**5. Treatment of neurobehavioral consequences of pediatric traumatic brain injury**

The long-term consequences of TBI are often more obvious in children because their longer life span and need for schooling make such deficits all the more apparent. The overall disability in children is often less than that in adults suffered TBI. However, in the majority of head-injured children neuropsychological studies have shown deficits in cognitive functions and learning skills ranging from subtle to obvious. Special supportive measures, including educational intervention, behavioral modification and medical treatment, are therefore important issues. Thus, the treatment of TBI cognitive and behavioral sequelae must be planned as multimodal.

The study of cognitive functioning and recovery 10 years after TBI in young children by Anderson et al. [51] confirmed the high risk of persisting functional deficits associated with severe early brain insult but demonstrated an "injury threshold" beneath which children may escape serious sequelae. In contrast to the "severity"-specific recovery observed in acute and subacute periods, findings

*Advancement and New Understanding in Brain Injury*

due to TBI or as a result of craniotomy.

less common with closed head injuries.

migraines, is promising [46].

In the International Classification of Headache Disorders (3rd edition) [43], PTH is considered a secondary headache defined by the onset of headache "within 7 days following trauma or injury, or within 7 days after recovering consciousness and/or within 7 days after recovering the ability to sense and report pain" [43]. PTH is further subdivided into "acute headache attributed to traumatic injury to the head" and "persistent headache attributed to traumatic injury to the head." If the headache resolves within 3 months of onset, it is characterized as acute PTH, whereas headaches that occur beyond 3 months are defined as persistent PTH. The most common headache phenotypes in PTH are tension-type-like headache and migraine-like headache. In our cohort of patients suffered closed TBI of moderate and severe degrees persistent PTH were observed in 268 of 283 patients (95% of cases) recurring from one episode in a week to daily attacks [18, 19]. Headaches usually affected the lifestyle of the children, resulted significantly on their mood, behavior, intellectual and physical endurance, school learning. Headaches causation was established by their onset in temporal relation to TBI and persistence for more than 3 months after head trauma. The most commonly seen pattern, resembling tensiontype headache, occurred in 72.4% of patients. Headache associated with the increase of intracranial pressure due to long-lasting disorders of cerebrospinal fluid circulation was confirmed in 12.3% of cases. Migraine-like headaches were diagnosed in 11.9% and neuralgic pains in the frontal or occipital regions in 3.4%. Thus, our data evidence

for the involvement of different causative mechanisms in PTH in children.

PTH pathophysiology remains largely unclear, but several possible mechanisms have been proposed, including impaired descending modulation, neurometabolic changes and activation of the trigeminal sensory system [39]. When indicating severe brain damage due to TBI and persistent PTH, it is necessary to exclude the epileptic origin of paroxysms. The combination of PTH and epilepsy, as well as epileptiform activity on the EEG in patients with PTH was firstly reported in 1963 by D.W. Cooper and D.C. Cavicke based on two cases [44]. Formisano et al. [45] revealed a high incidence of paroxysmal abnormalities on the EEG with the presence of sharp waves in 84.6% of patients with chronic PTH, which was also associated with the presence of fractures or damages to the skull and dura mater, either

Not only routine EEG, but also video-EEG monitoring with the recordings in different functional states (especially all phases of sleep) should be used in the examination of patients with chronic PTH. Studies on the use of multichannel EEG monitoring in combination with evoked brain potentials to assess the disruptions and delay of activation of neuronal networks in PTH, especially in posttraumatic

**Post-traumatic epilepsy** is one of the most threatening consequences of TBI. High risk of post-traumatic epilepsy is characteristic for patients with penetrating head injuries—as much as 50% of them develop seizures. Patients with focal neurological deficit and large cerebral lesions immediately after injury have the greatest risk for post-traumatic epilepsy. It is believed that post-traumatic epilepsy is much

We have determined the incidence of post-traumatic epilepsy in our cohort of children suffered moderate or severe closed TBI. A total of 18 cases of epilepsy were revealed in a total of 283 patients. A total of 16 patients (10 boys and 6 girls) or 5.7% developed secondarily generalized seizures, all in the period from 4 to 12 months post-injury; the severity of head injury was moderate in 12 and severe in 4 of them. In 2 of 18 patients head injury precipitated idiopathic generalized epilepsies: childhood absence epilepsy in a boy of 7 years of age and idiopathic epilepsy with grand mal seizures on awakening in a boy of 10 years of age. Although symptomatic posttraumatic epilepsy developed in 5.7% (16 of 283) of children suffered closed TBI of

**194**

illustrate that recovery trajectories plateau from 5 to 10 years for all groups, regardless of injury severity. This result is important because it questions previous speculation that children with severe brain insults "grow into deficits" with time since injury. After a protracted recovery period, these children gradually stabilize and begin to make some developmental gains, suggesting that even many years postinjury, intervention may be effective [51].

