and copying skills, and has also been associated to overall poorer performance on academic measures and fewer educational achievements. Their visuospatial impairments might display themselves in mathematical problems, which most of these children encounter in school. Moreover, arithmetic deficits tend to increase with age related to increasing complexity of mathematical problems encountered in higher grades. Other factors potentially impacting school performance like depressed processing speed, attention and executive skills have yet to be established. Presence of the cocktail party syndrome has been related to poorer outcomes on educational measures.

Children with aqueduct stenosis and resultant HYD have a more positive prognosis concerning academic success as opposed to other etiologies. These children also show less impairment in decoding and reading comprehension skills.

Illness-related factors

Illness-related factors also play a crucial role in determining neurological, cognitive and functional outcome of children with HYD. In particular, the condition’s etiology and severity, duration of increased ICP, presence of comorbid conditions and shunt-related complications play an important role in outcome. In the case of congenital, obstructive HYD, accumulation of deficits over time are commonly observed. It has been speculated that communicative HYD carries less risk of morbidity, since the CNS developed normally until injury impact, in contrast to disorders of early gestation. Research findings on this topic have been mixed so far. The specific site at which obstructions to the CSF flow occur do not appear to effect outcome in a systematical manner. There are also differences in congenital HYD subtypes. If these are uncomplicated as it is in the case in aqueduct stenosis, intelligence tends to be higher compared to complicated HYD in which other CNS malformation exist (spina bifida) or cerebral infections are present as well. The extend of corpus callosum damage negatively correlates with later intellectual outcome, with a fairly intact corpus callosum leading to highest scores on VIQ and PIQ across HYD populations. This raised the possibility that it is an essential structure for cognitive development and especially so for visuospatial processes. With respect to spina bifida, the level of lesion is closely related to IQ scores; with higher lesions leading to greater impairment. More detailed investigation indicates a threshold effect for lesions at the thoracic level (worst outcome), with no systematic differences between lumbar and sacral region. Overall, studies show mixed findings on whether level associates more to VIQ or PIQ scores. It has been hypothesized that children with higher lesions and greater associated mobility deficits have less opportunities of exploratory behaviors, subsequently impacting more nonverbal than verbal performance. Another illness-related factor involves surgical treatment. In general, children who required shunting perform more poorly on neuropsychological tests.

This is not surprising since more severe cases of HYD will be more likely to need a shunt to alleviate ICP. Above and beyond, lesion level in spina bifida is interacting with the presence of a shunt. Children with higher lesions tend to perform better if shunted, whereas lower level lesions are associated with better performance if no shunt is needed. The presence of surgical and shunt-related complications negatively affects developmental outcomes. At times a shunt gets blocked; IQ measures drop significantly, but increase to previous levels if the blockage is removed timely. Whether the side at which a shunt is inserted has influence on subsequent development, is problematic to assess. Under normal circumstances the preferred location of a shunt is within the right parietal lobe and only if this is unsuccessful the left parietal lobe is considered. The placement of a shunt itself affects the brain and might interfere with visuospatial skill development if placed in the right parietal lobe. In acute stages of HYD, fast and appropriate treatment is crucial to minimize following consequences. As the duration of increased ICP becomes longer, more irreversible cerebral damage will occur. As mentioned at the beginning, HYD can be associated with a number of comorbid conditions like seizure disorders, which then put further burden on the child’s development.

In cases of premature hemorrhage as underlying etiology of HYD, the severity of bleeding is related to IQ outcomes later in life. The relation between ventricular size and overall brain mass after shunting has also been associated with developmental outcomes, with larger ventricles logically resulting in poorer outcomes. In particular, PIQ scores seem to be sensitive to the effects of enlarged ventricles. Some studies aimed at isolating the pure effect of HYD on cognitive development. Results suggest that impairments of visuospatial and visual motor skills primarily stem from uncomplicated HYD. Deficits in other cognitive domains are better accounted for by related trauma, infection and associated brain anomalies.

HYD is somewhat different from other CNS disorders in that successful treatment will leave the child with no physical disabilities, no permanent neurological symptoms and therefore are also unlikely to require regular medical check-ups. Still, cognitive disturbances exists that might affect a child’s emotional and psychosocial functioning.

Overall, low IQ has been shown to impact academic success, self-esteem and to have impeding effects on their growth towards independence. Within the family system, the child’s condition influences parental expectations regarding the child, raises financial and practical problems and may lead to changes in family roles. During developmental transitions existing problems might be exacerbated and additional support for the child and their families should be provided. Visible motor handicaps may result in feelings of being damaged or different from others and might restrict social interactions with peers.

Also the neuropsychological profile of HYD children will compromise their socioemotional functions. For instance, their pattern of speech (hyper-verbal, over-familiarity, etc) is likely off-putting for normal children. In addition, these children have greater difficulties in interpreting nonverbal social cues which can result in inappropriate reactions towards others. Clinical reports often state high prevalence rates of depression and anxiety in HYD children. They have been reported as socially immature with poor socioemotional judgment abilities. In young children this manifests itself in an unnatural tendency to be indiscriminately friendly to people. As they grow older they show increased tendencies for social withdrawal. In contrast to studies indicating high incidences of psychosocial disturbances, a more recent study on children with shunted HYD suggests more positive trends. Results showed that many of the problems reported by parents reflected parental concerns about developmental, academic and cognitive outcomes; rather than true symptoms. For instance, on average these children received high ratings on Psychoticism which probably reflect higher dependence and immaturity rather than true psychoticism. Family-related variables impact the behavioral outcome of children with HYD. In particular, research has shown that good family cohesion and organization, low levels of conflict and high socioeconomic status can protect the child from emotional and behavioral disturbances.

Medical variables and degree of disability did not impact psychosocial outcomes. The CNS disorder does not only impact the child, but also the family. Studies on family impact have found high levels of parental stress commonly associated with depression, feelings of guilt and social isolation. So far, no relationship has been identified between parental distress and severity of HYD.

HYD is not a unitary unit. It can result from many pathologies manifesting itself at different stages of development, with no universal pattern of deficits. Only few characteristic features are shared among the different HYD conditions, one being cerebral white matter damage. Until today, no systematic study has been conducted so far that investigates the natural course of HYD and associated consequences from childhood into adulthood.

What are possible cerebral infections? - Chapter 7

Some viruses and pathogens, such as HIV, can enter the central nervous system and affect the developing fetus. Meningitis and encephalitis are the cerebral infections that occur most commonly in children after birth. The neuropsychological impairments resulting from such cerebral infections will be the focus of this chapter.

Bacterial meningitis

Aetiology and epidemiology

Meningitis is not a rare childhood disorder. In Meningitis the meningeal membranes surrounding the brain are inflamed, either from bacterial or viral infections. Bacterial meningitis is easier to diagnose than viral meningitis, but the viral type occurs more often. In bacterial meningitis, immaturity of the immune system seems to represent the strongest risk factor for its development. Psychosocial factors seem to play a great risk factor in meningitis as well, such as in neonatal meningitis due to poor maternal nutrition, health and hygiene. Before the development of antibiotics in the 1950, 90 % of bacterial meningitis cases led to death. With antibiotics in the picture, the death rates went down to 10 % overall.

Bacterial meningitis is treated with antibiotics, and furthermore with fluid restriction and anticonvulsant therapy if necessary. Due to nonspecific symptoms the diagnosis is often made very late. Bacteria in the cerebrospinal fluid (CSF) confirm the diagnosis, alongside with higher protein levels and CSF glucose. The pathogen needs to be specifically identified to administer the right antibiotic treatment. Steroids are additionally used in many cases to decrease CNS inflammation.

Pathophysiology

Bacterial meningitis patients are studied to further research on the effects of generalized central nervous system trauma on cognitive development. Bacterial meningitis in its acute stage may result in complications such as disrupted cerebrovascular and cerebrospinal fluid dynamics which then lead to hydrocephalus and edema for example. Other complications include hypoxic damage, respiratory difficulties and seizures. Furthermore cerebrovascular autoregulation may be lost, and may result in cerebral blood flow disruption. CSF flow might also be disturbed as a result of intracranial pressure and might result in permanent hearing impairments. Two types of cerebral pathology are linked to bacterial meningitis. The first is cerebrovascular changes and the second one is hydrocephalus.

In acute bacterial meningitis biomedical changes are also present. These changes might be present: less glucose in the cerebrospinal fluid and cellular electrolyte imbalance.

In half of all cases (55 %), acute-phase neurological impairments occur. This can lead to permanent CNS dysfunction. Neurological aftereffects are present in 16 % of survivors as meta-analysis show, such as total deafness in 11 % of cases. Haemophilus influenzae type b has more frequent cases of morbidity but less mortality cases.

Neuropsychological findings

Mildly depressed IQ scores, lower performance and full-scale IQ scores were found in patients that survived bacterial meningitis. Verbal IQ scores were found to be normal, but this was not always replicated in following studies. Further research on acute-phase neurological problems show that neurodevelopmental problems may only come to light when children fail to display certain skills that should be acquired in the associated developmental stage. In either case, general intelligence is impaired to some extent and complications in the disease exacerbate the impairments. Methodological differences may be responsible for varying outcomes across studies on disease sequelae in bacterial meningitis.

Language Skills

Hearing impairments or loss is common in bacterial meningitis, which is why language abilities are also often focus of research. Effects of the disease can affect language especially in the first 2 life years (when prevalence is highest) and occur more frequently in survivors of meningitis. Studies show that these language deficits can be traced back to a central auditory processing difficulty. Children who acquire bacterial meningitis before 12 months of age have shown to have poorer linguistic abilities than the ones who acquired it after 12 months. Research shows mixed results on verbal ability tests though.

Memory and Learning

Studies have found poorer scores on long-term memory, and most recent findings say only non-verbal memory deficits apply. Complex learning and memory tasks were better in controls than in post-meningitis children, which is said to be attributed to strategy and organization deficits.

Motor skills

Performance on gross and fine-motor tasks can be impaired due to long-term neurological abnormalities, which exist in 3%-7% of bacterial meningitis cases. In subtle motor skill deficits, it is suggested that a developmental delay is involved and a “catch-up” will happen rather than a long-lasting deficit being present. But studies also show ongoing deterioration rather than catch-ups, so the findings are mixed in that regard.

