**3. Epilepsy**

Epilepsy is a chronic cerebral disease characterized by recurrent unprovoked epileptic crises [19] of diverse etiology with consequences for the neurobiological, cognitive, psychological, and social planes/plans, negatively impacting the affected individual's quality of life [20, 21].

In the history of epilepsy there are accounts that in the neolithic period (Historical Period of Polished Stone X Millennium a. C.) trepanations were performed in skulls in order to free the bad spirits. Skulls scarred from these interventions were found in Egypt, Greece, Rome, the Orient, Equatorial Africa, in Mayan, Aztec and Brazilian indians, with curative objectives. In ancient Rome people with epilepsy were avoided for fear of contagion of the illness, and in the Middle Ages, they were pursued as witches [22].

In 1494, Malleus maleficarum, the witch hunting manual written by dominican priests linked to the Catholic Inquisition, was published. In this treatise, epileptic crises were a characteristic of witchcraft [23, 24]. This treatise's orientation led to the the persecution, torture, and death of more than 100.000 women, being that the majority were epileptics [23, 24].

Worldwide prevalence of active epilepsy is estimated around .5% to 1.0% of the population. The prevalence of epilepsy differs among ages, sex, ethnic groups, and socioeconomic factors [25]. The incidence of epilepsy adjusted for age in North America varies between 16 in 100,000 and 51 in 100,000 people per year. The adjusted prevalence by age varies from 2.2 in 1000 to 41 in 1000, depending on the country.

Partial epilepsy may constitute up to two thirds of incident epilepsies. The incidence increases in populations of lower socioeconomic status [25]. It is estimated that near 25–30% of the recently started crises are provoked or secondary to another cause. The incidence of epilepsy is higher in younger groups and continually increases after 50. The most common cause of convulsions and epilepsy in seniors is cerebrovascular disease [25, 26].

Among epilepsy's etiological factors, those that stand out are: electrolytic (hypoglycemia, hyponatremia, hypernatremia, hypocalcemia, use of drugs like Teofilina, Aminofilina, antidepressants, Ciclosporina, Cocaine, Crack, amphetamines, Lidocaine); acute toxic effects (antidepressants, sympathomimetics, others); irregular intake of prescribed antiepileptic medicine; Sepse, infections in the CNS; hypoxic cerebral lesions; cranial traumatism; ischemic or hemorrhagic stroke; inflammatory neoplasma (lupus cerebritis); fever and sleep deprivation [27].

Epilepsies can be classified according to the axes: topographic and etiological. On the topographic axis, generalized epilepsies occur that are manifested by epileptic seizures that start in both hemispheres simultaneously. In general, they are genetically determined and accompanied by altered consciousness; when present, motor manifestations are always bilateral. Absence seizures, myoclonic seizures and generalized tonic–clonic seizures (GTC) are its main examples [28].

In focal epilepsies, the epileptic crises begin locally in a specific area in the brain, and their clinical manifestations depend on the starting point and the speed of the spread of the epileptogenic discharge. The crises are divided into simple focals (without affecting consciousness) and complex focals (at least partially affecting consciousness during the episode). Finally, a focal crisis, be it simple or complex,

**45**

*Brain Injury and Neuroinflammation of the Gut-Brain Axis in Subjects with Cerebral Palsy*

when propagated throughout the cerebral cortex, can end up in a GTC, and

The symptomatic convulsions occur during the course of many clinical and neurological diseases, are generally self limited and do not persist if the subjacent disturbance is corrected. There may occur a reaction in the brain to physiological stress like sleep deprivation, fever, and abstinence from alcohol or other drugs such as sedatives. Other causes of symptomatic convulsions are hypertensive encephalopathy, renal insufficiency, sickle cell anemia, idiopathic thrombocytopenic purpura, systemic lupus, erythematosus, meningitis, encephalitis, traumatic brain injury and stroke. In these situations the cerebral function is temporarily

It must be pointed out, regarding characteristics of symptomatic convulsions, that fever is the most common cause of convulsions in children between six months and four years of age, with 30% chance of another convulsion, increasing the risk of subsequent epilepsy, though not associated, and do not cause intellectual deficit [21]. The objective of epilepsy treatment is to provide the best quality of life possible for the person with epilepsy, through adequate control of crises, and a minimum of adverse effects. Seventy percent of people that have epilepsy take control of the

