Perspective Chapter: Red Flags for Syndromic Epilepsy

*Bita Shalbafan*

#### **Abstract**

Despite the high frequency of seizures and propensity to develop status epilepticus (SE) most cases do not develop a long-term predisposition to seizures. So, investigating a patient with refractory epilepsy or unexplained status epilepticus is important to consider the possibility of treatable diseases i.e. treatable types of inborn error of metabolism, paraneoplasia, infections, and TLE due to temporal lobe encephalocele and IIH. Epilepsy syndrome (ES) refers to a cluster of features that should be paying attention to its red flags to narrow the wide differential diagnosis.

**Keywords:** syndromic epilepsy, paraneoplasia, inborn error of metabolism, encephaloceles, new-onset refractory status epilepticus

#### **1. Introduction**

Epilepsy can be observed during the course of many usually as part of a large clinical spectrum. Epilepsy Syndrome diagnosis step-by-step approach starts in the first level to detect seizure type semiologically, then Epilepsy type detection as the second level, *epilepsy syndrome* (ES) is diagnosed based on any co-morbidity in the third level [1].

#### **1.1 Definition**

An epilepsy syndrome (ES) refers to a group of features that includes seizure types, EEG, and imaging features that tend to occur together. There are many wellknown syndromes, such as childhood absence epilepsy, West syndrome, and Dravet syndrome, although it should be noted that there has never been a formal classification of syndromes. Therefore, it is important to note that epilepsy syndrome does not have a one-to-one correlation with an etiological diagnosis and serves a different purpose, such as guiding management [1].

#### **2. Epilepsy syndrome diagnosis**

#### **2.1 When should one suspect an epileptic syndrome?**

On analyzing the history, the following keys are to be identified for a syndromic diagnosis [1]:

Mixture of generalized and partial epilepsy; special seizure types i.e. temporal lobe epilepsy or myoclonic epilepsy; association with other impairments i.e. neurological impairments, mental retardation, other organ disorders (eyes, muscles spleen, etc.); seizures related to the times of eating, fasting, protein-rich meal; unexplained Status epilepticus; inefficacy or worsening with classical antiepileptic drugs; and paraclinical Findings.

#### *2.1.1 Diagnostic approach to syndromic epilepsy*

#### *2.1.1.1 Disease course*

One of the most important points that should be noted in the history of an epileptic patient is the *disease course*. Non-progressive course suggests a static nature of disorders like stroke, chromosomal diseases, perinatal hypoxia, etc. On the other hand, starting and tempered profiles in progressive disorders play three patterns:

Acute: The presence of abrupt and severe symptoms, along with periods of improvement and worsening, a connection to infections, fasting, or specific dietary habits, non-specific physical indications, and a positive reaction to symptomatic treatment, frequently indicates a deficiency in intermediary metabolisms, such as aminoacidopathies, organic acidemias, and fatty acid oxidation disorders.

Insidious onset: A gradual onset, persistent and progressive symptoms, and symptoms and signs that are independent of intervening events often suggest organelle disorders such as lysosomal storage disorders and peroxisomal disorders.

Episodic progression of symptoms: There are exceptions to this generalization. For example, Leigh's disease, which is an organelle disease, is characterized by a sudden onset of encephalopathy and an episodic course [2].

#### *2.1.1.2 Extra-neural involvements*

	- A child with sparse, light-colored hair, hair loss, and recurring skin rashes, along with regression and seizures that do not respond to treatment, may have biotinidase deficiency;
	- A child with seborrheic dermatitis, hypopigmented kinky hair, epilepsy, and regression in early infancy is immediately diagnosed with Menkes disease;
	- *hypertrichosis* is a feature of mitochondrial disorders, especially in *SURF1* positive Leigh disease.
	- A child has spastic paraplegia and leukoencephalopathy on an MRI, along with ichthyosis (a scaly skin condition), which may indicate Sjogren Larsson syndrome.
	- If a child has an abnormally large head (macrocephaly) and exhibits a startling response to sound, along with regression at around six months of age, may indicate a diagnosis of GM2 gangliosidosis.
	- Extreme irritability, incessant crying, opisthotonic posture, and regression are diagnostic clues to Krabbe disease.
	- In glutaric aciduria type 1, episodic regression occurs after febrile illnesses, especially mild diarrheal illnesses, together with macrocephaly and dystonia.
	- In a child with suspected leukodystrophy, a large head suggests a variety of diagnoses such as Canavans disease, Alexander disease, and megalencephalic leukodystrophy with subcortical cysts.
	- Macrocephaly can also be seen in another important late-onset metabolic disorder, L-2-hydroxyglutaric aciduria, in which there is evidence of leukoencephalopathy on MRI [2–4].
	- *Ocular anterior chamber examination:* The main points to look for are the presence of cataracts, lens luxation, and corneal opacity. When children present with progressive extrapyramidal signs, it is important to look for the Kayser Fleisher ring to establish a diagnosis of Wilson's disease. The presence of lens dislocation in a child with refractory neonatal-onset epilepsy may indicate isolated sulfite oxidase deficiency or molybdenum co-factor deficiency. In contrast, lens dislocation in a child with mental retardation, behavioral disturbances, and Marfanoid habitus may suggest homocystinuria. Corneal opacity is a characteristic feature of cerebrotendinous xanthomatosis, mucopolysaccharidoses, and mucolipidosis type 4. In these disorders, corneal opacity may be associated with ptosis, oculomotor disorders, retinal degeneration, optic atrophy, and spastic atactic syndrome. MRI may reveal a thin corpus callosum

and variable degrees of hypomyelination. However, visceromegaly and skeletal manifestations are typically absent in these children.