Executive functions

Poor learning and adaptive outcomes are a result of executive deficits that might be present in bacterial meningitis. This leads back to poor organizational strategies which are necessary in complex learning and memory tasks.

Academic skills

Reading deficits are evident in survivors of bacterial meningitis, with word recognition and comprehension being impaired. Other studies only show academic skill impairments in acute-phase bacterial meningitis survivors.

Illness-related predictors of outcome

Predictors of neuropsychological outcome are: nature of the pathogen, symptom duration (especially bad outcome if duration over 24 hours), biochemical imbalances, acute-phase neurological complications and age of onset of bacterial meningitis (with worse outcomes if onset was under 12 months of age), and the less strong predictors gender and family background. The acute-phase neurological complications have been strongly linked to cognitive, behavioral and educational outcome levels. Low glucose concentrations or high pathogen levels in in the cerebrospinal fluid furthermore indicate adverse sequelae. Acute-phase neurological complications are more common when there was also a longer symptom duration.

Regarding age of illness as a critical outcome determinant, there is mixed empirical evidence. Whereas some studies (Sell & Taylor, 1990) have found no evidence for age of illness and outcome being related, whereas Grimwood (1996) has found this to be a factor involved in illness outcome. Level of skill development has been found to be an important factor at onset of central nervous system trauma.

The “double hazard” hypothesis holds that early biological risk is exacerbated by a poor social environment. Nevertheless, more research needs to be done on social and demographic variables as potential factors influencing the course of the illness.

Psychosocial issues

A vaguely defined picture emerges from the research done so far on the psychosocial component in post-meningitis children. Studies show that post-meningitis children do not suffer from higher levels of impulsiveness and restlessness and irritability than controls. Nevertheless, post-meningitis boys displayed lower school adjustment scores and both female and male post-meningitis students were judged by teachers as suffering from more behavioral and adaptive problems.

Summary

Bacterial meningitis serves as a helpful model in studying the effects of transient cerebral dysfunction on the developing brain. Acute complications lead to both neurological as well as neuropsychological sequelae. Subtle impairments such as language, attention and psychomotor processing problems can emerge, but on the other side severe impairments such as hemiplegia, deafness, seizure disorders and intellectual decline may result from bacterial meningitis. A delay in skill development is often the case, in form of a “catch-up”, and long-term deficits may not become evident.

Encephalitis

Aetiology and epidemiology

Encephalitis is an illness that results from a virus or another microorganism invading the brain, with the cerebral tissues becoming acutely inflamed alongside with possible neuronal damage or death. Childhood infections such as rubella, varicella, Epstein-Barr, and cytomegalovirus, herpes simples virus can produce acute illness. The central nervous system is attacked by the virus, and this can happen through the bloodstream, the nose or the peripheral nervous system.

Forms of encephalitis are: acute viral encephalitis, postinfectious encephalomyelitis, chronic degenerative disease of the central nervous system, or slow viral central nervous system infection.

Some pathogens exert their effects during gestation and this may lead to abnormalities in the developing fetus. Non-specific symptoms characterize the early form of encephalitis, such as fever, headache, vomiting, lethargy, behavioral changes, motor, sensory, and speech disturbances. EEG shows a generalized slowing and CT and MRI show inflammatory and cerebral edema symptom-like changes. Around one third of patients suffer from neurological sequelae or cognitive impairment afterwards. The herpes simplex virus type 1 encephalitis occurs most commonly and also yields the worse outcome of all types. Full recovery only takes place in 13-14 % of all patients

Pathophysiology

Most comprehensive documentation on central nervous system changes come from herpes simplex virus type 1 encephalitis. In its acute type, herpes simplex virus type 1 encephalitis leads to necrosis, cerebral edema, and haemorrhage, whereby the mesiotemporal areas are most commonly affected. The orbitofrontal regions of the brain are in involved in severe cases. The standard is bilateral involvement, but unilateral involvement can also sometimes occur, most commonly in left-sided lesions. Damage to the hippocampal and adjacent medial temporal lobe structures, bilateral pathology in anterior and inferior temporal lobe gyri are seen in MRI. Focal damage in the central nervous system is typical in paraneoplastic encephalitis. Typical characteristic of the Rasmussen’s encephalopathy are microglial nodules, astrocytosis and neuronal degeneration in the hemisphere that is affected.

Neuropsychological findings

Brain-behavior relationships can be effectively studied in context of herpes simples virus type 1 encephalitis. This is because specific brain regions are targeted by the virus. Sequelae include dementia, mild memory and speech impairments, but general cognitive capacities are relatively spared. Even after aggressive treatment morbidity frequently follows. Many patients show a dense amnesia, but other patients do not suffer from memory problems. Nevertheless, most disablement resulting from herpes simplex virus type 1 encephalitis comes from amnesia and only a minority goes back to being employed again. Many studies corroborate the findings of amnesic syndromes resulting from herpes simplex virus type 1 encephalitis infection.

The IQ scores of the herpes simplex virus type 1 encephalitis survivors were relatively the same as to those of non-herpetic encephalitis patients, but they showed greater memory and verbal semantic function impairments. Initial acquisition of new information is less affected than encoding and consolidation in long-term memory. Daily living activities are disrupted by problems with episodic memory, which also prohibits patients to return to work. Later in the disease semantic memory loss occurs, and often these semantic memory problems are specific to a certain category, namely problems to identify livings things.

In children memory and learning impairments are more problematic in children with encephalitis and this could lead to a more disrupted generalized cognitive development. Therefore childhood encephalitis can impact a greater spectrum of specific skills, and this is corroborated by research which shows that the adult brain experiences less damage as a result of the illness.

Lower score of general intelligence were found in post-encephalitis children. The Rasmussen’s encephalitis yields the worse outcome, as most patients experience mild to moderate intellectual impairments as a result of progressive deterioration and social communication impairments.

There is a positive correlation between encephalitis severity and illness outcome. Most commonly language impairments and memory deficits result, and the extent to the impairment can vary from mild to severe. Anxiety is the most common behavioral change following encephalitis.

Illness-related predictors of outcome

The poorest outcome of encephalitis follows a young age of onset of illness, neurological impairments in the acute-phase and herpes simplex virus eliciting the illness. Bilateral disease usually yields a poorer outcome than unilateral disease. Bilateral disease has also been found to predict a more severe amnesia. In Rasmussen’s encephalitis, seizure control and hemispherectomy yield a more positive outcome.

Psychosocial Issues

Kluever-Bucy like syndromes are often found regarding the behavioral changes which follow encephalitis. This is due to disrupted emotional regulation via the corticolimbic pathways. Behavioral sequelae have been found to occur to a greater extent in right-sided encephalitis. Symptoms include a labile mood, depression and rages in episodes. When the prefrontal-cortex is affected as well, the patient displays impulsive, apathic, rigid behavior and a diminished self-awarenes and judgment. When prefrontal-cortex dysfunction occurs together with memory impairment, this results in severe disturbances regarding interpersonal relationships and daily living.

Case Study

Confusion and disorientation occur as part of the characteristic acute clinical features of childhood encephalitis, indicating generalized cerebral disruption. Some areas of impairment recover whereas others reside. The following case study is an illustration of the course of the illness.

Andrew suffered from a tonic-clonic seizure alongside with fever, breathing difficulties and headache of two weeks. A cerebral oedema was found via a CT scan and he was diagnosed with meningoencephalitis. Fluctuations in his conscious state were observed during his hospital stay. Andrew displayed irritated and lethargic behavior, judgment difficulties, speech impairments upon his release from the hospital. A neuropsychological assessment, which was conducted a week afterwards, revealed that he had problems in monitoring logical and relevant information. He displayed restlessness and agitation when given tasks to work on. The Digit Span task and sentence repetition revealed normal levels, but he quickly forgot instructions and story passages which he was presented with only shortly before. He also displayed episodic memory deficits. In a 6 and 18 months post-assessment it became evident that he was still easily angered and emotional fragile. He also gained weight due to constant great appetite and performed poorly in school, not doing all his work. In the 18 month evaluation he also seemed very impulsive and clearly had problems monitoring his performance. Semantic memory had improved gain, but it was still difficult for him to use new knowledge in complex scenarios. Very low scores were demonstrated on skills involving memory and learning and working memory and long-term memory were especially impaired. He had major problems replicating the Rey-Complex Figure after 5 minutes, showing a severe rapid forgetting. Rapid forgetting is typical following postencephalitis.

The changes in Andrews behavior were also a problem for the parents. Andrew had probems in behavioral and emotional regulation and did not participate in many social activities anymore. In addition he still had problems controlling his appetite and his sleep was disturbed and it was suggested that this was a result of the hypothalamus being affected or of a depression. What remained, despite confusion and inattention having resolved to a great extent, were the problems with memory and skills of higher-order. These greatly impact his life and have an especially great destructive effect on academic and social skills.

Conclusion

The central nervous system of children is more vulnerable to insult than that of adults. This is because the central nervous system is still in its developmental stage. In very young children, meningitis and encephalitis are most common. General intelligence has been shown to be affected in most cases, as well as specific skills such as executive funtions, language, perception, memory, and information processing.

The outcome of the disease is determined by an interaction between organic factors and developmental influences. Neurological sequelae most commonly occur when the onset of the cerebral infection takes place before the 12^th month of the child's life. Nevertheless, neurological sequelae can follow the illness after the 12 month span as well, but generally these patient experience a shorter course of illness and less complications in the acute-phase. Other factors, even though of little impact, are gender and socioeconomic factors. Neurological sequelae should be subject of investigation in the long run, as they are often only detected when it becomes obvious that the child is not successful in developing certain skills at the expected time.

What are the symptoms of the metabolic disorder phenylketonuria? - Chapter 8

The disorder phenylketonuria

Phenylketonuria (PKU) is a metabolic disorder resulting in abnormally high levels of phenylalanine. It is genetically transmitted by autosomal recessive processes. Incidents rates vary considerably according to region, with Japan having quite low rates and higher rates in Ireland. Gender differences have not been found. Mostly the disorder results from either a reduced activity of the phenylalanine hydroxylase enzyme (which is the case in mild PKU), or from complete absence of that, which is then referred to as classical PKU. Consequently, phenylalanine (Phe) is not converted into tyrosine which is an important constituent of protein. This excess in Phe impacts the immature brain and ongoing development of the child. If untreated, classical PKU resultant cerebral pathology involves reduced brain size and weight as well as anomalies in myelination.