Epilepsy is one of the most common comorbidities associated with motor damage in individuals with CP, and affects close to 77% of that population [30]. Clinical treatment for epilepsy is based on long term antiepileptic drug therapy which reduces the frequency of crises, raising the threshold of motor neurons in the cortex, reducing abnormal electrical discharges of the brain and limiting the

Regarding gamma-aminobutyric acid, (GABA) it was possible to identify specific benzodiazepine receptors in the CNS structures, principally in the limbic system, allowing the comprehension of the action mechanism of these medications. By connecting to these receptors, the benzodiazepines facilitate GABA's action, which is the primary inhibitory neurotransmitter of the CNS. The specific activation of GABA receptors induces the opening of chloride channels in the neuron membrane, amplifying the influx of this anion into the cell, which results in decreased excitability and the spread of excitatory impulses. Among the effects observed for these drugs are described the reduction of salivary flow, the vomiting

Voltage-dependent Na + is one of the principal channels responsible for the rapid depolarization of the widely and disorganized presence and neuronal membrane in the epileptic processes [34]. These channels represent the important site of connection for several antiepileptic drugs such as hydantoin, carbamazepine,

The first evidence of the possible participation of channels Ca + 2 dependent on voltage in epilepsies came from the verification that the accentuated reductions in extracellular concentration of this ion can create epileptic activity in cerebral tissue such as the dentate gyrus and other hippocampal structures. It is known that the acute increase in Ca + 2 influx is important to maintain the reflex hyperexcitability, which occurs in convulsive processes. In this context, the Ca + 2 channels dependent on voltage have an important role in the functional processes of the nervous system. For example, the presynaptic Ca + 2 entry is associated with the liberation

The antiepileptic pharmaceuticals act through different mechanisms which may or may not be favorable for the treatment [31]. The antiepileptic pharmaceuticals act through one or several mechanisms such as increasing gabaergic inhibition, blocking sodium channels, blocking calcium channels or connecting to protein

*DOI: http://dx.doi.org/10.5772/intechopen.95763*

compromised [21].

denominated a secondarily generalized focal crisis [29].

crises with the appropriate use of anticonvulsant medicine [30].

dissemination of the excitement of the abnormal foci [29].

reflex and the relaxation of skeletal muscles [33].

valproic acid, lamotrigine, among others [33].

SV2A of the synaptic vesicle [32].

#### *Brain Injury and Neuroinflammation of the Gut-Brain Axis in Subjects with Cerebral Palsy DOI: http://dx.doi.org/10.5772/intechopen.95763*

when propagated throughout the cerebral cortex, can end up in a GTC, and denominated a secondarily generalized focal crisis [29].

The symptomatic convulsions occur during the course of many clinical and neurological diseases, are generally self limited and do not persist if the subjacent disturbance is corrected. There may occur a reaction in the brain to physiological stress like sleep deprivation, fever, and abstinence from alcohol or other drugs such as sedatives. Other causes of symptomatic convulsions are hypertensive encephalopathy, renal insufficiency, sickle cell anemia, idiopathic thrombocytopenic purpura, systemic lupus, erythematosus, meningitis, encephalitis, traumatic brain injury and stroke. In these situations the cerebral function is temporarily compromised [21].

It must be pointed out, regarding characteristics of symptomatic convulsions, that fever is the most common cause of convulsions in children between six months and four years of age, with 30% chance of another convulsion, increasing the risk of subsequent epilepsy, though not associated, and do not cause intellectual deficit [21].

The objective of epilepsy treatment is to provide the best quality of life possible for the person with epilepsy, through adequate control of crises, and a minimum of adverse effects. Seventy percent of people that have epilepsy take control of the crises with the appropriate use of anticonvulsant medicine [30].

Epilepsy is one of the most common comorbidities associated with motor damage in individuals with CP, and affects close to 77% of that population [30]. Clinical treatment for epilepsy is based on long term antiepileptic drug therapy which reduces the frequency of crises, raising the threshold of motor neurons in the cortex, reducing abnormal electrical discharges of the brain and limiting the dissemination of the excitement of the abnormal foci [29].