#### **3. Etiologies of syndromic epilepsy**

#### **3.1 Structural**

It is important for neurologists, particularly epileptologists, and those working on multidisciplinary epilepsy teams to recognize the link between structural brain abnormalities and epilepsy. Tumors, trauma, bleeding, abscesses, and encephalitis can be difficult to detect with conventional imaging methods [6]. In some cases, imaging with 3 T MRI and high-resolution CT of the skull base may be required to confirm temporal lobe sclerosis and encephaloceles, particularly in patients with nonlesional temporal lobe epilepsy (TLE). Treatment of drug-resistant TLE due to temporal lobe encephalocele and sclerosis is primarily surgical and most patients have a good outcome (postoperative Engel Class I).

Temporal lobe encephaloceles are increasingly recognized as a cause of epilepsy. Recent studies have found an association between temporal lobe encephalocele and IIH, suggesting that TLE may be an unusual manifestation or complication of IIH. It has been suggested that pulsatile forces in the cerebrospinal fluid (CSF) due to increased intracranial pressure can lead to the development of prominent arachnoid villi that form CSF pockets, leading to the formation of spontaneous CSF fistulas and encephaloceles [7].

Patients with temporal lobe epilepsy (TLE) and temporal lobe encephalocele have similar demographic characteristics as patients with idiopathic intracranial hypertension (IIH); including female dominance and high body mass index (BMI). Several studies have also shown a high prevalence of raised intracranial pressure (RAD-IH) in patients with TLE and temporal lobe encephalocele, including enlarged or empty sella, enlarged Meckel's cavity, optic nerve sheath distension, flattening of the posterior bulb, and transverse venous sinus stenosis. Other symptoms and signs of IIH, such as headache, visual disturbances, pulsatile tinnitus, and papilledema, are rare in patients with TLE and temporal lobe encephalocele. However, some patients with TLE and temporal lobe encephalocele have elevated cerebrospinal fluid (CSF) opening pressure greater than 25 cm H2O, supporting an association with IIH [7–14].

**Figure 1.**

*Bilateral encephaloceles showing by red arrows in brain MRI (a) T2 weighted coronal cut; (b) T2 weighted axial cut at the same level; (c) T1 weighted axial cut at the same level (Bita Shalbafan courtesy).*

In a large series of 474 patients examined over 5 years in a center for epilepsy surgery, temporal lobe encephalocele was identified in 25 (5.3%) patients. In these patients, the temporal lobe encephalocele was regarded as an epileptogenic focus in 48% of the cases. Temporal lobe encephaloceles are thought to cause mechanical irritation of the temporal lobes, and secondary changes such as inflammation and gliosis serve as a starting point for seizures. Most temporal lobe encephaloceles are asymptomatic and are discovered incidentally in patients with no history of seizures. However, in a small proportion of patients with drug-resistant temporal lobe epilepsy, temporal lobe encephaloceles associated with an anterior middle fossa defect (anteromedial and anteroinferior temporal lobe encephaloceles) appear to lateralize to the side of seizure onset, showing high concordance with studies including PET, scalp EEG and seizure semiology (**Figure 1**) [7–14].

#### **3.2 Infectious diseases**

Various infections of the central nervous system can cause both acute seizures and epilepsy. The pathogenesis and clinical presentation of seizure disorders can vary significantly depending on the infectious agent. The exact mechanisms underlying these differences are not well understood, but they appear to be at least partially related to factors such as the type of pathogen, the extent of cortical involvement, delays in treatment, and the host's inflammatory response.

Acute viral encephalitis can be caused by a variety of viruses, including herpes viruses, enteroviruses, paramyxoviruses, and arthropod-borne and zoonotic viruses. Some of the most common viruses associated with acute viral encephalitis include [15, 16]:

Herpes simplex virus type 1: This is the most commonly diagnosed sporadic encephalitis.

Enterovirus 71: This virus is associated with epidemic hand, foot, and mouth disease, aseptic meningitis, brainstem encephalitis, and myelitis.

Measles virus: This virus can cause acute post-infective encephalitis, subacute encephalitis, and subacute sclerosing panencephalitis.

West Nile virus: This virus is found in North America, Southern Europe, the Middle East, and West and Central Asia, and is associated with flaccid paralysis and Parkinsonian movement disorders.


#### **Table 1.**

*Seizure-induced parasitic infections.*

Japanese encephalitis virus: This virus is found in Asia and is associated with flaccid paralysis and Parkinsonian movement disorders.

Rabies virus: This virus is transmitted by dogs, cats, and bats, depending on the location.

Other viruses that can cause acute viral encephalitis include varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, mumps virus, and tick-borne encephalitis virus. It is important to note that viral causes of chronic encephalitis, such as JC virus, are not included in this list. A thorough evaluation by a neurologist or other specialist is necessary to determine the underlying cause of encephalitis and develop an appropriate management plan.

It is important to note that while these parasitic infections can cause seizures, they are relatively rare in developed countries (**Table 1**) [15, 16].

#### **3.3 Autoimmune diseases and paraneoplasia**

Despite the high seizure frequency and propensity to develop status epilepticus (SE) in the acute stage of autoimmune encephalitis (AE), most patients with AE do not develop a long-term predisposition to seizures. This important concept was highlighted by the International League Against Epilepsy (ILAE) in 2020 when the Autoimmunity and Inflammation Taskforce proposed two main diagnostic entities: "acute symptomatic seizures secondary to AE" and "autoimmune-associated epilepsy". The latter occurs in a minority of cases and is often due to the development of structural abnormalities after the resolution of the inflammation (eg, mesial temporal sclerosis) or to a persistent antigenic trigger (eg, cancer in paraneoplastic cases). The amount of new information in this area over the last decade regarding clinical specifics, laboratory diagnostics, and treatment options has made it difficult for neurologists to target patients with AEs and seizures [17–21].