Children with TBI represent a challenge to pediatric rehabilitation professionals as they may improve neurologically for months or years after the injury and may recover much of the knowledge and skills acquired before their injury despite substantial new problems of learning and behavioral self-regulation.

A child with a TBI is unique not only in comparison with peers of the same age, but also to other children with brain injuries. Each child's recovery process and outcomes are different and individual. Outcomes from pediatric TBI are rarely predictable and neither is the student's progress in school. Therefore, before the child returns to school, it is necessary for him, his parents, educators and rehabilitation professionals to develop an Individual Education Program (IEP). An IEP is essential for the successful academic progress of a child suffered TBI. An IEP is an educational plan outlining the special learning needs of a child, including:


Cognitive rehabilitation refers to the process of retraining individuals in the way they take in, store, and use information. Cognitive rehabilitation therapy is sometimes provided through hospitals or rehabilitation facilities immediately following acute hospitalization. When the student is reintegrated into school, it is necessary to continue some form of cognitive training. Cognitive rehabilitation and training help the student function within the environment. Although this treatment may initially be coordinated between an outpatient rehabilitative program and school, eventually it will become a school-based intervention program.

Cognitive training focuses on the foundation skills necessary for learning. The treatment goals are improvement in these skills as well as development of compensatory strategies. Skill development should be addressed both in individual and group settings where abilities such as social/verbal pragmatic competence can be addressed more suitably. Academics as well as functional life activities need to be included within the treatment to aid with generalization of identified skills.

The home environment and parenting style have long-term impacts on functional outcomes of children recovering from TBI. Interventions to promote more effective parenting may be useful for preventing or ameliorating morbidity following TBI [52].

The brain preserves a capacity to recover and adapt secondary compensatory mechanisms when neural tissue is compromised. This capability is due to neuroplasticity, a unique feature that makes the neural circuits malleable and is at the basis of memory formation and learning as well as in adapting to injuries and traumatic events throughout life [53–56].

Neuroplasticity is a process of biological adaptation based on brain structural and functional reorganization, aimed at restoring lost or impaired functions after brain damage [54, 55]. Neuroplasticity can be implemented at the molecular,

**197**

nent target.

*Neurobehavioral, Cognitive, and Paroxysmal Disorders in the Long-Term Period of Pediatric…*

synaptic, neuronal or multiple levels. It is based on modulating the functioning of neurons, restoring synaptic transmission, and activating inter-neuronal connections. To varying degrees, activation of neuroplasticity is accompanied by stimulation of the expression of certain genes, biosynthesis of receptor and ion channel molecules, filamentous proteins of the synaptic cytoskeleton, neurotransmitter, synaptic membrane components, intercellular adhesion molecules, formation of immature contacts, their maturation, activation, hypertrophy, and reorganization of active synapses [54]. Reparative neuroplasticity provides restoration of functional systems of the brain after their damage and is implemented by the entire spectrum of increasing the efficiency of the synaptic pool, from activation of preserved synapses to neosynaptogenesis and growth of nerve processes-a phenom-

The goal of TBI treatment is to restore normal neuroplasticity. Important tasks of neuroprotection in patients with TBI are prevention of secondary damage processes, blocking of biochemical cascades that lead to the death of neuronal cells, as well as stimulation and maintenance of neuroregeneration and neurogenesis. The discovery of neurotrophic peptide factors served as a justification for peptidergic neurotrophic therapy of many brain diseases and the consequences of TBI in particular [55, 56]. The pharmacological potential of neuropeptides is linked with the treatment of cerebral diseases associated with secondary brain damage, including TBI. Specifically, in the area of "traumatic penumbra," neurotrophins may offer protection from a secondary injury by stimulating growth and differentiation and

Novel therapeutic strategies for TBI should attempt to stimulate endogenous repair-regeneration mechanisms while antagonizing deleterious processes. Peptide extracts from animal brains have been used as the basis for several multicomponent organ-specific medicinal formulations which are currently use in the treatment of brain diseases, including TBI [55–58]. These formulations have one very important property in common: they contain hundreds of potentially active peptide components extracted from the brain. The complex peptide formulations from the brain are optimal for simultaneous actions on different targets in the brain maintaining optimal neuroplasticity, which can in turn be regarded as a global multicompo-

Cortexin is a complex of polypeptides and L—amino acids with a mass of 1 to 10 kDa. Mechanisms underlying the neuroprotective properties of cortexin as well as its numerous positive effects in cerebral diseases in clinical and experimental studies have been reported [56–62]. Experimental studies have shown that cortexin's neuroprotective and nootropic actions are based on its ability to reduce neuroapoptosis and mitochondrial dysfunction, which are complex pathological