On a functional level, children grow up to become mentally retarded; they often suffer from seizures and show behavioral disturbances. There are some common physical characteristics among children that are affected by PKU; many are pale, blue-eyed and have blond hair. An additional characteristic of PKU children is their musty odor that is especially apparent in their urine. There is now evidence that the gene for Phe is located on chromosome 12q24.1. Nevertheless the underlying genetic basis for PKU is not yet completely understood. The Guthrie test is the primary screening tool for PKU and is routinely administered between the fourth and sixth day after birth. In the case of positive testing, treatment is immediately implemented. Treatment is based on a Phe- and protein-restricted diet, but the duration of it is not universally agreed upon. Some argue for remaining on the diet until adulthood, whereas others claim that after the age of eight the CNS is no longer vulnerable to excessive levels of Phe and dieting can stop. The earlier treatment is implemented, the more favorable is the child’s prognosis of later outcomes. If brain damage occurred before treatment, these cannot be reversed. Nevertheless a diet should be implemented to prevent further deterioration of the CNS. For women with PKU it is advisable to recommence the diet before pregnancy to prevent microcephaly and mental retardation of the baby.

Pathophysiological changes

In classical PKU a number of cerebral changes accompany the disorder, including structural, biochemical and electrophysiological abnormalities. High levels of Phe interfere with neuronal metabolism of tyrosine and tryptophan. These two are precursors of dopamine, serotonin and noradrenalin; consequently the brain is lacking these neurotransmitters. MRI studies have found that children with PKU show changes of the periventricular white matter. This is especially pronounced in parieto-occipital regions and in very severe cases might even affect frontal regions. Underlying mechanisms are not known yet, but on the p side at least partial regression is possible after tremendous improvements in dietary control. It follows, that strict maintenance of the diet at least reduces the risk of white matter anomalies. Moreover, these findings imply that underlying changes in metabolism are responsible for cerebral changes and these might improve once Phe levels have normalized again (through diet for example). Some changes and deficits found within the PKU population might be transient. This hypothesis is based on evidence, that some anomalies have a stronger correlation with current Phe levels than with level of dietary control and time since treatment implementation. Despite this, the immature CNS is more vulnerable to metabolic abnormalities in PKU. During periods of rapid development the disturbances may cause permanent demyelination. About half of all children with PKU exhibit white matter abnormalities that are associated with a range of cognitive deficits as opposed to children without associated white matter damage. These deficits include: lower cognitive and information-processing skills, specifically more pronounced in domains of verbal abilities and memory, auditory selective attention and arithmetic skills.

It is unknown so far whether there are critical periods in which dietary control has the greatest effect on the CNS. Research has found universal changes in EEG patterns in patients with untreated PKU. Even in patients that are treated early the probability of abnormal EEG pattern is high. These patters change with age, with infants exhibiting hypsarrhythmia which is characterized by irregular and slow waves and spikes.

With age, the pattern shows general slowing, but eliptiform patterns become less frequent. The EEG pattern of PKU children is increasingly abnormal up until the age of ten and decreases occur thereafter in spite of increasing Phe levels. Some also found sudden increases in abnormal EEG activity after cessation of the protein-restricted diet. Others found no relationship between EEG recordings and age of treatment implementation or level of dietary control. It remains a controversial issue in need of further investigation to shed more light on pathological changes associated with PKU.

Neurological functioning

With respect to PKU effects on neurological functioning, early treatment implementation is associated with the most favorable outcome. Most children in which PKU is detected early generally perform with the normal range on IQ measures. More detailed investigation points towards more subtle, but significant differences between children with PKU and their siblings. In specific, these children often present with mild cognitive and perceptual residuals. In particular, visuomotor integration, visual perception, conceptual reasoning, complex problem-solving, sustained and selective attention tend to be compromised by PKU. These impairments cannot be explained on the basis of relative poor IQ performance when compared to siblings. On a cellular basis, the abnormal availability of dopamine neurotransmitters in combination with disruption to myelination at a critical period of development, are thought to underlie neurobehavioral manifestations. Language and memory capabilities are more insensitive to effects of PKU. Furthermore, within the PKU population including early treated children, higher incidence rates of learning disabilities have been reported, and more so for arithmetic skills. PKU is associated with mild generalized brain damage, with IQ scores best discriminating the PKU children from their non-PKU siblings. Other approaches towards the PKU conceptualization are built on the resultant dopamine depletion within the cortex. These approaches hold that brain areas that normally have a high level of dopamine turnover are especially vulnerable to effects of PKU. Such regions include the prefrontal cortex and tertiary association areas. Moreover, the same regions are mainly myelinated postnatally, when the infant is no longer protected by the mother’s metabolism. As a consequence, cognitive abilities mediated by these regions are most likely compromised by PKU, namely higher-order and integrative skills. By the same token, regions that mature prenatally like midbrain structures are insensitive to PKU effects. Other brain regions have also been shown to mature after birth, therefore the dopamine depletion hypothesis needs to take a more global perspective on resultant residuals. This is supported by reports of various cognitive skills that can be depressed in children with PKU, in addition to the specific impairments associated with prefrontal lobe dysfunction. Ongoing research on compromised cognition has shown that children which are treated early initially display problems in executive functioning while non-executive skills are performed normally. Findings from these children revealed that with older ages these impairments decreased and finally vanished. In conclusion, children with PKU show a delay in prefrontal cortex myelination, instead of permanent damage. This is inconsistent with the dopamine depletion hypothesis which suggests that the problems persist. Animal studies provide further proof of myelination delay. Qualitative analysis of cognitive functioning in PKU children consistently found impairments indicative of prefrontal cortex and tertiary association area involvement. Typically PKU children display higher-order deficits, a tendency of preservation, problems in planning and an inability to integrate information. In contrast, children with PKU perform equally to controls on tasks that required skills mediated by the temporal and parietal region. These findings have to be interpreted with caution, since confounding variables like compromised attentional abilities are not accounted for. Future studies have to be carefully designed in order to isolate executive components of a task from other lower-order task requirements.

Illness-related factors

The illness-related factors are most greatly impacting neuropsychological performances in PKU sufferers. Some potential predictors have been identified, including Phe levels at the time of testing and initial diagnosis, age at treatment implementation and cessation, as well as overall dietary control. Prediction is complicated by possible interactions of nature and timing of neurochemical disruptions with the current level of brain development. Right after birth, the infantile CNS is especially sensitive to high Phe levels within the brain.

In general, mildly affected children with early diet adherence are likely to have high IQ scores later, whereas children with very high initial serum level of Phe or later implementation of treatment have a poorer prognosis. Age at treatment inception and exposure to high Phe levels within the first six years of life both predict intellectual outcome in children; the former having an even stronger relationship to outcome. Taken together, it is crucial to screen for PKU soon after birth with subsequent diet adherence in order to optimize cognitive outcomes for children with PKU. High serum levels can lead to permanent as well as transient changes. Current high levels at times of testing have been related to increased error rates, compromised attention and slowing in response times in children and adults. These problems tend to level off once normal Phe levels are re-established. When assessing the influence of high serum levels on cognitive performance, results depend on measures taken. High levels negatively impact performance on higher-order and speeded tasks, whereas simple tasks performance was unaffected. Research on cognitive outcome and effects of lifetime control of diet is hard to conduct, since reliable and retrospective estimates of dietary adherence are hard to establish. Results have been mixed, but overall current level of Phe exerts more influence on cognitive outcome than lifetime levels. Others have postulated that specific cognitive abilities (executive functions and dynamic information-processing) are more influenced by current Phe level in the brain.

In contrast, depression of IQ scores is related to early and irreversible brain damage, but is relatively insensitive to effects of temporary rises of Phe. Study findings supports this with early cerebral injury being most predictive of intellectual abilities later in life, and current Phe levels predicting performance on novel problem-solving tasks. In the past, dietary adherence was required until the child turned eight; thereafter the CNS was believed to be insensitive to Phe levels. Now there is a growing body of research indicating that the toxic effects of Phe excess impact the CNS well beyond that age. Research on age at diet cessation revealed that discontinuation of protein-restriction at least before the age of ten was related to declines in intellectual and educational performance. In conclusion, some argue that good dietary control predicts good intellectual outcome and cessation best predicts losses in intellectual functioning.

Positive effects of diet increase with longer duration given good dietary control. Age at discontinuation appears to be the best predictor of discrepancies in IQ scores between the PKU child and those of siblings and parents. When comparing children that continued the diet with children that stopped the diet at age five, it was found that children remaining on the diet performed on average significantly better and within a normal range on intellectual measures. Common neuropsychological changes associated with later diet cessation are conceptual and academic reasoning problems, visuoperceptual deficits and increased reaction times. Additionally, patients exhibit atypical patterns of sensory evoked potentials. Some of these changes are only transient and markedly improve once normal Phe levels are re-established. Another crucial factor for good prognosis is the time at which the diet is started. There is relatively little benefit of dieting, if it is delayed beyond the third month of life. Too much irreversible brain damage accumulates within this time period resulting in mental retardation. Overall, some difficulties exhibited by children with PKU may underlie early brain damages, which are not readily accessible through testing in early childhood. These only become apparent at the point when children fail to make age-appropriate improvements in cognitive skills.

What are the symptoms of the neurological disorder epilepsy in children? - Chapter 9

Epilepsy is the most common neurological disorder in children. It differs from other CNS conditions previously presented, as it is not a cause, but a symptom of underlying brain pathology. It can result from many disorders and is an additional burden to the child’s development. Based on animal studies, childhood epilepsy differs from its adult counterpart with regard to underlying location, mechanisms of seizure control and pattern of spread. Generally, the way the disorder manifests itself behaviorally as well as subsequent treatment are dependent on the child’s age at seizure onset. In the past, animal studies support the idea that the immature CNS is relatively insensitive to impacts of seizure. More recently, epileptic features have been shown to impact the ongoing development of affected children. Two percent of the general population will experience epilepsy over the course of their lives. Of these people approximately 75 percent will have seizure onsets before the age of 20. Incidents rates are highest for the first year of life, with prevalence rates between 0.3 and 0.5 percent. Boys appear to be slightly more affected by epilepsy than girls.