The antiepileptic pharmaceuticals act through different mechanisms which may or may not be favorable for the treatment [31]. The antiepileptic pharmaceuticals act through one or several mechanisms such as increasing gabaergic inhibition, blocking sodium channels, blocking calcium channels or connecting to protein SV2A of the synaptic vesicle [32].

Regarding gamma-aminobutyric acid, (GABA) it was possible to identify specific benzodiazepine receptors in the CNS structures, principally in the limbic system, allowing the comprehension of the action mechanism of these medications. By connecting to these receptors, the benzodiazepines facilitate GABA's action, which is the primary inhibitory neurotransmitter of the CNS. The specific activation of GABA receptors induces the opening of chloride channels in the neuron membrane, amplifying the influx of this anion into the cell, which results in decreased excitability and the spread of excitatory impulses. Among the effects observed for these drugs are described the reduction of salivary flow, the vomiting reflex and the relaxation of skeletal muscles [33].

Voltage-dependent Na + is one of the principal channels responsible for the rapid depolarization of the widely and disorganized presence and neuronal membrane in the epileptic processes [34]. These channels represent the important site of connection for several antiepileptic drugs such as hydantoin, carbamazepine, valproic acid, lamotrigine, among others [33].

The first evidence of the possible participation of channels Ca + 2 dependent on voltage in epilepsies came from the verification that the accentuated reductions in extracellular concentration of this ion can create epileptic activity in cerebral tissue such as the dentate gyrus and other hippocampal structures. It is known that the acute increase in Ca + 2 influx is important to maintain the reflex hyperexcitability, which occurs in convulsive processes. In this context, the Ca + 2 channels dependent on voltage have an important role in the functional processes of the nervous system. For example, the presynaptic Ca + 2 entry is associated with the liberation

*Advancement and New Understanding in Brain Injury*

cytokine synthesis in epileptic individuals [18].

individual's quality of life [20, 21].

they were pursued as witches [22].

the majority were epileptics [23, 24].

seniors is cerebrovascular disease [25, 26].

**3. Epilepsy**

country.

modulated through dietary restrictions, intestinal dysfunction, and medication intake. Convulsions alone stimulate the pro-inflammatory and pro-convulsive

Epilepsy is a chronic cerebral disease characterized by recurrent unprovoked epileptic crises [19] of diverse etiology with consequences for the neurobiological, cognitive, psychological, and social planes/plans, negatively impacting the affected

In 1494, Malleus maleficarum, the witch hunting manual written by dominican priests linked to the Catholic Inquisition, was published. In this treatise, epileptic crises were a characteristic of witchcraft [23, 24]. This treatise's orientation led to the the persecution, torture, and death of more than 100.000 women, being that

Worldwide prevalence of active epilepsy is estimated around .5% to 1.0% of the population. The prevalence of epilepsy differs among ages, sex, ethnic groups, and socioeconomic factors [25]. The incidence of epilepsy adjusted for age in North America varies between 16 in 100,000 and 51 in 100,000 people per year. The adjusted prevalence by age varies from 2.2 in 1000 to 41 in 1000, depending on the

Partial epilepsy may constitute up to two thirds of incident epilepsies. The incidence increases in populations of lower socioeconomic status [25]. It is estimated that near 25–30% of the recently started crises are provoked or secondary to another cause. The incidence of epilepsy is higher in younger groups and continually increases after 50. The most common cause of convulsions and epilepsy in

Among epilepsy's etiological factors, those that stand out are: electrolytic (hypoglycemia, hyponatremia, hypernatremia, hypocalcemia, use of drugs like Teofilina, Aminofilina, antidepressants, Ciclosporina, Cocaine, Crack, amphetamines, Lidocaine); acute toxic effects (antidepressants, sympathomimetics, others); irregular intake of prescribed antiepileptic medicine; Sepse, infections in the CNS; hypoxic cerebral lesions; cranial traumatism; ischemic or hemorrhagic stroke; inflammatory neoplasma (lupus cerebritis); fever and sleep deprivation [27]. Epilepsies can be classified according to the axes: topographic and etiological. On the topographic axis, generalized epilepsies occur that are manifested by epileptic seizures that start in both hemispheres simultaneously. In general, they are genetically determined and accompanied by altered consciousness; when present, motor manifestations are always bilateral. Absence seizures, myoclonic seizures and

generalized tonic–clonic seizures (GTC) are its main examples [28].