The predisposition to cause enduring seizures in autoimmune encephalitis is dependent on the mechanism that drives the immune response, ranging from a high predisposition in cytotoxic T cell-mediated encephalitis (intracellular antigens) to a moderate or absent predisposition in antibody-mediated encephalitis (surface antigens). Among the latter, the severity of the seizures and the likelihood of developing epilepsy vary according to the antigen. Additionally, all these disorders occur with a variable degree of inflammation that could have downstream effects on synaptic function, hyperexcitability, and epileptogenesis. Several autoimmune antibodies to: Glutamate/NMDA-NR1, Glutamate/AMPA-GluR3, Glutamate/NMDA-NR2, GABA-R, GAD-65, GLY-R, LGI1, VGKC, CASPR2, and β2 GP1, found in subpopulations of epilepsy patients. AMPA-GluR3B peptide antibodies as Glutamate receptor antibodies seem so far the most

*Perspective Chapter: Red Flags for Syndromic Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.113765*

**Figure 2.** *Multiple inflammatory/innate immunity mechanisms triggered by seizures and epileptogenesis.*

exclusive and pathogenic autoimmune antibodies in AE. They kill neural cells by three mechanisms: reactive-oxygen-species, excitotoxicity, and complement fixation, and facilitate and/or induce brain damage, seizures, and behavioral impairments. Also, the additional autoantibodies GABA-R, dopamine-R, Ach-R, adrenergic-R, and serotonin-R are present in various neurological diseases (**Figure 2**) [17–21].

From a clinical perspective, only a few seizure types are pathognomonic for an autoimmune etiology, including faciobrachial dystonic seizures (FBDS) and seizures originating in perisylvian (islet-opercular) regions. FBDS are very brief (<3 s) tonic muscle contractions in the arm and face, and more rarely in the leg. They are usually unilateral, but can also independently affect both sides asynchronously and occur up to 100 times a day, including during sleep. FBDS are thought to be pathognomonic of anti-LGI1 encephalitis, and their early detection (and consequent initiation of immunotherapy, particularly corticosteroids) can prevent the onset of cognitive dysfunction characteristic of the disease. Seizures with perisylvian semiology, including autonomic and somatosensory/viscerosensory symptoms, are not associated with a specific antibody but are often indicative of an immune-mediated etiology. A multicenter study found that autoimmune etiologies were more common than infection in NORSE (new-onset refractory status epilepticus), with autoimmune etiologies comprising 19% nonparaneoplastic and 18% paraneoplastic cases. These results suggest that autoimmune pathogenesis is much more likely in NORSE than viral infection. Therefore, after a thorough investigation of the infection, it is possible to consider NORSE as a potentially autoimmune epilepsy that requires active immunotherapy. A similar condition has been described in children, which is defined as febrile infectious epilepsy syndrome (FIRES). In these cases, the presence of a febrile episode between 2 weeks and 24 hours before the onset of RSE is required. Some authors argue that NORSE and FIRES are different entities. However, the two syndromes share many similarities and nowadays FIRES is considered a subcategory of NORSE (**Figure 3**) [17–21].

Timely identification of an autoimmune cause of seizures is crucial as it has relevant therapeutic implications. Several criteria and scoring systems for autoimmune

#### **Figure 3.**

*The diagnostic approach to autoimmune epilepsy begins with a detailed history-taking and neurological examination. To exclude other etiologies of epilepsy, various diagnostic workups including blood laboratory tests, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) studies are performed. Empirical immunotherapy can be applied during the diagnostic tests. The final diagnosis is made based on the results of the tests and the response to immunotherapy. Blood laboratory tests may include autoimmune antibody panels, complete blood count, erythrocyte sedimentation rate, C-reactive protein, and liver and kidney function tests. EEG can help identify seizure activity and epileptiform discharges. Brain MRI can detect structural abnormalities and inflammation. CSF studies can detect inflammation and the presence of specific antibodies. Empirical immunotherapy may include corticosteroids, intravenous immunoglobulin, or plasma exchange. The response to immunotherapy can help confirm the diagnosis of autoimmune epilepsy.*

seizures and epilepsy have been proposed, such as the Autoantibody Prevalence in Epilepsy Score (APE) and its subsequent revision (APE2), the Antibody Contribution to Focal Epilepsy Signs and Symptoms (ACES) score, and others. A clinician should be certain that the panel chosen includes antibodies for the suspected etiology (**Table 2**) and screen for antibodies associated with conditions that present similarly (ie, GQ1B, ANA, and TPO/thyroglobulin antibodies) [17, 18].

#### **3.4 Inborn errors of metabolism (IEMs)**

Although IEMs are a rare etiology in child and adult epileptic cases, these are important to recognize for several reasons: dramatic response to specific treatments; early treatment can stop disease progression in neural and extra-neural tissues; some antiepileptic drugs interfering with metabolic pathways may worsen the clinical condition; specific genetic counseling can be provided.