Eplilepsy

Epilepsy has been defined as a chronic condition that is characterized by a tendency of recurrent seizures. Seizures are believed to result from some form of imbalance between inhibitory and excitatory neurotransmitters, but the exact underlying processes are still unclear. With decreases in the brain’s main inhibitory neurotransmitter Gamma-amniobutyric acid (GABA) or, alternatively, increases in the main excitatory neurotransmitter glutamate, both processes can lead to neural hyper-excitability with subsequent seizures. This implies that everyone may experience seizures given the right circumstances. In transient neurological changes following a fever, traumatic brain injuries and drug withdrawal, seizure may occur. Under these conditions, seizures will not fall under the category of epilepsy.

Epilepsy in children

There is a shift towards a more general definition of epilepsy that includes other behavioral manifestations than seizures. Certain seizure disorders are specific to children, like febrile seizures, which commonly occur in infants and children between the ages of three months and five years. Approximately three percent of all children are affected and about a third of these children with initial febrile seizure will have subsequent ones. This type of seizure is associated with occurrence of fever that cannot otherwise be explained. Only a minority runs the risk of developing afebrile seizures later in life. Influencing factors are presence of premorbid neurodevelopmental anomalies, complex seizures and a positive family history of epilepsy. Febrile seizures alone are not predictive of later outcome. The status epilepticus is defined as a state of ongoing seizure for at least 30 minutes or repeated seizures without periods of regaining normal levels of alertness. If untreated it may result in severe cerebral damage or death. More recently, a non-convulsive status has been accepted, in which alterations in consciousness extend over a prolonged period of time in absence of seizures. The term psychogenic seizure (pseudo seizure) refers to seizure-like behavioral manifestations that do not result from epileptic activity. Normally differential diagnosis is based on EEG findings during a seizure. These psychological seizures might reflect a patient’s attempt to gain some control over their seizure disorders, or can be the response to stressful situations.

EEG measures are one of the major diagnostic tools in diagnosing and investigating childhood epilepsy. Brain activity can be measured at different times with regard to seizure occurrence. Specific terminology has been introduced to describe these times.

1. Ictal, meaning during the time of seizure

2. Interictal, meaning between two episodes of seizures

3. Postictal, meaning the time immediately after a seizure.

Classification of epilepsy

First efforts to classify epilepsy were based on seizure features and EEG findings.

The Commission on Classification and Terminology of the International League against Epilepsy (ILAE), proposed a first classification system for epilepsy in 1964, with revision in 1981. This classification system of the IALE differentiates epilepsy on the basis of seizure types. It involves two major classes of seizure types which each can be further subdivided.

The first are partial seizures, which is characterized by initial seizure onset in a restricted and focal region within one hemisphere. It can be further subdivided into three categories.

1. Simple partial seizures are seizures in which the sufferer shows no changes in consciousness

2. Complex partial seizures are seizures in which the state of consciousness is altered, but not lost.

3. Partial seizures with secondary generalization are seizures that start out in a specific location and then spread throughout the cortex. The simple partial component is then called the aura which can take on many forms depending on the underlying brain region involved. This is usually the last thing a person can recall, before losing consciousness. In addition, automatisms are commonly present, which are automatic behaviors like chewing and senseless repetition of words or phrases.

Generalized seizures make up the second major seizure class. These seizures show initial epileptic activity within both hemispheres and can also includes a number of subcategories.

1. Absence seizures or petit mal are seizures characterized by sudden onset, with abrupt interruption of ongoing actions and a blank stare with brief upward rotation of the eyes. It can be further classified by additional behavioral manifestations.

2. Tonic-clonic seizures or grand mal are seizures characterized by initial sharp tonic contractions which make the sufferer fall to the ground. It is followed by an episode of clonic convulsive movements.

3. Myoclonic seizures are marked by sudden, brief, shock-like contractions and involve either specific or widespread muscle groups. Clonic seizures are characterized by clonic repetitive jerks.

4. Tonic seizures, which are sudden muscular contractions, sustain limbs in an unnatural position.

5. Atonic seizures entail a sudden loss of muscle tone either in specific body parts or the whole body resulting in the person falling to the ground. If these are very brief they are referred to as “drop-attacks”.

In addition, the category of unspecified epileptic seizures contains other forms of seizures that do not fit within the aforementioned categories. Many childhood-related seizures fall within this category. There is a recent trend to move away from this traditional classification system due to recognition epilepsy that can result in behavioral manifestations other than seizures. More recently, epilepsy has been regarded as a syndrome; accordingly epileptic disorders are defined in terms of characteristics and symptoms commonly occurring together. This view led to the presentation of a classification system by syndrome. In addition to seizure type other illness-related variables contribute to categorization, namely age of seizure onset, results from neurological examination and neuro-imagining studies. This approach enables a more accurate and detailed picture of a patient’s condition. Categorization follows two major divisions.

1. First dimension: separate epilepsy with generalized seizure from those with partial seizures

2. Second dimension: separate epilepsy with known etiology (symptomatic) from those with unknown etiologies (idiopathic)

Moreover, there are epilepsies described as cryptogenic when the underlying cause is hidden. This classification system emphasizes the importance of different etiologies and behavioral manifestations in the association with different types of epilepsy. Overall, of all the people that will exhibit epilepsy at some point in their life, only about a quarter will do so as a result of non-genetic causes like acquired mass lesions disturbing the CNS. The majority will have a genetic etiology underlying their condition. Some relatively rare inherited disorders are associated with epilepsy occurrence, namely tuberous sclerosis and some neurodegenerative disorders. But for most people with genetic causes, a complex interaction between several genes and the environment will underlie epileptic activity. The dynamic process by which epilepsy develops has been termed epileptogenesis. In order to understand it and its specific manifestations in children, it is essential to take a developmental perspective on the issue. It has been established that age, growth and development are not only predictive in terms of epilepsy occurrence, but also in terms of its specific behavioral and electrical manifestation. For one, there appears to be an interaction between age of disorder onset and etiology. Younger children have higher rates of neurological disorders resulting in epilepsy compared to adults. Common causes of epilepsy at the neonatal stage are: infection, hemorrhage, metabolic and genetic disorders, hypoxic-ischemic encephalopathy and congenital brain malformations. Summarizing research findings, the epilepsy syndrome reflects age-related epileptic reactions to nonspecific CNS damages acting at numerous age-specific stages of development. The most common cause of congenital malformations is the genetic condition of tuberous sclerosis. In general, congenital malformations like spina bifida with associated HYD are highly epileptogenic in nature. Some family studies found genetic evidence for partial epilepsies located at the chromosome 2q. Other family studies found that mutations on the gene mediating the coding of sodium channel subunits have been associated with febrile seizures extending beyond the age of six and subsequent development of generalized seizures.

In addition, some idiopathic epilepsies have been linked to the gene responsible for ion channels and its associated seizures are thought of as “channelopathies”.

Diagnosis

Diagnosis is mainly based on EEG findings. Measurements are taken by electrodes on the scalp for about twenty minutes. In normally developing children, the EEG pattern changes with age reflect structural and neuronal maturation of the CNS. Under different conditions a child will be monitored for abnormalities indicating epileptic activity. Abnormal patterns include sudden changes in frequency with increases or decrease in voltage. Ictal recordings are particularly helpful in establishing a diagnosis when abnormal activity occurs at the onset of a seizure. In contrast, interictal data is neither sufficient for establishing nor excluding an epilepsy diagnosis. Above and beyond, the recordings are routinely employed to help categorize seizure types and to indicate potential underlying causes of seizures. Mass lesions, infections and some tumors may be identified by abnormal activity patterns. If such conditions are suspected, other imagining techniques like CT and MRI are employed to further investigate underlying pathologies. Functional imagining methods (SPECT and PET) help to indentify brain regions of seizure focus. In order to differentiate between true seizures and seizure-similar events like psychogenic seizures, the EEG recording is often combined with video monitoring.

Treatment

Primary treatment in epilepsy is the administration of anti-epileptic drugs (AEDs) which are hoped to completely or at least partially control seizure occurrence. The underlying mechanisms of seizure control depend on the specific drug. In general, drugs can take one of three actions modes. (1) The drug can enhance modulation of the voltage-dependent neuronal ion channels, (2) it can enhance the amount of inhibitory neurotransmitters within the brain, mostly acting on GABA or (3) it can suppress excitatory amino acids, mainly glutamate. The effectiveness of a certain drug depends on its concentration within the brain and especially its availability in the synaptic cleft. The level of available drug in cortex is indicated by the serum concentration, which reflects the amount of it in the blood. Drugs should generally be administered with slow initial introduction to the system and close monitoring of serum levels. Close monitoring is essential to establish levels that are high enough to control seizures, but low enough to prevent neurotoxicity accompanied by higher levels. The duration of the drug’s effect depends on the rate of biotransformation. This is an individualized process that depends on a number of variables, namely the drug itself and interactions with other drugs as well as individual factors like genetic make-up, sex, age and diet. Drug dosage needs to be adjusted to effectiveness and tolerability within each person.

In cases of young children (below age five), more intense monitoring and adjustment is needed since their metabolism works faster than in adults; consequently the drugs have higher rates of biotransformation. With puberty onset, drug dosage tends to be increased and approaches adult levels. Most drugs are administered twice a day, with some exceptions in which patients required up to four administrations. Ideally, a patient can adequately control seizures by taking only one drug (monotherapy), but often a single one is not sufficient and is combined with other drugs (polytherapy) with possible interaction effects.

Overall, drug treatment is effective for many patients; still a range of side effects may occur including adverse effects on the CNS. Moreover, weight gain, excessive hair growth, behavioral changes and cognitive problems have been reported. As with other drugs, there is always the possibility of individual reactions towards the drug which cannot be anticipated beforehand. These acute side effects have been well researched, but more chronic impacts are also possible. It is crucial to balance possible side effects and benefits associated with drug administration. One of the major AEDs used is Phenobarbitone (PB), which is highly effective, but especially in children has been documented to lead to behavioral and sedating side effects. A number of drugs are available on the market, with differing effectiveness dependent on seizure type and age of patient.

Carbamazepine (CBZ). The drug has been introduced in the 1960’s and is the first choice in treating partial and general tonic-clonic seizure in children. It is a rather ineffective treatment for absence and myoclonic seizures, and shows only very limited effectiveness in generalized epilepsy with idiopathic cause. On average, the drug is very well-tolerated with no cosmetic side effects and only small impacts on mood, behavior and cognitive functions. Cases of acute toxicity have been fairly unusual. Nevertheless, higher doses and in particular fast introduction of the drug have been associated with dizziness, drowsiness and gastrointestinal symptoms. Some patients may show signs of hypersensitivity towards the drug which appear as skin rashes or similar presentations. In extremely rare cases more serious side effects may occur, which impact a patient’s bone marrow and liver functioning.