The neuroprotective and neuroregenerative properties of this peptidergic drug

Since neuroinflammation is a significant factor in the pathogenesis of TBI consequences, the results of animal experiments that confirmed the anti-inflammatory effect of cortexin, which had both a systemic and tissue-specific character, are of particular interest [60]. At the CNS level, its action led to normalization of free

are based on the ability to influence the neurotrophins system and, indirectly, neuroplasticity, neurogenesis, and degenerative changes in neurons [58, 59]. The potential molecular mechanisms of cortexin's neuroprotective properties are diverse and relate to key processes underlying neuroplasticity: signal transduction, energy metabolism, protein proteolytic modification, brain cell structure, and neuroinflammation processes. Tissue specificity is important, as well as the multicomponent nature of the drug's action, which determines its potential beneficial effect on

*DOI: http://dx.doi.org/10.5772/intechopen.93733*

enon of synaptic sprouting [54, 55].

promoting recovery of injured brain neurons [53].

processes leading to persistent cognitive disorders [57, 58].

different targets in the brain simultaneously [56].

#### *Neurobehavioral, Cognitive, and Paroxysmal Disorders in the Long-Term Period of Pediatric… DOI: http://dx.doi.org/10.5772/intechopen.93733*

synaptic, neuronal or multiple levels. It is based on modulating the functioning of neurons, restoring synaptic transmission, and activating inter-neuronal connections. To varying degrees, activation of neuroplasticity is accompanied by stimulation of the expression of certain genes, biosynthesis of receptor and ion channel molecules, filamentous proteins of the synaptic cytoskeleton, neurotransmitter, synaptic membrane components, intercellular adhesion molecules, formation of immature contacts, their maturation, activation, hypertrophy, and reorganization of active synapses [54]. Reparative neuroplasticity provides restoration of functional systems of the brain after their damage and is implemented by the entire spectrum of increasing the efficiency of the synaptic pool, from activation of preserved synapses to neosynaptogenesis and growth of nerve processes-a phenomenon of synaptic sprouting [54, 55].

The goal of TBI treatment is to restore normal neuroplasticity. Important tasks of neuroprotection in patients with TBI are prevention of secondary damage processes, blocking of biochemical cascades that lead to the death of neuronal cells, as well as stimulation and maintenance of neuroregeneration and neurogenesis. The discovery of neurotrophic peptide factors served as a justification for peptidergic neurotrophic therapy of many brain diseases and the consequences of TBI in particular [55, 56]. The pharmacological potential of neuropeptides is linked with the treatment of cerebral diseases associated with secondary brain damage, including TBI. Specifically, in the area of "traumatic penumbra," neurotrophins may offer protection from a secondary injury by stimulating growth and differentiation and promoting recovery of injured brain neurons [53].

Novel therapeutic strategies for TBI should attempt to stimulate endogenous repair-regeneration mechanisms while antagonizing deleterious processes. Peptide extracts from animal brains have been used as the basis for several multicomponent organ-specific medicinal formulations which are currently use in the treatment of brain diseases, including TBI [55–58]. These formulations have one very important property in common: they contain hundreds of potentially active peptide components extracted from the brain. The complex peptide formulations from the brain are optimal for simultaneous actions on different targets in the brain maintaining optimal neuroplasticity, which can in turn be regarded as a global multicomponent target.

Cortexin is a complex of polypeptides and L—amino acids with a mass of 1 to 10 kDa. Mechanisms underlying the neuroprotective properties of cortexin as well as its numerous positive effects in cerebral diseases in clinical and experimental studies have been reported [56–62]. Experimental studies have shown that cortexin's neuroprotective and nootropic actions are based on its ability to reduce neuroapoptosis and mitochondrial dysfunction, which are complex pathological processes leading to persistent cognitive disorders [57, 58].

The neuroprotective and neuroregenerative properties of this peptidergic drug are based on the ability to influence the neurotrophins system and, indirectly, neuroplasticity, neurogenesis, and degenerative changes in neurons [58, 59]. The potential molecular mechanisms of cortexin's neuroprotective properties are diverse and relate to key processes underlying neuroplasticity: signal transduction, energy metabolism, protein proteolytic modification, brain cell structure, and neuroinflammation processes. Tissue specificity is important, as well as the multicomponent nature of the drug's action, which determines its potential beneficial effect on different targets in the brain simultaneously [56].