When a metabolic disease is suspected, the approach to metabolic investigations should be guided by the type of epilepsy, associated signs, and the presence or absence of mental retardation. In critical situations, such as an unexplained status epilepticus, ammonia measurement and search for porphyries should be mandatory. In other situations, simple examinations aimed at identifying treatable diseases should be seen as a priority. Metabolic investigations may include blood tests to assess electrolyte levels, glucose, liver and kidney function, and thyroid


*Abbreviations: CSF, cerebrospinal fluid; FLAIR, fluid-attenuated inversion recovery.*

#### **Table 2.**

*Autoantibody prevalence in epilepsy score.*

function. Urine tests may also be performed to assess for metabolic abnormalities. Genetic testing may be considered in patients with suspected inherited metabolic disorders. In patients with suspected mitochondrial disorders, muscle biopsy may be necessary to assess mitochondrial function. Magnetic resonance spectroscopy (MRS) can also be used to evaluate brain metabolism and detect metabolic abnormalities. It is important to note that metabolic investigations should be conducted in consultation with a metabolic specialist or neurologist with expertise in metabolic disorders, as the interpretation of results can be complex and require specialized knowledge (**Figure 4**) [2, 19].

To recognize the type of IEM clinical history needs to be analyzed considering the following points [2]:

#### *3.4.1 Pattern of inheritance*


A maternal inheritance pattern suggests a mitochondrial disorder, which is caused by mutations in the mitochondrial DNA (mtDNA) that is inherited from the mother. It is important to note that mitochondrial disorders can also follow a Mendelian

#### **Figure 4.**

*Diagnostic approach in an epileptic patient in order not to miss an IEM summarize presumed hereditary predisposition critical problem of inherited stigma in some parts of the world causes us to prefer the idiopathic labeling to these epileptic cases instead of genetic names. Also, findings of many de novo mutations cannot confirm the pathogenicity of these genetic findings in both mild and severe epilepsies.*

pattern of inheritance, such as autosomal dominant or recessive inheritance, depending on the specific mutation and the proportion of mutant mtDNA in the affected individual.

In some cases, an apparent autosomal inheritance pattern may mask a maternal inheritance. This can occur when a mutation in the mtDNA is present in both the mother and father, but the father's contribution of mtDNA to the offspring is much lower than the mother's. As a result, the offspring may appear to inherit the mutation in an autosomal dominant or recessive pattern, when in fact it is a mitochondrial disorder with maternal inheritance.

Therefore, when evaluating a patient with suspected mitochondrial disorder, it is important to consider both the maternal inheritance pattern and the possibility of Mendelian inheritance. Genetic testing, including mtDNA sequencing and analysis of nuclear genes involved in mitochondrial function, may be necessary to confirm the diagnosis and determine the mode of inheritance (**Table 3**) [2].

It is important to recognize that the clinical presentation and imaging features of the same disease can vary in different age groups. Therefore, it is essential to be familiar with the variable presentation of these disorders in different age groups to make an accurate diagnosis and develop an appropriate management plan. For example, Tay Sachs disease or infantile GM2 gangliosidosis typically presents with neuroregression and an exaggerated startle response to sounds. In contrast, the presentation of juvenile-onset GM2 gangliosidosis includes neuroregression, gait difficulty, ataxia, peripheral neuropathy, and psychosis. The classical early infantile Krabbe leukodystrophy presents with regression, irritable cry, and opisthotonic posturing, while juvenile onset Krabbe leukodystrophy presents with spastic paraparesis or visual impairment. In addition to the clinical presentation, the magnetic resonance imaging (MRI) findings can also vary in different age groups. For example, in early infantile Krabbe leukodystrophy, MRI typically shows diffuse white matter abnormalities, while in juvenile-onset Krabbe leukodystrophy, MRI may show focal white matter

*Perspective Chapter: Red Flags for Syndromic Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.113765*


**Table 3.**

*Neurometabolic disorders with epilepsy as the main manifestation.*

abnormalities. Therefore, a thorough evaluation by a neurologist or other specialist is necessary to make an accurate diagnosis and develop an appropriate management plan, taking into account the age of the patient and the variable presentation of the disorder in different age groups [2].

#### *3.4.2 Key clinical symptoms and signs with special focus on sites of neuraxis*

When evaluating a patient with a suspected neurological disorder, it is important to determine whether the primary symptoms and signs are related to gray matter

involvement, white matter involvement, behavioral or psychiatric manifestations, extrapyramidal system involvement, or peripheral nerve system involvement. Gray matter involvement can present with symptoms such as seizures, visual impairment, and cognitive decline. Examples of disorders that primarily involve gray matter include epilepsy, Alzheimer's disease, and Huntington's disease. White matter involvement can present with symptoms such as gait difficulty, abnormalities in tone (spasticity/hypotonia), and sensory deficits. Examples of disorders that primarily involve white matter include leukodystrophies, multiple sclerosis, and cerebral palsy. Behavioral or psychiatric manifestations can present with symptoms such as aggression, irritability, and anxiety. Examples of disorders that primarily involve behavioral or psychiatric manifestations include autism spectrum disorder, attention-deficit/ hyperactivity disorder (ADHD), and schizophrenia. Extrapyramidal system involvement can present with symptoms such as dystonia, tremor, and choreoathetosis. Examples of disorders that primarily involve the extrapyramidal system include Parkinson's disease, Huntington's disease, and dystonia. Peripheral nerve system involvement can present with symptoms such as polyneuropathy and pes cavus. Examples of disorders that primarily involve the peripheral nerve system include Charcot-Marie-Tooth disease and hereditary neuropathies. Therefore, a thorough evaluation by a neurologist or other specialist is necessary to determine the primary symptoms and signs and develop an appropriate management plan based on the underlying pathology [2].

#### *3.4.2.1 Association with extraneural impairments*

It was explained in detail in part 2.1.1.2.