In focal epilepsies, the epileptic crises begin locally in a specific area in the brain,

and their clinical manifestations depend on the starting point and the speed of the spread of the epileptogenic discharge. The crises are divided into simple focals (without affecting consciousness) and complex focals (at least partially affecting consciousness during the episode). Finally, a focal crisis, be it simple or complex,

In the history of epilepsy there are accounts that in the neolithic period (Historical Period of Polished Stone X Millennium a. C.) trepanations were performed in skulls in order to free the bad spirits. Skulls scarred from these interventions were found in Egypt, Greece, Rome, the Orient, Equatorial Africa, in Mayan, Aztec and Brazilian indians, with curative objectives. In ancient Rome people with epilepsy were avoided for fear of contagion of the illness, and in the Middle Ages,

**44**

of these neurotransmitters and to their postsynaptic entry with sustained neuron depolarization. Blocking the Ca + 2 channels can produce several effects on the neuronal functioning: (a) blocking Type T channels (associated to absence crisis treatment); (b) blocking type L channels (associated with partial crisis treatment); (c) blocking Ca + 2 channels can prevent the liberation of excitatory neurotransmitters such as glutamate and (d) blocking these channels reduces the concentration of Ca + 2 ions in the neuronal cytoplasm, reducing the possibility of excitotoxic cellular damage [33].

The first study, which evaluated the association between intestinal constipation, use of antiepileptic drugs (AEDs), and gingivitis in subjects with spastic CP, was published by our work group (**Figure 2**) [35]. It was clearly demonstrated an association between intestinal constipation and the use of GABA antiepileptic drugs (phenobarbital, primidone, benzodiazepines including diazepam, lorazepam, and clonazepam; topiramate, felbamate, ezogabine); GABA transporter tiagabine GABA transaminase (vigabatrin); synaptic release machinery SV2A (levetiracetam, brivaracetam α2δ gabapentin, gabapentin enacarbil, pregabalin).

#### **Figure 2.**

*Gingival bleeding and medication type: bleeding is measured by the percentage of teeth which bled after periodontal probing. Each kernel density estimation plot shows clustering by the type of medication taken by subjects. (A) Green figure show constipated subjects; (B) blue figure show non-constipated subjects; (C) Greento-Blue figure show the full population.*

**47**

tryptophan [39].

*Brain Injury and Neuroinflammation of the Gut-Brain Axis in Subjects with Cerebral Palsy*

It was described that the use of AEDs should be considered as a causal factor of constipation in CP subjects. A wide range of AEDs has been used either in the form of monotherapy or polytherapy for seizure control. Monotherapy has the advantage of lowering the potency of toxicity and side effects. Nevertheless, polytherapy may be recommended for the most neurologically compromised, despite its greater side effects and toxicity to the users of this treatment modality. GABA is localized in the

Regarding those people with epilepsy, it is necessary to emphasize the caution needed in the occurrence of a GTC in an odontological office. It characteristically occurs in two phases: Initially there is loss of consciousness followed by muscular convulsions. The steps to be taken are to immediately stop the odontological procedure, position the patient in lateral decubitus, and activate the medical

Another situation to be observed is the possibility of leukopenia and thrombocytopenia induced by antiepileptic drugs such as phenytoin, carbamazepine, and

Another prevalent condition refers to drug-induced gingival overgrowth, also referred to as drug-induced gingival enlargement, and previously known as drug-induced gingival hyperplasia, is a side-effect of certain drugs where the gingival tissue is not the intended target organ. The key offending drug classes are anticonvulsants, immunosuppressants, and calcium channel blockers [36]. Gingival overgrowth impedes proper dental hygiene and, apart from the cosmetic damage, causes painful chewing and eating. Therefore, patient education and information

The gut-brain axis is an information exchange platform which allows bidirectional communication between the host's intestine and nervous system. The information can be exchanged through a neural network, hormones, and immunological