Sodium valoproate or valproic acid (VPA). This drug was discovered in the 1960’s and entered the market ten years later. Its specific mechanisms to control seizures have not been established yet, but it is speculated to enhance GABA levels in the synaptic cleft. It is especially effective in treating myoclonic generalized seizures and typical as well as atypical absence seizures. With regard to the latter two, it reduces the frequency and duration of abnormal electrical brain activity. The effectiveness is about the same compared to other AEDs when treating tonic-clonic generalized seizures.

In addition, it is useful in photosensitivity epilepsy, complex and simple partial seizures and epilepsies related to the Lennox-Gastaut syndrome (infantile spasms). In general, it is well-tolerated with only occasional changes in behavior, including irritability, hyperactivity and aggressiveness.

In rare cases, hepatotoxic reactions have been reported, but with close monitoring and serum control this has become fairly unusual. Additional side effects include cosmetic changes like weight gain and hair loss, which can be especially damaging to the well-being of adolescent girls. In a number of children treated with this drug, hyperammonaemia has been report. Even though it is mostly asymptomatic, even mild forms can impact cognitive functions.

Phenytoin (PHT). This drug is effective for a wide range of seizures, with absence seizures being the only exception. In the case status epilepticus, two drugs make up initial treatment. First, benzodiazepines are administered in order to gain control over it and then, PHT helps to prevent its reoccurrence. Despite its well-established effectiveness, PHT is seldom the first choice in continuous seizure treatment. A great number of serious side effects accompany this drug, and intoxication incidences are higher than with other drugs. Intoxication mainly results in cerebellar symptoms of nystagmus (uncontrolled movements of the eyes), ataxia and dysarthria. Some less serious and common side effects include excessive body hair growth and gum hypertrophy, therefore it should not be used in prepubertal children (especially girls).

Vigabatrin (VGB). It is a synthetic derivate of GABA and inhibits its breakdown. Consequently, GABA availability increases in the synaptic cleft to counteract excitatory activities and thereby controls for seizures. It is primarily used as an add-on drug in cases of chronic and intractable epilepsy of children and adults. Interaction effects with other drugs have hardly been reported for it. Partial seizures with and without secondary generalization are well-controlled by VGB. It can also be used as a primary drug in more child-specific seizure forms like infantile spasms. General side effects are fatigue, drowsiness, dizziness and some behavioral changes; which might even result in acute psychosis for adult patients. Specific behavioral side effects for children include insomnia, agitation, hyperactivity and excitement. At times the drug has been associated with intensified seizures for patients suffering from the Lennox-Gastaut syndrome or non-progressive myoclonic seizures. Weight gains have also commonly been reported with VPA usage. More recent findings of related visual field constriction and retinal atrophy demand regular eye examinations for patients treated with VGB.

Lamotrigine (LTG). This drug has been introduced in the 1990’s and is believed to control seizures by means of inhibition of sodium channels and glutamate release. It is often employed as an add-on drug in children exhibiting a range of generalized seizures types like typical and atypical absence, tonic, atonic and myoclonic seizures. Its effect on partial seizures is comparable to CBZ, but it is better tolerated in childhood. In addition, LTG has positive effects on pre-existing cognitive impairments in alertness, speech and mobility. These positive effects have been documented even in the absence of seizure control. It has fewer sedative effects than other drugs and shows marked increases in alertness especially for children suffering from encephalopathic epilepsy (e.g. Lennox-Gastaut syndrome). Potential side effects include agitation, drowsiness and ataxia. When used in combination with other drugs, it might either show increase or decrease of biotransformation. In particular, if LTG is added to CBZ it can dangerously increase its neurotoxic effects (diplopia and dizziness). In about five percent of children allergic rashes have been reported and in a tiny subgroup of adult patients rashes may even become life-threatening. Slow introduction of the drug is recommended to minimize the risk of rash development.

Topiramate (TPM). This drug has only been recently released and further research is needed to establish its effectiveness. In general, it is believed to be effective in treating childhood epilepsy, especially in cases of intractable partial seizures. In adult samples it has been associated with a number of cognitive side effects.

Another more drastic treatment approach in epilepsy involves neurosurgery. Surgery is considered for patients that do not respond sufficiently to medication and is especially effective in intractable epilepsies.

Surgical treatments

These kinds of treatments are increasingly used in young and very young children, in addition to adults. It can either be resective or functional in nature.

Resective surgery. This kind of surgery involves the removal of malfunctioning brain parts. The most common form is temporal lobe resection, in which parts of the temporal neocortex or mesial temporal structures are removed. The latter is then referred to as amygdala-hippocampectomy. In most cases both structures are removed. The frontal lobe resection is the most commonly performed resection apart from temporal lobe resection. Probably the most dramatic neurosurgery is the hemispherectomy in which most parts of or even an entire cerebral hemisphere is removed. Nowadays, some posterior and anterior regions might be left, but functionally isolated within the cortex since the corpus callosum is routinely cut. It is mainly performed in cases of very severe but unilateral disorders, with present hemiplegia and uncontrollable seizures. Generally, it is performed in early childhood in order to prevent damage to the unaffected hemisphere from ongoing seizures. All surgeries are guided by electrocorticography to increase the precision of surgery with minimal damage to healthy tissue.

Functional surgery. This type of surgery aims at changing brain functioning in order to improve seizure control. One commonly performed functional surgery is Callosomy, which involves the division of callosal fibers to prevent the spread of epileptic activity across hemispheres. Complete seizure control is unlikely to result from the surgery, but it can relieve certain seizures like drop attacks. Another approach is Multiple supial Transaction (MST), in which blocks of cortical neurons are isolated by multiple supial cuts into the cortex. It controls for the horizontal spread of epileptic activity while preserving vertical communication between neurons. As in resective surgery, the procedure is guided by electrocorticography.

Not every patient can undergo surgical interventions. In order to be considered for surgery a patient has to meet the following three criteria:

1. The patient experiences disabling seizures which are non-responsive to drug treatment.

2. The seizure onset can be traced to a well-defined brain area.

3. The epileptogenic zone has to be within a functionally silent cortex.

In general, potential benefits of the surgery have to be weighed against adverse effects resulting from it. Before surgery, the seizure focus has to be identified in a stage-like manner first by employing the least invasive and then gradually the more invasive methods.

At the first stage, EEG recordings are combined with video monitoring; this allows for initial investigation of changes in electrical activity and behavior associated with ictal periods. This provides first information about the focus of epilepsy. These measures can be taken across all ages. At the next stage structural imagining techniques (MRI) are employed to identify underlying cerebral abnormalities related to the epileptic focus. Furthermore, functional imagining techniques like SPECT and PET can help to precisely localize seizure focus when used during EEG recordings. In particular, regions that are involved in seizures will be hypermetabolic during the seizure and hypometabolic at rest in comparison to surrounding areas.

In terms of post-operative consequences, it is necessary to identify which hemisphere is dominant for language functions. Functional MRI is one way to non-invasively investigate brain functioning during language tasks, but this approach is not perfected yet for this purpose. In the future it is likely to replace more invasive methods especially for children. The utility of EEG recordings in localizing epilepsy focus can be tremendously improved when placing electrodes to the brain base. Electrodes placed at the sphenoidal or foramen help to establish lateral side and location of seizure onset.

Precision can be further improved by so called depth electrodes that are inserted into the cortex or by subdural electrodes which are inserted subdurally just above the brain’s surface. The more invasive the measures become the more concern there is with regard to children. The later is especially useful for the functional mapping of sensory, motor and language cortex, conducted before surgery to minimize potential risk of post-operative impairments in these. Moreover, these electrodes are good in identifying lateral temporal and extratemporal locations of seizure onset. With respect to temporal lobe epilepsy, the presence of underlying hippocampal sclerosis can be detected by more non-invasive means of MRI.

In addition, neuropsychological assessment is routinely administered to investigate a patient’s fulfillment of the second and third criteria. Above all, it can provide useful information about specific deficits in line with the epileptic focus and about potential post-operative cognitive consequences. One complicating factor in assessment and data interpretation is the potential for neurological reorganization in cases of very early brain pathology. Ideally, results of the neuropsychological assessment are compatible with findings of the neurological investigation.

Intracartoid sodium amytal (WADA) is another method routinely used in pre-surgery assessments, mostly for candidates of temporal lobe surgery. Its main purposes are to imitate brain functioning after surgery, lateralize language functions and to assess potential risk of post-operational amnesia. The procedure involves several steps starting with an injection of sodium amytal (an anesthetic agent) into one internal carotid to anesthetize one hemisphere. This results in contralateral hemiparesis and since in most people the left hemisphere is the language hemisphere, hemiparesis of the left hemisphere will result in speech arrest.

It is usually combined with EEG monitoring of electrical activity, whereby the EEG pattern shows general slowing in the hemisphere after injection, language and memory tests are administered. With only one hemisphere awake, the patient is then asked to remember three items and once the other hemisphere awakens is asked to repeat these. This assesses if the hippocampus which remains after surgery is sufficient to mediate memory functions. If two items can be recalled, the test is passed. A better predictor of memory abilities however, is to ask the child to remember certain aspects of the test. This method can be utilized in children as young as eight years old, even in cases of intellectual disability. This procedure can exclude post-operative amnesia, but it is insensitive to more subtle memory impairments. Overall, it is a very demanding assessment method which requires extensive training and familiarity for accurate administration and interpretation. On average, these surgeries are highly effective and prevent intractable childhood epilepsies.

Careful selection procedures mentioned above optimize surgery outcome for children with respect to reduced or totally absent seizure and no or only little additional deficits. On an individual level, the outcome depends on the size and nature of the lesion as well as on the surgical approach taken. For instance in children with temporal lobe epilepsy and small underlying lesions that can easily be removed, 70 to 85 percent are seizure free post-surgery. When patients have larger and harder-to-remove lesions (dysplasia), underlying epilepsy prognosis tends to be much poorer in terms of subsequent seizure control. There is a growing tendency to perform surgery early in life in order to prevent or minimize accumulation of behavioral, cognitive and psychosocial problems often related to epilepsy. In addition to underlying brain pathology often found in childhood epilepsy, seizures themselves have adverse effects on the ongoing cerebral development of children.