#### *3.4.2.2 Progressive myoclonic epilepsy*

This is a group of disorders characterized by a specific set of clinical features, electroencephalography (EEG) findings, and response to treatment. However, in some cases, the clinical presentation of epilepsy may not match with any classical ES. This is known as an atypical electro-clinical presentation. Atypical electro-clinical presentation can refer to a variety of features, including an unusual combination of seizure types, an unusual age of onset, or an unusual response to antiepileptic drugs. For example, a patient may present with a mixture of generalized and partial epileptic manifestations, such as the association of myoclonus and partial seizures in a given patient. In such cases, a thorough evaluation by a neurologist or other specialist is necessary to determine the underlying pathology and develop an appropriate management plan. This may include further diagnostic tests, such as brain imaging or genetic testing, to identify the cause of the atypical presentation. Treatment may involve a combination of antiepileptic drugs and other therapies, such as surgery or behavioral interventions, depending on the specific features of the atypical presentation. It is important to note that atypical electro-clinical presentation is relatively rare and may require specialized expertise to diagnose and manage. Therefore, referral to a specialist center or epilepsy center may be necessary in some cases (**Table 4**) [2]*.*

#### *3.4.2.3 Other red flags*

Anti-epileptic drugs may exacerbate epilepsy or trigger a metabolic attack in patients with IEMs (**Table 5**) [20].

*Perspective Chapter: Red Flags for Syndromic Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.113765*


*TMS, Tendom Mass Spectroscopy; HPLC, High Performance Liquid Chromatography; MRS, Magnetic Resonance Spectroscopy.*

#### **Table 4.**

*Progressive myoclonic epilepsy syndromes.*


#### **Table 5.**

*List of IEMs that may be exacerbated by anti-epileptic drugs.*

#### *3.4.3 Paraclinic*

Pattern of white matter abnormalities on magnetic resonance imaging (MRI) is one of the most important tools in the diagnosis of specific IEM types (**Figure 5**) [3]:

#### **Figure 5.**

*Patterns of white matter abnormalities on magnetic resonance imaging (MRI) in IEM.*

Abnormalities on *proton magnetic resonance spectroscopy*: for instance, creatine deficiency or increased in lactate in Mitochondrial disorders.

*Electroencephalogram* showing slowing of the background activity or photoparoxysmal responses during the photic intermittent stimulation at low frequencies (1–6 H).

#### *3.4.4 Treatable IEMs*

When investigating a patient with refractory epilepsy or unexplained status epilepticus, it is important to consider the possibility of treatable diseases [20]. The following investigations may be considered:

1.Glucocerebrosidase activity: This test can help diagnose Gaucher disease, a rare


*Perspective Chapter: Red Flags for Syndromic Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.113765*


#### **4. Conclusion**

When evaluating a patient with a suspected neurological disorder, the age at onset of symptoms is an important factor to consider. If the patient has a baseline developmental delay, the age at onset of neurological symptoms or regression is regarded as the age of onset.

It is useful to classify neurological disorders into broad groups based on the age at onset. For example, infancy is typically defined as the period from 1 to 12 months of age, while the late infantile/early juvenile onset period is from 1 to 5 years of age. The early infantile, late infantile/early juvenile, and late childhood periods are from 0 to 2 years, 2 to 6 years, and 6 to 12 years, respectively.

This classification can help guide the diagnostic workup and management of the patient. For example, certain neurological disorders, such as infantile spasms, are more common in the early infantile period, while others, such as Rett syndrome, typically present in the late infantile/early juvenile period.

In addition to the age at onset, other factors such as the pattern of inheritance, family history, and clinical features can also help narrow down the differential diagnosis and guide the diagnostic workup. A thorough evaluation by a neurologist or other specialist is necessary to make an accurate diagnosis and develop an appropriate management plan.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Epilepsy During the Lifespan – Beyond the Diagnosis and New Perspectives*

#### **Author details**

Bita Shalbafan Neurologist, Tehran, Iran

\*Address all correspondence to: b-shalbafan@alumnus.tums.ac.ir

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### **Chapter 5** Childhood Absence Epilepsy

*Luigi Vetri, Carola Costanza, Margherita Siciliano, Francesco Precenzano, Beatrice Gallai and Marco Carotenuto*

#### **Abstract**

Childhood absence epilepsy (CAE) is a common epilepsy syndrome characterized by absence seizures affecting young children and representing 18% of all diagnosed cases of epilepsy in school-age children. Absence seizures are classically very frequent during the day and each seizure lasts a short time, from about 10 to 20 seconds, it ends abruptly, and awareness and responsiveness are severely impaired. The typical EEG pattern in CAE is a bilateral, synchronous, and symmetrical discharge of complex spike-wave rhythms at 3 Hz (range of 2.5–4 Hz), with sudden onset and termination. CAE is genetically determined, the mode of inheritance and genes involved remain not fully clarified but the final outcome is the dysregulation of corticothalamic-cortical circuit that plays a crucial role in the pathophysiology of absence seizures. CAE may have an impact on patients' lives in terms of negative consequences in neurocognitive and neuropsychological aspects that should always be considered during a global evaluation of a child with epilepsy.

**Keywords:** childhood absence epilepsy, absence, seizure, epilepsy, EEG

#### **1. Introduction**

Childhood absence epilepsy (CAE) is a common form of idiopathic generalized epilepsy of childhood, corresponding to 18% of all diagnosed cases of epilepsy in school-age children. CAE is characterized by multiple typical absence seizures, together with, on the electroencephalogram, synchronous and symmetrical bilateral discharges of 2.5–4 Hz generalized spike-waves [1].

In 2017, the International League Against Epilepsy (ILAE) classification [2] CAE was included in the group of idiopathic generalized epilepsy (IGE) together with juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic–clonic seizures alone (GTCA). In 2022, the Task Force on Nosology and Definitions defined IGE as a distinct subgroup of Genetic Generalized Epilepsies because they generally have a good prognosis, a polygenic inheritance, an overlap symptomatology, similar EEG findings, and they do not evolve in epileptic encephalopathy but can evolve into each other [3].