The enteric nervous system consists of approximately 200 million neurons which control the entire digestive tract. It is composed of a web of intrinsic nerve fibres and ganglia, the myenteric and the submucous plexus. The myenteric plexus mainly controls motility of the digestive tract (peristalsis) and is located deep between the longitudinal and the circular layers of the entire digestive tract. It is mainly composed by a network of ganglia connected by unmyelinated fibres which are connected to the vagus nerve and to sympathetic ganglia. The submucous plexus (Meissner plexus) is located more superficially and closer to the intestinal lumen. It is mainly composed by nerve fibres and ganglia which control the mucous secretions, vascular flow and absorption [38]. The vagus nerve allows the direct connection between the intestine and the brain. By controlling motility and intestinal secretion, the vagus nerve can alter the intestinal environment and the response to the enteric immunological system with direct consequence to the intestinal microbiota. On the other hand, the intestinal bacteria produce metabolites which can influence the CNS and enteric and affect the production of neurotransmitters, such as GABA, acetylcholine, and the serotonin precursor,

Intestinal microbiota composition is regulated by extrinsic factors, such as lifestyle, precocious exposure to microbiota and diet, and intrinsic factors, such as metabolism, genetic history and the host's immunological and hormonal systems activity [40]. Intestinal dysbiosis can have an infinite amount of consequences for

valproic acid, requiring the request for additional tests (blood count).

*DOI: http://dx.doi.org/10.5772/intechopen.95763*

emergency system.

**4. Gut-brain axis**

system [37].

gastrointestinal tract and is present in enteric nerves [35].

about the condition and its management are essential.

#### *Brain Injury and Neuroinflammation of the Gut-Brain Axis in Subjects with Cerebral Palsy DOI: http://dx.doi.org/10.5772/intechopen.95763*

It was described that the use of AEDs should be considered as a causal factor of constipation in CP subjects. A wide range of AEDs has been used either in the form of monotherapy or polytherapy for seizure control. Monotherapy has the advantage of lowering the potency of toxicity and side effects. Nevertheless, polytherapy may be recommended for the most neurologically compromised, despite its greater side effects and toxicity to the users of this treatment modality. GABA is localized in the gastrointestinal tract and is present in enteric nerves [35].

Regarding those people with epilepsy, it is necessary to emphasize the caution needed in the occurrence of a GTC in an odontological office. It characteristically occurs in two phases: Initially there is loss of consciousness followed by muscular convulsions. The steps to be taken are to immediately stop the odontological procedure, position the patient in lateral decubitus, and activate the medical emergency system.

Another situation to be observed is the possibility of leukopenia and thrombocytopenia induced by antiepileptic drugs such as phenytoin, carbamazepine, and valproic acid, requiring the request for additional tests (blood count).

Another prevalent condition refers to drug-induced gingival overgrowth, also referred to as drug-induced gingival enlargement, and previously known as drug-induced gingival hyperplasia, is a side-effect of certain drugs where the gingival tissue is not the intended target organ. The key offending drug classes are anticonvulsants, immunosuppressants, and calcium channel blockers [36]. Gingival overgrowth impedes proper dental hygiene and, apart from the cosmetic damage, causes painful chewing and eating. Therefore, patient education and information about the condition and its management are essential.

## **4. Gut-brain axis**

*Advancement and New Understanding in Brain Injury*

cellular damage [33].

of these neurotransmitters and to their postsynaptic entry with sustained neuron depolarization. Blocking the Ca + 2 channels can produce several effects on the neuronal functioning: (a) blocking Type T channels (associated to absence crisis treatment); (b) blocking type L channels (associated with partial crisis treatment); (c) blocking Ca + 2 channels can prevent the liberation of excitatory neurotransmitters such as glutamate and (d) blocking these channels reduces the concentration of Ca + 2 ions in the neuronal cytoplasm, reducing the possibility of excitotoxic

The first study, which evaluated the association between intestinal constipation, use of antiepileptic drugs (AEDs), and gingivitis in subjects with spastic CP, was published by our work group (**Figure 2**) [35]. It was clearly demonstrated an association between intestinal constipation and the use of GABA antiepileptic drugs (phenobarbital, primidone, benzodiazepines including diazepam, lorazepam, and clonazepam; topiramate, felbamate, ezogabine); GABA transporter tiagabine GABA transaminase (vigabatrin); synaptic release machinery SV2A (levetiracetam,

*Gingival bleeding and medication type: bleeding is measured by the percentage of teeth which bled after periodontal probing. Each kernel density estimation plot shows clustering by the type of medication taken by subjects. (A) Green figure show constipated subjects; (B) blue figure show non-constipated subjects; (C) Green-*

brivaracetam α2δ gabapentin, gabapentin enacarbil, pregabalin).