There is evidence that seizures interfere with age-appropriate skill acquisition and might also undermine established skills. Consequently the child presents with developmental deterioration. Most striking evidence comes from research on children after hemispherectomy, which indicates that younger age at surgery is associated with fewer language and motor problems compared to older children or adults. In general, there is no evidence on severe post-operative consequences in children. Nevertheless, even mild cognitive impairments are likely to impact the developing child. It is recommended to address all potential outcomes after surgery including mild deficits. At times it might be feasible to delay surgery until specific skills have manifested or vocational therapy is completed. Even in cases of successful surgery and subsequent seizure control, the child and family may face some challenges, since other behavioral or cognitive problems will likely persist.

For instance, in adolescents impairments in social interactions will likely continue. The point is that even after successful surgery ongoing support for children and their families will be needed.

Other treatments

In addition to drug and surgical treatment of epilepsy a number of other interventions have been reported. Vagal nerve stimulation is another surgical intervention in which a small stimulator is implanted into the left vagal nerve. It is supposed to activate a range of subcortical regions which leads to seizure inhibition, but the specific underlying mechanisms are not known yet. It has been shown to decrease seizure frequency in adults with chronic partial seizures and might be beneficial as an adjunctive therapy. However, its usefulness in treating children has not been established so far.

Dieting is another approach towards epilepsy treatment. A high-fat diet produces ketosis and acidosis which seem to affect all seizure types positively. It might be especially useful for children with epilepsies that are generally hard to treat like in Lennox-Gastaut syndrome-related epilepsies. When the children are able to strictly adhere to the diet, up to half of them are able to completely control seizures and there is at least some benefit to others.

The last approach towards treatment differs from the previous ones, since the focus shifts from biological interventions to psychological ones. Psychological interventions have been suggested in epilepsy treatment because external factors can lower a child’s seizure threshold and thereby increase frequencies. Such lowering can follow after non-specific and fairly common situations like stress, strong emotional reactions and sleep deprivation. Some forms of epilepsy are more sensitive to specific stimulation or activities like fast flickering light and respectively, exhausting physical exercises. Interventions target these situations and form appropriate preventative strategies. For instance, myoclonic seizures are sensitive to sleep deprivation and a possible preventative strategy could be the establishment of regular sleeping patterns. In cases of rare reflex epilepsies in which seizures occur in response to a specific stimulus, classical conditioning paradigms have been implemented. Relaxation techniques and cognitive behavioral techniques are useful in epilepsies that are sensitive to intense emotional reactions and interpersonal stress. Moreover, EEG and biofeedback trainings can be beneficial. Patients can be taught to recognize pre-seizure symptoms and then try to inhibit the seizure from occurring by producing non-convulsive EEG patterns. One major problem which tends to occur in adolescence is poor compliance with drug prescriptions which increases seizure frequencies by up to 50 percent. Psychological interventions can be useful in targeting noncompliance.

Childhood disorders associated with epilepsy

Epilepsy can result from many underlying pathologies either congenital or acquired, which influence its specific manifestations. In the following, a number of childhood disorders with associated epilepsy will be presented.

West syndrome is one of the epileptic encephalopathies occurring in infancy. It usually emerges between the age of three and eight months and entails three core features. (1) Infantile spasms, which are clusters of abrupt briefly sustained movements of the head, neck and limbs involving the axial muscles. (2) Hypsarrythmia, which describes an interictal pattern of EEG activity that is marked by high-voltage slow waves, spikes and sharp waves occurring randomly from all cortical regions.

It conveys the impression of overall disorganization of cortical electric activity. (3) Infants exhibit marked psychomotor delay. The syndrome can include cryptogenic and symptomatic varieties. In addition, multiple etiologies can underlie its manifestation, including tuberous sclerosis, metabolic disorders and prenatal as well as perinatal brain injuries. On average, the prognosis is poor with common reports of autism, mental retardation and hyperactivity in these children. Only about 12 to 25 percent develop normally which highly depends on the presence and nature of underlying brain pathology. Treatment generally involves AEDs and corticosteroids. Surgery might be performed in cases of local cerebral abnormalities causing seizures. One quarter of affected children will show spontaneous remission of the condition within one year.

In contrast, without subsequent seizure control, children carry high risks of developing other seizure disorders with age. Of these, about 25 percent will develop the Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is another epileptic encephalopathy with onset in early childhood. It is mainly characterized by multiple occurring seizure types, mental retardation and EEG patterns that show slow spike-wave discharges and that typically occur in children between one and seven years of age. In about 70 to 75 percent of these cases the syndrome is either associated with visible cerebral abnormalities or with premorbid developmental delay or epilepsy (25 percent have a history of West syndrome). The primary treatment of related seizures is AED administration. Prognosis is poor with permanent mental retardation and psychosocial problems. Especially with early onset before the age of two, children exhibit poorer outcomes and more seizures that are hard to control. On average, the multiple seizures tend to evolve into one predominant type by young adulthood.

Temporal lobe epilepsies (TLE) include two subtypes and are generally characterized by simple and complex partial seizures, secondarily generalized seizures or a combination of these. The most common type is hippocampal TLE, which includes aura features of epigastric discomfort, nausea and more autonomic signs such as associated auras. The other common type is lateral TLE. In contrast, auras commonly related to lateral TLE are marked by auditory hallucinations, dreamy states and illusions. Onset is usually in childhood or young adulthood. Additionally, affected children often have a history of febrile seizures and stem from families with positive epilepsy history.

Frontal lobe epilepsies (FLT) are characterized by many different seizure types, namely simple partial, complex partial and secondarily generalized seizures. Some common features of these seizures are automatisms, bilateral movements, short episodes with high frequency of occurrence, and minimal confusion after seizures disperse. They are commonly categorized according to specific areas of the frontal lobe that are involved in epileptic activity.

Overall, this kind of epilepsy is relatively rare in children. Two main characteristics have been proposed in FLD:

1. It is marked by very brief episodes of unresponsiveness, without complete loss of consciousness and functional language comprehension

2. It includes either tonic or clonic motor phenomena, involving the arms and faces of affected children.

In addition, it may include inappropriate laughter, crying, screaming and sexual behaviors. Patients often display symptoms typical of frontal lobe dysfunction, namely intellectual abilities within the normal range, but executive dysfunction and behavioral disturbances like impulsiveness. AEDs are the primary treatment approach, but most often these epilepsies are hard to control.

Childhood absence epilepsy normally emerges when children enter school. Its main characteristics include very brief episodes of altered conscious state, sudden discontinuation of activities and a blank stare. After the seizure the child usually picks up on the previous activity without any signs of postictal confusion. In cases where a family history of epilepsy or previous febrile seizure exists, children are at increased risk for developing absence seizures. In contrast to other epileptic disorders, absence seizures tend to occur multiple times a day. It is often first detected by teachers describing children as daydreaming or vague. These episodes of impaired consciousness interfere with subsequent skill acquisition and academic performance despite average intellectual functioning. It can be well-controlled by drug treatment and with continued control, over a period of two years, the seizures tend to remit.

Acquired epileptic aphasia. Is also referred to as Landau-Kleffer syndrome and usually appears in toddlers and preschool-aged children. It has only recently been introduced as an epilepsy type with primary manifestations of cognitive, language and behavioral impairments. Particularly striking in this condition is the regression of previously acquired language abilities, including receptive and expressive language capabilities, as well as word deafness and auditory agnosia. It is usually accompanied by abnormal EEG recordings with no specific pattern, but sharp spike-wave complexes. Together with seizure activity, these abnormalities tend to abate at around 15 years. Prognosis is very variable, but a majority will sustain permanent language problems. Specific underlying pathologies have not been established so far, only abnormal metabolic activity of the temporal lobes, which vanishes together with seizure remission. This epilepsy is hard to treat with AEDs, but corticosteroids might have some benefit. In addition, multiple supial transection surgery has been successful at least in some cases.

Epilepsy with continuous spike-waves during slow-wave sleep is another more cognitively manifested epilepsy form. It is mainly characterized by cognitive and behavioral disturbances in combination with atypical absence and other seizures. EEG findings indicate continuous spike-wave activity during slow-wave sleep. Onset is typically between the ages of four and five and affects about 0.5 percent of all children regardless of previous development. Diagnosis is mostly based on findings of EEG sleep recordings, seizure onset after normal development, behavioral changes and intellectual regression. With regard to language abilities, children display a very specific pattern of functional expressive abilities and disorganized language content. In line with this, behavioral problems suggest a higher-order dysfunction (disinhibition, lack of insight and preservation tendencies). Epileptic systems also show a tendency of remission at around the age of 15, with only limited elevation of cognitive and behavioral problems. Overall, treatment with AEDs and corticosteroids only show limited success in seizure control.

Benign epilepsy of childhood with centrotemporal spikes. This is the most common type of epilepsy associated with childhood onset, accounting for a quarter of all epilepsy incidences before the age of twelve. The onset somewhat peaks between seven and nine years of age, and shows remission after 16. It is characterized by brief simple partial hemifacial seizures, in combination with somatosensory symptoms, which are likely to evolve into grand mal seizures. Commonly, seizures occur in the hours of falling asleep. They show abnormal EEG recordings, but on average develop normally with no apparent neurological symptoms. Furthermore, it tends to run in families suggesting some genetic basis.

In comparison to healthy peers, epileptic children demonstrate higher rates of behavioral, cognitive and intellectual impairments. Even compared to children with physically chronic illnesses they are at higher risk of academic failures and behavioral problems. Still many children with epilepsy function within normal ranges. In general, children with underlying brain pathologies independent of epilepsy have an increased risk for developing psychological problems. It follows that children with symptomatic epilepsy present more such problems as opposed to children with idiopathic epilepsy.