#### **2. Epidemiology**

CAE incidence is 6.3–8.0 cases per 100,000 per year [4], and it represents 18% of epilepsy in school-aged children. In a cohort study of children, the CAE prevalence was estimated between 0.4 and 0.7 per 1000 people [5]. CAE, with some exceptions, is more frequent in girls than in boys (75 vs. 60%) [6]. Usual CAE onset is between 4 and 10 years of age with a peak at 5–7 years [7].

#### **3. Clinical presentation**

CAE is characterized by frequent absence seizures, up to 100 daily seizures, in otherwise typically developmental children although comorbid neurodevelopmental disorders may be present [1, 8, 9]. The sudden loss of awareness is the essential characteristic of CAE absence seizures, with loss of contact with the surrounding environment, lack of response to calls, and psychomotor arrest [10].

Absence seizures are typically multiple during the day and can be often underrecognized.

Many children stop their activities, but some may continue to carry out their tasks in an impaired manner, and at the end of the seizure, there is an immediate return to normal activity [11]. Another important ictal-associated clinical feature consists of fixed gaze, regular eye movements at 3 Hz, and eyes opening in cases where they are initially closed [11]. Frequently, automatisms can be observed, especially in longer crises and during hyperventilation.

The automatisms are mostly oro-alimentary or gestural movements and are repeated in a similar way in the same child. In any case, these movements may not be present in all absence seizures even in the same child, and their presence is not influenced by age or state of vigilance [12].

Mild clonic and tonic movements may also be present during the first seconds of the absence seizure, while tonic drops are never mentioned. Pallor is also common.

Urine incontinence occurs in exceptional cases [13]. Furthermore, some studies report perioral myoclonus and arrhythmic and single myoclonic jerks of the limbs, head, or trunk present during seizures in some children [11, 14]. These are mostly retropulsive movements of the head [9].

The duration of seizures is influenced by various factors: induction (hyperventilation or intermittent light stimulation), the state of arousal, sleep deprivation, pharmacological treatment, and individual factors [12, 15]. The typical duration of absence seizure is 3–20 seconds; a seizure duration of less than 4 seconds or more than 30 seconds is not typical of CAE [7]. Generalized tonic–clonic may rarely occur in the period of a high frequency of seizures and sometimes during adolescence, they can underline the evolution to another IGE [16].

#### **4. Electroencephalogram**

The typical EEG pattern of CAE is a bilateral, synchronous, and symmetrical discharge of complex spike-wave rhythms at 3 Hz (range 2.5–4 Hz), with sudden onset and termination. Often, a recovery of function is observed towards the end of the crisis and sometimes functions can be spared **(Figure 1)** [10]. However, EEG discharges sometimes have maximum frontal amplitude or may exhibit initial unilateral focal spikes [17].

#### *Childhood Absence Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.114001*

#### **Figure 1.**

 *EEG example of patient with CAE with typical 3 Hz spike and wave discharges.* 

 Sadleir and colleagues meticulously described the electroclinical characteristics of absence seizures and analyzed videos of 339 absence seizures from a cohort of 47 children with a recent diagnosis of AIH. The authors demonstrated that the mean seizure duration was 9.4 seconds (ranging from 1 to 44 seconds), shorter than the 12.4 seconds previously reported. In 50% of CAE seizures, the initial generalized discharge is characterized by a typical spike-wave, while others are characterized by single spikes, polyspikes, or an atypical irregular generalized slow wave.

 Seizures without a regular slow wave discharge are rare. The majority of discharges consist of spike-wave complexes with one or two spikes per wave. Children with photosensitivity are more likely to have three or four spikes per wave. The discharge may show a degree of variability at the end of the seizure, especially coinciding with drowsiness, sleep, or hyperventilation. In these circumstances, the regular ictal discharge can be interrupted by slow waves, complexes of different frequencies and/or morphology, or brief and transient interruptions of the ictal discharge [ 18 ].

 Hyperventilation induces absence seizures in 83% of patients while intermittent light stimulation induces absence seizures in 21% of patients [ 11 ].

 The interictal electroencephalographic activity of CAE is characterized by normal background activity but in 92% of cases, it is possible to document paroxysmal interictal activity consisting of bursts of generalized spike-wave discharges. However, focal epileptiform interictal discharges could be present not only in central areas but also in frontal, temporal, and parietal areas [ 11 , 18 ].

 Delta, rhythmic, intermittent occipital activity, also described as delta, rhythmic, bilateral, posterior activity is another interictal abnormality of CAE. This activity is characterized by rhythmic bursts at 2.5–4 Hz over the occipital regions, and it is enhanced by hyperventilation and drowsiness while attenuated by eye opening and deep sleep [ 11 , 19 ]. The presence of multiple spikes (more than three), 3–4 Hz spikewave paroxysms of less than 4 seconds, or segmentation of the ictal discharge are not typical of CAE and suggest a worse prognosis [ 7 ].

#### **5. Pathophysiology of CAE**

Theories on epileptogenesis. The mechanisms underlying the generalized spike-andwave discharges of absence seizures have been analyzed in many studies, for more than 7 decades, but the debate continues [1]. Absence seizures evidently involve bilateral cortical and subcortical networks that are part of the default state system [20]. In 1941, Jasper and Kershman, analyzing the electroencephalograms of patients suffering from childhood petit mal, proposed a subcortical origin of absence seizures, imagining a thalamic pacemaker that projected simultaneously to both cerebral hemispheres. Subsequently, a second thalamo-cortical projection system was hypothesized to contribute to the spread of spike-wave discharges originating from the intralaminar nucleus of the thalamus [21].