**46**

**Figure 2.**

*to-Blue figure show the full population.*

The gut-brain axis is an information exchange platform which allows bidirectional communication between the host's intestine and nervous system. The information can be exchanged through a neural network, hormones, and immunological system [37].

The enteric nervous system consists of approximately 200 million neurons which control the entire digestive tract. It is composed of a web of intrinsic nerve fibres and ganglia, the myenteric and the submucous plexus. The myenteric plexus mainly controls motility of the digestive tract (peristalsis) and is located deep between the longitudinal and the circular layers of the entire digestive tract. It is mainly composed by a network of ganglia connected by unmyelinated fibres which are connected to the vagus nerve and to sympathetic ganglia. The submucous plexus (Meissner plexus) is located more superficially and closer to the intestinal lumen. It is mainly composed by nerve fibres and ganglia which control the mucous secretions, vascular flow and absorption [38]. The vagus nerve allows the direct connection between the intestine and the brain. By controlling motility and intestinal secretion, the vagus nerve can alter the intestinal environment and the response to the enteric immunological system with direct consequence to the intestinal microbiota. On the other hand, the intestinal bacteria produce metabolites which can influence the CNS and enteric and affect the production of neurotransmitters, such as GABA, acetylcholine, and the serotonin precursor, tryptophan [39].

Intestinal microbiota composition is regulated by extrinsic factors, such as lifestyle, precocious exposure to microbiota and diet, and intrinsic factors, such as metabolism, genetic history and the host's immunological and hormonal systems activity [40]. Intestinal dysbiosis can have an infinite amount of consequences for

the CNS. Microbes can stimulate the liberation of small molecules, like cytokines, and produce metabolites which work as neuromodulators, such as short-chain fatty acids (SCFAs), GABA and serotonin precursors [41–43].

One of the most studied extrinsic factors is diet, since it can alter the intestinal microbiota. Epidemiological studies show a positive correlation between the increase in risk of cognitive decline and high ingestion of animal protein, refined sugar and foods with high content of saturated fats [44]. Patients with refractory epilepsy can benefit from a ketogenic diet, since it can influence the intestinal microbiota [39]. The commensal bacteria in the intestine degrade the dietary fibre and lead to the production of SCFA, which are beneficial to the brain [44].

SCFAs are important bacterial metabolites which can reduce the inflammatory response, promote CNS plasticity, and increase the hematoencephalic permeability [45]. An exacerbated inflammatory response in the hippocampus is associated with a diet rich in fructose, and can be a consequence of alterations in intestinal bacteria [46].

Colonization with Akkermansia Mucinophilia e Parabacteroides bacterias offers protection against convulsions, altering the level of cerebral neurotransmitters in the hippocampus, including GABA and glutamate. Intestinal microbiome dysbiosis can alter GABA, which is the main inhibitory neurotransmitter in the brain, and the reduced levels have been known to exacerbate convulsions [47–49]. But the reduction of Prevotellaceae and increase of Lactobacilliaceae are related to neuroinflammation and were discovered in neurodegenerative diseases such as Parkinson's Disease [49]. An increase in Proteobacteria and Cronbacteria was found in patients with epilepsy [50]. Individuals with epileptic CP (CPE) exhibited lower proportions of Anaerostipes, Faecalibacterium e Bacteroides [51] which can produce butyrate with acetate [52] since butyrate can stimulate the differentiation of regulatory T cells (Treg) and relieve the neuroinflammation charge [53]. Nevertheless, great quantities of acetate would accumulate in these individuals, which could activate the parasympathetic nervous system [54] and unchain a convulsion. Besides that, the reduction of Bacteroids would also reduce butyrate secretion and attenuate its neuroprotector effect in patients with CPE [53]. On the other hand, a greater abundance of Enterococcus, Bifidobacterium, Clostridium IV and Akkermansia were discovered in patients with CPE [51]. A deeper analysis of the microbial functions revealed an increased systemic immunological and neurodegenerative diseases in patients with CPE [51], and that neuroinflammation probably carried out a fundamental role in CPE pathology [55].