Functional outcome

Overall, a child’s functional outcome will depend on disorder-related factors, presence of neuropsychological residuals and psychosocial burden that comes with epilepsy. In addition to disorder effects on cognition, AEDs can have adverse impacts as well. Depending on the specific type of epilepsy, children show a deterioration of functioning over time, especially in cases of encephalopathies. Many IQ studies have shown stable performance on measures, but it is well possible that on an individual level deterioration might be masked by overall group stability. In addition, as mentioned before, IQ is insensitive to more subtle cognitive deficits, which even in mild forms can severely impact ongoing development in children. Nevertheless, some studies report increments in IQ after a period of two years without seizures. Other researchers found deterioration in academic performance. In general, different IQ measures taken at different times as in these two conflicting findings are not directly comparable. In addition, previous research neither accounted for individual variability in performance nor for AED serum levels at time of assessment.

In predicting intellectual deterioration over time, nature and presence of brain abnormalities play a crucial role.

With respect to seizure-related factors impacting on outcome, several factors and potential interactions have been suggested; including age of seizure onset and its severity, seizure type, laterality and location of seizure focus, laterality and age of onset and subclinical epileptic activity.

Age of seizure onset and seizure severity. A large-scaled longitudinal study of the National Institute of Health (NIH) compared children with febrile status epilepticus with their healthy siblings on IQ measures. Results indicated no significant difference between the two, but presence of more subtle cognitive impairments has not been investigated. Of all children with acute symptomatic epilepsy or epilepsy with associated progressive encephalopathy, about 27 percent showed marked neurological deficits. On average, these children tend to be younger and hence more vulnerable to CNS disruption. Another study found a strong relationship between cognitive impairments and presence of seizure and severe EEG abnormalities. Children in this study with severe brain damage and no associated seizures performed better than children with less severe brain damage and associated seizures. This provides evidence that seizure disorders have an independent and serious effect on cognitive abilities, regardless of presence and severity of underlying brain pathology.

Others found that early age at seizure onset is strongly related to lower scores on VIQ, PIQ and the Trail Making Test, irrespective of seizure type. On the whole, the epileptic population shows higher incidences of academic problems. Ranging from most to least common, deficits include arithmetic skills, spelling, reading comprehension and word recognition. These tend to be more pronounced in older children. Children with early seizure onset, higher total lifetime seizures and presence of multiple seizure times bear the greatest risk of developing academic problems. Seizure-related factors and other factors have been investigated regarding their potential impact on children’s behavioral development. Taking a multi-etiologic approach, gender and seizure control appear to be the strongest predictors of behavioral outcome, with parental marital status and monotherapy versus polytherapy also contributing. These factors are not independent though. Other studies found that the severity of seizures in the preceding year is a strong predictor of current behavior.

A body of evidence supports the relation between earlier seizure onset and therefore longer duration of the disorder and poorer cognitive outcome. This is further supported by findings that patients with different degrees of mesial temporal sclerosis (MTS) also differed in cognitive performance, with more severe cases demonstrating more impairment. More serious forms of MTS are related to earlier seizure onset. It remains a very rare condition in children, but is the most common underlying cause for adult TLE. Prolonged febrile seizures and status epilepticus presence are risk factors for later MTS. Animal studies have shown that the immature CNS is more insensitive to impacts of repetitive seizures, but they are still not immune to damage. In contrast, seizures are likely to delay brain growth even in absence of visible lesions, but catch-up effects have also been documented in animal studies.

There is existing evidence that functional differences are related to seizure type. This also applies to academic and behavioral functioning. For instance, it is possible to discriminate children with different seizure types based on their arithmetic skills. For example, children with generalized seizures perform significantly more poorly than children with partial seizures. In addition, in cases of multiple seizure types, performance is more depressed across all academic areas. Findings with regard to behavioral outcomes have been controversial. Some studies found a relation between social outcome and seizure type, with simple partial seizures yielding most favorable outcomes.

The specific pattern of neuropsychological deficits depends on laterality and exact location of seizure focus. In terms of temporal lobe focus, traditionally, left-sided location has been associated with poor verbal memory before and after surgery, and right-sided location with poorer visual and non-verbal memory.

It is well-established that bilateral hippocampal lesions results in severe amnesia, but unilateral lesion effects are not as clear-cut as previously suggested. Many studies found a relation between left temporal lobe focus and more generalized cognitive impairment. It has been speculated that early verbal memory problems interfere with subsequent normal skill and knowledge acquisition resulting in lower general intellectual functioning. Further, the degree of memory impairment correlates with hippocampal cell damage in MTS. Up until today, child-based studies could not establish any specific right temporal lobe memory deficits. There are different findings in children and adults, with children showing more generalized cognitive impairments, whereas adults display more material-specific problems after temporal lobe lesions. One study found expected poorer performance on verbal memory tasks in children with left-sided TLE, whereas no differences were found in visual and spatial memory tasks. One possible explanation is that the right temporal lobe is simply functioning in a different manner than the left, or alternatively, it might be harder to develop non-verbal memory measures. Independent of underlying structural abnormalities, localization of epileptic focus determines specific cognitive problems. Children with left-sided focus, as based on EEG recordings, show more impairment on verbal tests, whereas children with bilateral and right-sided EEG anomalies have greater problems in visuospatial judgments. From an academic point of view, children with left-sided EEG anomalies had more problems in reading comprehension, not reading itself. In addition, left TLE is likely associated with poorer arithmetic skills.

Moreover, there seems to be an interaction between laterality and age of onset. For instance, children with earlier onset and left-sided focus achieved significantly lower scores on the VIQ, than if only one condition was present. By the same token, risk of intellectual impairment in left-sided focus tended to decrease with increasing onset age. Poor non-verbal performance is more likely in children with early onset, extratemporal focus, and atypical speech lateralization. This might reflect functional reorganization in early left hemisphere damage and an associated crowding effect. Others have speculated that early onset age might actually be protective for further memory disturbances.

The association between age and laterality also exists in FLE cases, in terms of executive and primary motor functions. In contrast to left focus, early right-sided FLE resulted in less motor impairment compared to later onset. No consistent pattern exists for executive functions. Overall, different ages of onset and different locations in FLE will lead to very different patterns of neuropsychological impairments. Generally, there is a complex interaction between seizure-related variables.

Many epilepsy sufferers show dysfunction during seizures, but also fluctuate in performance between seizures. One possible explanation relates to the concept of subclinical epileptic activity, in which abnormal activity is evident on EEG in absence of behavioral manifestations (seizures). The allied concept of transitory cognitive impairments (TCI) has been introduced as a momentary cognitive deficit associated with occurrences of subclinical discharges. TCI can also be view as an ictal phenomenon, namely as a very brief seizure. This might possibly explain parental reports on children’s variability in functioning. If so, it might shed light on better managing these children. It may then also account for variation in assessment results over time. One study found that children who exhibited subclinical discharges during test performance achieved significantly lower scores on cognitive measures than children with normal brain activity. Taking into account the discharge location, right-sided focus resulted in relatively more impairment on visuospatial tasks and left more in verbal. This condition might be alleviated by administering AEDs to suppress discharges in order to improve cognitive functioning.

Cognitive and behavioral outcomes

When investigating children’s cognitive and behavioral outcomes, it is important to take adverse effects of drug treatments into account. Studies conducted in the 70’s and 80’s provided first evidence of detrimental effects some AEDs had on cognition. Subsequently, the focus of treatment shifted from mere seizure control to prevention of harmful cognitive deficits. In general however, it is difficult to isolate the effect of AEDs on cognition from seizure and other underlying brain pathology influences. Furthermore, most cognitive measures are not sensitive enough to detect drug-related cognitive residuals.

More computer based neuropsychological tests of processing speed, information-processing, attention and memory function have been shown to be more sensitive to adverse drug effects. If children are treated with only one drug, withdrawal from it is only associated with limited improvement of motor speed. This indicates little impact on overall cognitive functioning in cases of monotherapy. Another study investigated subjective ratings of children either on or off medication by themselves and their parents. Interestingly, children on medication did not report to feel any different and when off medication they reported to feel less tired. With respect to parental reports, off medication was associated with reported improvements of the child’s drowsiness, alertness, concentration and attention, whereas children on the medication were more often rated as being under-aroused. These findings were similar across varying AEDs, epilepsy duration and seizure-free episodes. Others looked more into detail of short-term drug effects on cognition in newly diagnosed children.

Accordingly, in the case of drug introduction at least within the first six months, no adverse effects were found. There exists more consensus about older drugs, especially for PB, which quite often exacerbates pre-existing symptoms of hyperactivity and aggression. Similar, but milder impairments follow after PHT intake. Overall, it can be said that most AEDs are fairly well-tolerated by children with little associated impairments when kept at standard level. Most adverse drug effects are related to elevated drug serum levels within the brain and to other drugs that have been combined for seizure control. In the latter, drug interaction effects can affect each other’s metabolism rates and thereby serum levels. Despite these general findings, individual variation is possible, so that in some cases even small amounts of drugs can result in unexpected and paradoxical side effects. To minimize side effects, close monitoring and slow drug introduction are recommended.

Some patient subgroups with premorbid problems of hyperactivity and attentional deficits are more impacted by drug effects with relative high risk of intensification of these symptoms. Many short-term effects can easily be detected by a general physicist, with subsequent drug adjustment. In terms of more chronic and long-term effects, especially when mild effects are involved, these are much harder to detect. It is important to remember that even mild cognitive problems can seriously interfere with a child’s ongoing development depending on age. Special concerns of AED usage arise in cases of pregnancy, infants and very young children, since drugs are likely to impact the fast developing CNS in these stages. With drug administration during pregnancy, resulting effects are increased incidence rates of birth defects. These rates reflect the teratogenic effect of AED, which mostly interfere at stages of embryogenesis leading to severe malformations of the neuronal tube for instance, or to milder deformations like dysmorphic facial features. So far the role of other related factors in pregnancy has not been determined, including maternal age, heredity and occurrence of seizures during pregnancy. It has been speculated that maternal seizures during pregnancy are more predictive of intellectual outcomes than AED usage. Further evidence of serious impacts PB has on neural development comes from studies which artificially bred spinal cord neurons. Results showed that prolonged exposure to PB decreased cell survival, length, as well as the number of dendritic branches. In animal studies artificially induced seizures in rats were subsequently treated with PB. Results indicated that without PB treatment rats functioned very poorly, but more interestingly, rats with seizures and unsuccessful seizure control after PB treatment performed even poorer. In conclusion, it was suggested that PB intensified the impact of seizures on the CNS. This topic remains somewhat controversial, but it is evident that at least with mild cognitive residuals resulting from AEDs, chances are high that these severely impact further development in infants and young children. Another important study investigated children treated for febrile seizures with PB. Foremost, they could not find any benefit of PB administration in terms of seizure reduction. Consequently, there may be no benefits to weigh against negative consequences. Even though no intellectual impairments were apparent at a three year follow-up, it is likely that adverse impacts will show up later in life when age-expected advances do not manifest normally.