These results led Jasper and Droogleever Fortujn, in 1947, to the first experimental model of spike-and-wave: the cat thalamic stimulation model. A stimulation of 3 cycles/sec in the intralaminar nucleus of the thalamus can produce a bilateral and synchronous 3 Hz spike-and-wave EEG discharge, associated with an absence-like behavioral modification [22].

In 1954, Penfield introduced the expression "centrencephalic epilepsy", to indicate the genesis in the trunk and diencephalon, responsible for the origin of generalized seizures with initial loss of consciousness and bilateral onset synchronous on the EEG [23].

In 1952, Gibbs and Gibbs questioned the centrencephalic theory, hypothesizing instead that a diffuse cortical process was at the origin of spike-and-wave discharges. Data in favor of these hypotheses were produced by administering proconvulsant substances via the arterial route: the intracarotid injection determined the appearance of bilateral and synchronous spike-and-wave -type EEG discharges; the same substances were ineffective when administered into the vertebral arteries. Further data in support of a cortical origin of the absences were obtained through depth recordings carried out in patients suffering from lesional epilepsy of the frontal lobe and generalized EEG anomalies [24]; the latter led Luders and Niedermeyer to formulate the hypothesis of a fronto-mesial origin of absences and, more generally, of idiopathic generalized epilepsies [25, 26].

At the end of the 1960s, Gloor proposed a reticulocortical mechanism, attributing an essential role to the genesis of bilateral and synchronous POs to both the cortex and the thalamus and trunk. The theory was based on the stimulation of the thalamus in the cat, capable of inducing PO discharges only after the application of penicillin in the cortex. This led to the belief that the factor necessary for the genesis of PO discharges was in the condition of cortical hyperexcitability [27, 28].

The intrathalamic network. In 1991, Buzsaki studied the thalamo-cortical system in a strain of rats with spontaneous PO discharges, hypothesizing a "thalamic clock", initially responsible for discharges, located in the thalamic reticular nucleus. In this nucleus, one would find the cells capable of triggering the recruitment of the intrathalamic network and the thalamo-cortical connections, at the basis of the origin of the physiological spindle figures.

PO discharges would be the result of an abnormal rhythmic oscillation of the intrathalamic network, which would impose its own rhythm on the cortex [29]. This theory, which revived the concept of "centrencephalic epilepsy", was subsequently supported by further studies on different strains of epileptic rats (GAERS, WAG, Rij). In these animals, both lesions to the reticular nucleus of the thalamus and deactivation of the cortex resulted in the disappearance of spontaneous PO discharges, demonstrating that both structures are necessary for the generation of absences [30].

In recent studies, the temporal relationships between thalamic and cortical structures during spike-and-wave discharges have been clarified with nonlinear signal analysis methods.

The result is evidence of a cortical "focus" at the level of the perioral region of the somato-sensory cortex, from which the discharges then propagate to other areas of the cortex, for example, to the thalamus [31].

Conversely, some studies have shown that the onset of spike-wave activity is in the thalamus [32, 33]. According to other researchers, these findings would be false representations of cortical activities occurring in sites distant from the typical focus of the somatosensory cortex [34].

Based on this conflicting evidence, the general consensus is that although some forms of spike-and-wave activity may originate from the cortex or thalamus, the entire thalamocortical circuit is required to generate typical spike-and-wave discharges [20].

In particular, one hypothesis is that the initiation of the discharge is induced by the cortex, and that the thalamic structures are subsequently responsible for its amplification and maintenance through the thalamo-cortical connections. In this way, the theory of the "cortical focus" underlying absence seizures appears to be a synthesis between the cortical and reticulocortical theories [34].

Today, the cortico-thalamic-cortical circuit is considered to play a crucial role in the pathophysiology of absence seizures. Neurons of the thalamic nucleus reticularis can fire in an oscillatory pattern or continuously in single spikes. Changes in the type of firing patterns depend on low-threshold transient calcium channels known as T-type channels neurons from the thalamic nucleus reticularis. After depolarization, T-type channels before becoming inactive allow a little calcium inflow. The reactivation of these channels requires a long hyperpolarization facilitated by GABA-B receptors. Therefore, T-type channel abnormalities or GABA-B hyperactivation can provoke abnormal oscillatory rhythms. Similarly, mutation in genes coding for T-type calcium channels and GABA receptors has been related to CAE etiopathogenesis [35].

#### **6. EEG-fMRI studies**

Associated EEG-fMRI studies have shown changes in activity in all components of the default state system [20, 31]. Many studies describe activation of the thalamus, as well as inactivation of the medial frontal cortex, medial parietal cortex, anterior and posterior cingulate cortex, lateral parietal cortex, and simultaneous activationinactivation of the lateral frontal cortex [36–38].

Increased activity in the primary motor, somatosensory, visual and auditory cortex, and cerebellum are also reported on fMRI, while decreased activity is often observed in the basal ganglia and pons [36, 37, 39].

Only a few studies have attempted to relate fRMI in absence seizures to reduced behavioral performances [36, 37]: The results suggest widespread changes as behavior deteriorates. An important challenge appears to be represented by fMRI studies that simplify the analysis of hemodynamic response functions related to brain activity.

Time-course analyses have shown that an activation in fMRI begins in the medial frontal and parietal cortex 10 seconds before the onset of the absence seizure on the EEG [40, 41]. These early changes in fMRI are followed by complex sequences of activation and inactivation with different time courses in cortical and subcortical structures, most of which cannot be measured by standard hemodynamic functional responses used for conventional fMRI analysis [10].