Dysbiosis and frequency of epileptic events are frequently correlated, suggesting that the drugs can interact directly with the intestinal microbiota, modifying their metabolism and, therefore, affecting the efficacy and toxicity of the drugs [56]. Drugs are transformed into bioactive metabolites, inactive or toxic through direct microbial action or host-microbial co-metabolism. These metabolites are responsible for therapeutic effects or collateral effects induced by these medications [57]. Alteration in the microbiome can affect absorption and medicine metabolism, influencing their efficacy and resistance to the drug [58].

The antiepileptic medication is normally used in long-term clinical treatment, and for this reason can cause serious collateral effects in the childhood development of patients with CP and epilepsy, such as: gastrointestinal complications including oral dysbiosis, gingival bleeding (GB) and increase in systemic inflammation [35, 59].

CP's inaccessibility and vulnerability to oral care and consequently the development of caries and gingival diseases can also phenotypically affect the intestine

**49**

**Figure 3.**

*whiskers mark the 5% confidence interval.*

*Brain Injury and Neuroinflammation of the Gut-Brain Axis in Subjects with Cerebral Palsy*

through the microbiome's oral-intestine axis. These facts do not alone indicate alterations in the microbiome, but indicate that the gingival bleeding index suggests dysbiosis in the host-microbial interactions in the oral mucosa interface which then

Current literature indicates that intestinal disturbances play a prominent role in inflammatory responses and neurological conditions [60]. This line of evidence is fundamental in identifying the effects of dysbiosis in mucosa inflammation in the entire digestive tract. Significantly higher levels of IL-1β, IL-6, IL-8 and IL-10 were found in constipated individuals with GB (**Figure 3**), besides this, presence of chemokine IL-8 induces the secretion of lymphocytes, monocytes, epithelial cells, fibroblasts, tumor cells, bone reabsorption and IL-1β [61, 62], indicating a continuous inflammatory process and progression of the periodontal disease [61–64]. The use of this medication caused individuals with CP to present reduced salivary flow, increase in the salivary osmolarity, dry mouth and gingivitis, which is represented

There is an elevated risk of immunological system diseases in these vulnerable individuals, and oral and intestinal dysbiosis is attributed to an exacerbated increase of Akkermansia in patients with CPE [51]. The excessive increase in Akkermansia would degrade the mucin in the mucous layers and would increase the mucous permeability [65], which allows for more bacterial antigens to be exposed to the host's immunological system, unchaining systemic immune reactions in

*Constipation actions on Inflammatory Cytokine Levels. Distributions of each measured cytokine—(A) TNF*α*, (B) IL1*β*, (C) IL6, (D) IL8, and (E) IL10— in constipated subjects (blue) and non-constipated subjects (green) are mapped using a violin plot. White dots mark the means, bars show the inner quartiles, and* 

can influence an individual's systemic inflammatory profile.

by elevated levels of inflammatory cytokines in tetraplegics [59].

*DOI: http://dx.doi.org/10.5772/intechopen.95763*

individuals with CPE.

#### *Brain Injury and Neuroinflammation of the Gut-Brain Axis in Subjects with Cerebral Palsy DOI: http://dx.doi.org/10.5772/intechopen.95763*

through the microbiome's oral-intestine axis. These facts do not alone indicate alterations in the microbiome, but indicate that the gingival bleeding index suggests dysbiosis in the host-microbial interactions in the oral mucosa interface which then can influence an individual's systemic inflammatory profile.

Current literature indicates that intestinal disturbances play a prominent role in inflammatory responses and neurological conditions [60]. This line of evidence is fundamental in identifying the effects of dysbiosis in mucosa inflammation in the entire digestive tract. Significantly higher levels of IL-1β, IL-6, IL-8 and IL-10 were found in constipated individuals with GB (**Figure 3**), besides this, presence of chemokine IL-8 induces the secretion of lymphocytes, monocytes, epithelial cells, fibroblasts, tumor cells, bone reabsorption and IL-1β [61, 62], indicating a continuous inflammatory process and progression of the periodontal disease [61–64]. The use of this medication caused individuals with CP to present reduced salivary flow, increase in the salivary osmolarity, dry mouth and gingivitis, which is represented by elevated levels of inflammatory cytokines in tetraplegics [59].