In addition, not only is the CNS in infants and young children especially vulnerable to disruptions by seizure, but the epilepsy forms most common in these ages tend to be more severe and hard to treat. Overall, the same debate of AED effects on cognition exists for seizure impacts.

These controversies about AEDs have several clinical practice implications. Parents show a tendency to quickly attribute emerging problems solely to drug effects, which is hard to establish. Furthermore, on average most drugs are safe to use and parents need to be reassured about that safety. In cases of difficult-to treat epilepsies, dilemmas of keeping the balance between adequate seizure control and unacceptable side effects might occur. In the end, it is the parents’ responsibility to keep this balance in consultation with the child’s physician. This might be somewhat easier to do for overt behavioral changes and other obvious consequences after drug intake, but it is generally more complicated for subtle and insidious side effects. The latter are likely to be first recognized later in life, when the child shows abnormal or delayed development.

In terms of neurological impairments, the degree of cognitive impairment in children with epilepsy is the single most important predictor of later academic performance, behavioral and social outcomes. As a general rule, cognitive functioning is expected to mirror the complex interplay of several factors within an individual. Factors of interest are underlying brain damage, seizure-related variables, and drug treatment-related variables in combination with genetic and environmental factors. Since epilepsy is not a unitary disorder, it is not surprising that research has failed to establish a specific profile of neuropsychological deficits for children with epilepsy.

One very common finding is that of attentional deficits, even in absence of any other neurological findings. Studies with adults and children revealed that both show depressed attention, reaction time and motor speed, which all can impact overall performance on cognitive tests. Epilepsy has been associated to specific attentional deficits that are independent of other factors like IQ scores. More detailed investigations of epileptic children revealed that performance was very poor on tasks of visual and verbal attention even in relation to overall test performance, which supports the notion of specific attentional impairments. A pattern of attentional deficits has also been reflected in parental reports on children, which persisted even after exclusion of children with comorbid attention deficit hyperactivity disorder (ADHD).

Moreover, these cognitive problems will also be reflected in their academic performances. Evidence has consistently been found in high incidences of academic underachievement in the epileptic population, which are likely related to attentional deficits described previously. There is no convincing evidence on specific learning disabilities associated with childhood epilepsy. Therefore, it has been suggested that attentional difficulties stem from AED effects on the brain. In contrast, some studies have found impaired alertness independent of AED effects and postulated that this might be a common attentional disorder in epileptic children.

One study aimed at identifying neuropsychological correlates related to academic functions. The study compared successful achievers (average school performance) with unsuccessful achievers (below expected performance). On average, the two groups did not differ in general intellectual abilities, but showed marked differences in favor of the successful achievers in measures of attention, concentration and verbal abilities. Besides, difficulties of unsuccessful achievers are very similar to those experienced by children with specific learning disabilities, but without epilepsy. These difficulties mainly include: problems in auditory-visual integration, word knowledge, short-term verbal memory and verbal expression as well as verbal conceptualization. In contrast, others found more quantitative differences, with poorer academic performance mainly associated with relatively low IQ scores (still within normal range) and more severe visuomotor impairments.

Social competence has been shown to be severely affected by the level of cognitive ability. One especially strong relationship exists between cognitive functions and behavioral as well as emotional adjustments. According to this relationship, children with poorer neuropsychological functioning show higher incidences of aggressive behavior and overall psychopathologies, as opposed to higher functioning children. In general, the overall neurocognitive status is the strongest predictor of behavioral outcome in epileptic children. In a similar vein, cognitive performance in childhood has been shown to be highly predictive of psychosocial outcomes in later adulthood.

A cohort study of children with epilepsy performing within normal ranges on IQ tests has provided evidence that comorbid learning disabilities strongly influence social outcome. Whether these disabilities are a result of early cognitive impairments in children with epilepsy or if they are of independent nature has not been identified. Another population-based study on psychosocial outcome in young adults with previous history of epilepsy revealed that these individuals on average showed delayed social growth into adulthood when compared to healthy controls. This was mainly based on the higher tendency of patent-based living styles and a lack of gainful vocational education in affected participants. Identified risk factors included presence of cognitive impairment and learning disabilities. This study found no significant impact on social outcomes by epilepsy itself or drug treatment.

Psychosocial outcomes

For the epileptic population, several individual, environmental, social and additional factors have been associated to psychosocial outcomes later in life.

One relevant factor influencing psychological well-being is stigmatization, with about 90 percent of adults with epilepsy stating to feel stigmatized, whereas only about one third can state a specific instance of discrimination. In cases of children, the parent’s perception of stigma is an influencing factor. Reports of social stigma are mainly concerned with fears of losing self-control (seizure) in a public situation. This heightened anxiety about body and behavior control is likely to negatively affect the development of a child’s healthy self-image, especially in adolescence.

In terms of the latter, they are distrustful of their own bodies and selves regardless of seizure type, level of seizure control and age of seizure onset. It is not the poor self-image itself that is predictive of psychosocial outcomes; rather it is the relative difference between that self-image and the one anticipated without epilepsy. In line with this, greater discrepancies are related to poorer outcomes. In general, children with chronic illnesses and especially so in case of epilepsy, show increased incidence rates of psychosocial disturbances in face of less than optimal family environments. In line with this, family separation or divorce is predictive of behavioral problems like depression regardless of the child’s gender. In addition, parental disharmony has been associated with poor medical compliance in adolescents, which further emphasizes the important and complex interaction between family and child factors. Families with epileptic children that also exhibit behavioral problems are mainly characterized by less intrafamily esteem and communication, poorer behavioral family functioning, less financial security and limited support from the extended family.

The other way around, children with epilepsy influence their family’s functioning, with poorly controlled seizures having a disruptive impact. It is not the disorder severity per se that predicts family dysfunction, but rather it is the subjective perception of burden on and disruption of the family caused by the disorder. In comparison to families without epileptic children, mothers of an epileptic child tend to have more prominent roles within family discussions and tend to be more strongly linked to the child. With regard to the epileptic child, it is more likely to have passive roles in families with reduced involvement in family decision as opposed to healthy controls. Moreover, existing epilepsy places a family at greater risk of problematic communication patterns, cohesion and integration. Parental reactions towards the child’s disorder commonly affect the child’s appraisal of the illness and its effects. As a general rule, a complicated web of interacting factors will predict an individual child’s psychosocial outcome. Relevant factors are: the specific characteristics of the child’s epilepsy, type of medication, degree of perceived stigma and lifestyle limitations resulting from seizures as well as parenting styles. In particular, the parents’ reactions towards epilepsy seem to mediate the effect of seizures and medication on behavioral and emotional outcomes. A multi-etiological approach investigated the relative contributions of demographic, seizure-related and family factors on behavioral outcomes in children with epilepsy. It followed that children with poorer outcomes had higher frequencies of poor seizure control, stemming from troubled families characterized by mothers not receiving sufficient support from other family members. In a longitudinal study, it was found that sociocultural factors played a major role in ongoing anxiety and that negative parental attitudes were a key player in epilepsy. These exaggerated and inappropriate fears linked to the child’s epilepsy persisted despite continuous efforts of educating parents. This was especially true for families from acculturated families and when parental education was low.

Overall, biological factors like cognitive outcome and illness-related variables have greater impact on behavioral outcomes than more social factors (parenting styles).

Academic achievement

Less research has investigated the relationship between psychosocial factors and academic achievement. In general, it has been found that chronic illness factors, general and epilepsy-specific, public misconceptions about the disorder, as well as teacher and parent behaviors and attitudes towards epileptic children impact overall academic performance. Moreover, parental tendencies towards overprotection of epileptic children and lower expectations of teachers as well as parents negatively influence outcomes.

These lowered expectations have been associated with academic underachievement that is often observed in the epileptic population. Additionally, the child’s own attitudes impact educational success. In terms of school-related self-perception, children with epilepsy tend to show poorer self-concepts concerning their intellectual abilities. This manifests in higher rates of worrying about test taking and more nervous reactions when called by teachers. Taken together, this might result in a learned helplessness pattern. More recent study also found condition severity, level of school adaptive functioning and a child’s attitudes towards their disorder to impact academic outcomes. Generally, evidence supports a stronger predictive value of psychosocial factors on a child’s psychological functioning as opposed to biological influences. This especially applies to children with idiopathic epilepsy without underlying cerebral abnormalities. Since subjective perceptions of parents and affected children about epilepsy highly influence a child’s well-being, intervention programs should target better education for both of them.

Overall, it has been very difficult to isolate specific effects of drug treatment from other factors like seizure types, psychosocial difficulties and underlying brain pathologies. In the majority of treated children however, the drug only rarely results in harmful effects. Nevertheless, even minor cognitive deficits depending on age have been shown to result in delayed or abnormal development. Since seizures can stem from a wide range of brain dysfunctions with or without associated brain anomalies, it cannot be considered as a unitary unit. With current refinement in epilepsy classifications by syndromes and simultaneous increases in understanding individual seizure disorders, future studies will be better able to define homogenous subgroups.

Consequently, influential factors for specific epilepsy disorders can be better identified and understood, resulting in better prediction and treatment in the long run. Past research has often been biased by selecting participants from special hospital units which only make up a small and rather severely affected proportion of the epileptic population. With advances in recruiting more representative samples, more information on how to clearly define different seizure disorders will be provided. It is generally accepted now, that epilepsy places an additional burden on already compromised brains. Therefore, surgeries are being performed at increasingly younger ages to minimize serious effects of seizures on healthy brain tissue and the overall ongoing development of children. With different kinds of intervention programs for childhood epilepsy, it is essential that neuropsychologists monitor the effectiveness of these in terms of long-term outcomes in several domains (cognitive, psychosocial, behavioral, etc.). In addition, epilepsy still remains a poorly understood condition for the normal population, which often accompanies stigmatization of affected children and adults.

To counter these social burdens, educational interventions targeting the general public have been proposed. Neuropsychologists will be very important for these interventions, since they possess good knowledge about brain-behavior relationships and might consequently be in a favorable position of educating others about epilepsy.