Since neuroinflammation is a significant factor in the pathogenesis of TBI consequences, the results of animal experiments that confirmed the anti-inflammatory effect of cortexin, which had both a systemic and tissue-specific character, are of particular interest [60]. At the CNS level, its action led to normalization of free

*Advancement and New Understanding in Brain Injury*

injury, intervention may be effective [51].

b.The educational and learning goals

it will become a school-based intervention program.

revised yearly)

including:

illustrate that recovery trajectories plateau from 5 to 10 years for all groups, regardless of injury severity. This result is important because it questions previous speculation that children with severe brain insults "grow into deficits" with time since injury. After a protracted recovery period, these children gradually stabilize and begin to make some developmental gains, suggesting that even many years post-

Children with TBI represent a challenge to pediatric rehabilitation professionals as they may improve neurologically for months or years after the injury and may recover much of the knowledge and skills acquired before their injury despite

A child with a TBI is unique not only in comparison with peers of the same age, but also to other children with brain injuries. Each child's recovery process and outcomes are different and individual. Outcomes from pediatric TBI are rarely predictable and neither is the student's progress in school. Therefore, before the child returns to school, it is necessary for him, his parents, educators and rehabilitation professionals to develop an Individual Education Program (IEP). An IEP is essential for the successful academic progress of a child suffered TBI. An IEP is an educational plan outlining the special learning needs of a child,

a.The amount of special education or resources which needs to be provided

c.The frequency of the interventions within and without the school (usually

Cognitive rehabilitation refers to the process of retraining individuals in the way they take in, store, and use information. Cognitive rehabilitation therapy is sometimes provided through hospitals or rehabilitation facilities immediately following acute hospitalization. When the student is reintegrated into school, it is necessary to continue some form of cognitive training. Cognitive rehabilitation and training help the student function within the environment. Although this treatment may initially be coordinated between an outpatient rehabilitative program and school, eventually

Cognitive training focuses on the foundation skills necessary for learning. The treatment goals are improvement in these skills as well as development of compensatory strategies. Skill development should be addressed both in individual and group settings where abilities such as social/verbal pragmatic competence can be addressed more suitably. Academics as well as functional life activities need to be included within the treatment to aid with generalization of identi-

The home environment and parenting style have long-term impacts on functional outcomes of children recovering from TBI. Interventions to promote more effective parenting may be useful for preventing or ameliorating morbidity following TBI [52]. The brain preserves a capacity to recover and adapt secondary compensatory mechanisms when neural tissue is compromised. This capability is due to neuroplasticity, a unique feature that makes the neural circuits malleable and is at the basis of memory formation and learning as well as in adapting to injuries and traumatic

Neuroplasticity is a process of biological adaptation based on brain structural and functional reorganization, aimed at restoring lost or impaired functions after brain damage [54, 55]. Neuroplasticity can be implemented at the molecular,

substantial new problems of learning and behavioral self-regulation.

**196**

fied skills.

events throughout life [53–56].

radical balance and prevention of excessive inflammatory processes, which is the basis for potential optimization of neuroplasticity.

Another study identified four brain proteins that interact with cortexin peptides [61]. The identified molecular partners of cortexin peptides are the cytoskeletal proteins actin and the brain-specific isoform of tubulin, the brain-specific adaptive protein 14-3-3 and creatine kinase—the first potential primary targets of the drug. All these proteins are involved in fundamentally important processes. The actin cytoskeleton is known to regulate important cellular processes in the brain, including division and proliferation, cell migration, cytokinesis, and differentiation. The neuronspecific protein tubulin β5, a component of the cytoskeleton microtubules, is critical for the emergence and maturation of neurons, their migration, differentiation, and integration into neural networks. Protein 14-3-3 (alpha/beta) is the important adaptive protein of the brain that interacts with a large number of proteins, determining their localization and function in the cell, and thereby affecting a variety of cellular and physiological processes. Regulating the activity of enzymes, protection from dephosphorylation of proteins, the formation of triple complexes and sequestration processes, protein 14-3-3 participates in pathogenesis and performs neuroprotective functions in neurodegenerative diseases and other neurological and mental disorders. If we assume that binding to cortexin peptides modulates the activity of creatine kinase type B, another molecular partner identified in this study, then the positive effect of the drug on the energy supply of brain tissue becomes clear [61].

Cortexin was demonstrated to be effective in the treatment of neurological, cognitive consequences of TBI and PTH in both pediatric and adult patients [56, 58]. Taking into account the risk of post-traumatic epilepsy in the long-term period of TBI, data on the dose-dependent antiepileptic activity of cortexin obtained in experiments in animals when modeling chronic convulsive activity (model of temporal epilepsy) are important [59, 62].

The potential multicomponent nature of cortexin, containing a multitude of different neuropeptides, may be favorable for simultaneous actions on multiple targets [58, 59]. The brain tissue specificity of these molecular mechanisms is important, as to a significant extent it determines the efficacy of the formulation in cerebral diseases, including consequences of TBI.