There is an elevated risk of immunological system diseases in these vulnerable individuals, and oral and intestinal dysbiosis is attributed to an exacerbated increase of Akkermansia in patients with CPE [51]. The excessive increase in Akkermansia would degrade the mucin in the mucous layers and would increase the mucous permeability [65], which allows for more bacterial antigens to be exposed to the host's immunological system, unchaining systemic immune reactions in individuals with CPE.

#### **Figure 3.**

*Advancement and New Understanding in Brain Injury*

brain [44].

bacteria [46].

mental role in CPE pathology [55].

influencing their efficacy and resistance to the drug [58].

acids (SCFAs), GABA and serotonin precursors [41–43].

the CNS. Microbes can stimulate the liberation of small molecules, like cytokines, and produce metabolites which work as neuromodulators, such as short-chain fatty

One of the most studied extrinsic factors is diet, since it can alter the intestinal microbiota. Epidemiological studies show a positive correlation between the increase in risk of cognitive decline and high ingestion of animal protein, refined sugar and foods with high content of saturated fats [44]. Patients with refractory epilepsy can benefit from a ketogenic diet, since it can influence the intestinal microbiota [39]. The commensal bacteria in the intestine degrade the dietary fibre and lead to the production of SCFA, which are beneficial to the

SCFAs are important bacterial metabolites which can reduce the inflammatory response, promote CNS plasticity, and increase the hematoencephalic permeability [45]. An exacerbated inflammatory response in the hippocampus is associated with a diet rich in fructose, and can be a consequence of alterations in intestinal

Colonization with Akkermansia Mucinophilia e Parabacteroides bacterias offers protection against convulsions, altering the level of cerebral neurotransmitters in the hippocampus, including GABA and glutamate. Intestinal microbiome dysbiosis can alter GABA, which is the main inhibitory neurotransmitter in the brain, and the reduced levels have been known to exacerbate convulsions [47–49]. But the reduction of Prevotellaceae and increase of Lactobacilliaceae are related to neuroinflammation and were discovered in neurodegenerative diseases such as Parkinson's Disease [49]. An increase in Proteobacteria and Cronbacteria was found in patients with epilepsy [50]. Individuals with epileptic CP (CPE) exhibited lower proportions of Anaerostipes, Faecalibacterium e Bacteroides [51] which can produce butyrate with acetate [52] since butyrate can stimulate the differentiation of regulatory T cells (Treg) and relieve the neuroinflammation charge [53]. Nevertheless, great quantities of acetate would accumulate in these individuals, which could activate the parasympathetic nervous system [54] and unchain a convulsion. Besides that, the reduction of Bacteroids would also reduce butyrate secretion and attenuate its neuroprotector effect in patients with CPE [53]. On the other hand, a greater abundance of Enterococcus, Bifidobacterium, Clostridium IV and Akkermansia were discovered in patients with CPE [51]. A deeper analysis of the microbial functions revealed an increased systemic immunological and neurodegenerative diseases in patients with CPE [51], and that neuroinflammation probably carried out a funda-

Dysbiosis and frequency of epileptic events are frequently correlated, suggesting that the drugs can interact directly with the intestinal microbiota, modifying their metabolism and, therefore, affecting the efficacy and toxicity of the drugs [56]. Drugs are transformed into bioactive metabolites, inactive or toxic through direct microbial action or host-microbial co-metabolism. These metabolites are responsible for therapeutic effects or collateral effects induced by these medications [57]. Alteration in the microbiome can affect absorption and medicine metabolism,

The antiepileptic medication is normally used in long-term clinical treatment, and for this reason can cause serious collateral effects in the childhood development of patients with CP and epilepsy, such as: gastrointestinal complications including oral dysbiosis, gingival bleeding (GB) and increase in systemic

CP's inaccessibility and vulnerability to oral care and consequently the development of caries and gingival diseases can also phenotypically affect the intestine

**48**

inflammation [35, 59].

*Constipation actions on Inflammatory Cytokine Levels. Distributions of each measured cytokine—(A) TNF*α*, (B) IL1*β*, (C) IL6, (D) IL8, and (E) IL10— in constipated subjects (blue) and non-constipated subjects (green) are mapped using a violin plot. White dots mark the means, bars show the inner quartiles, and whiskers mark the 5% confidence interval.*