Furthermore, new approaches are indispensable to detect these important fMRI changes that may be related to the deterioration of consciousness. All studies support the conclusion that spike-and-wave discharges are the result of epileptic activity generated within the cortico-thalamocortical circuit. Therefore, the EAI sticks to the definition of an epileptic system understood as a condition underlying a persistent susceptibility of the thalamic-cortical system, capable in its fullness of generating seizures. The epileptic system hypothesis postulates that the propensity to generate seizures depends on a specific susceptibility of a specific neural system to an epileptogenic factor.

Available data support the idea of a trigger zone within a specific area of the thalamo-cortical system that has a genetically determined epileptogenic susceptibility [1], a pretreatment topological disruption is present and primarily affects the prefrontal-thalamocortical circuit underlining that an alteration brain network topology and structural–functional connectivity is an intrinsic feature of CAE [42].

#### **7. Spike and wave discharges pathophysiology**

Spike and wave discharges are the electrographic hallmarks of CAE. On the intracellular microelectrode level, cortical neurons show depolarization coinciding with the spikes and hyperpolarization corresponding to the wave of the EEG spikewave complexes. Very briefly, the rhythmicity of the spike-wave complexes is the consequence of intrathalamic and thalamo-cortical oscillatory electrical activity [43], which would be generated in genetically predisposed subjects [1].

Key components of this circuit include cortical pyramidal neurons, relay nuclei neurons of the thalamus, and the reticular nucleus of the thalamus [1]. The intrathalamic and thalamo-cortical oscillatory circuits would depend on the activation of transmembrane calcium currents, defined as transient T, on which the genesis, at the cortical level, of the rhythmic discharges of spike-wave complexes at 3 Hz would depend.

On a neurotransmitter level, the ideal condition for the genesis of these discharges is given by a high level of both glutamate-asparthaergic excitation and GABA A-mediated inhibition [44]. Furthermore, the role of GABA B receptors appears crucial at the level of the thalamic relay nuclei, the activation of which would facilitate the genesis of spike-wave discharges [43].

In particular, the main synaptic connections of the thalamic-cortical circuit include glutamatergic fibers extending from the neocortical pyramidal cells to the thalamic reticular nucleus (NRT) and GABAergic fibers extending from the thalamic reticular nucleus to the thalamic relay neurons. The cellular events that guarantee the maintenance of oscillatory rhythms are ensured by the presence of Ca ++ channels and T-Transient at the level of the neurons of the reticular nucleus of the thalamus (NRT) [1].

According to the cortical focus theory, spike-and-wave activity rapidly propagates through cortico-cortical networks from the cortical focus of origin. Oscillatory circuits of the thalamic-cortical network amplify and sustain discharges [45]. The origin of the ictal discharge is characterized by the activation of the dorsolateral frontal and orbital frontal regions [45].

#### **8. Genetics**

Although CAE is genetically determined, the mode of inheritance and genes involved remain not fully clarified. In most cases, CAE susceptibility is likely due to the influence of multiple genes and only a few genes confer a monogenic risk for CAE.

The calcium channel genes are associated with CAE especially CACNA1H and CACNG3 genes [46]. Also, GABA A and B receptor genes such as GABRG2, GABRA1, GABRB3, GABAB1, and GABAB2 genes have been implicated in the epileptogenesis of CAE [47]. Moreover, there is literature evidence of the involvement of chloride channels genes (CLCN2) as a susceptibility locus in CAE [48]. If there are atypical clinical features such as early onset, drug resistance, intellectual disability, and movement disorders, a glucose transporter 1 deficiency (SLC2A1 gene) should be suspected [49].

Mutations in patients with CAE were sometimes described in SLC2A1 gene coding for glucose transporter type 1 although the mutation rate in patients with CAE seems to be low [50].

Lastly, there are also recurrent CNVs that must be considered within the multiple possible genetic causes of CAE such as 15q11.2, 15q13.3, and 16p13.11 microdeletion [51].

#### **9. Pharmacological treatment of CAE**

The first-line antiseizure medications (ASMs) commonly used for CAE is ethosuximide (ETX), valid alternatives as initial treatment for CAE, valproic acid (VPA), and lamotrigine (LTG). VPA has more adverse effects, and LTG is less effective compared to ETX [52].

Topiramate, zonisamide, and levetiracetam [53–55] can be considered when other treatments fail.

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, tiagabine, and vigabatrin may worsen absence seizures or cause absence status epilepticus and should not be administered [56].

#### **10. The evolution and prognosis of CAE**

Studies on the evolution and prognosis of CAE are relatively incomplete due to the inaccuracy of diagnosis, definitions, and inclusion and exclusion criteria. Furthermore, the variability of the prognosis depends on the duration of follow-up [1]. CAE, if correctly recognized using correct diagnostic criteria recently revised in 2022 by ILAE (**Table 1**), has an excellent prognosis for seizure remission and for successful treatment with ASMs**.** The rate of remission cases reported in literature varies in the range of 56–84% [57, 58].

In a prospective study, Callenbach et al. observed that the total duration of epilepsy and the average age at the end of remission corresponded to 3.9 years and 9.5 years, respectively; the two criteria studied increased in children who presented seizures 6 months after enrollment. Few children, equal to 7%, of those who presented crises after 12–17 years of follow-up showed a good prognosis [57].

Retrospective studies highlight the possibility that patients in remission were under-reported and this contributed to an apparently lower remission rate. Grosso et al., however, demonstrated that the inclusion criteria had a notable influence on the outcomes of these results [59].

Patients were classified into two groups: the first with a diagnosis based on the ILAE classification and the second with a diagnosis established on more rigid diagnostic criteria proposed by Loiseau and Panayiotopoulos [7]. The second group showed a higher remission rate defined by the percentage of seizure-free patients in the absence of ASMs treatment for a period of ≥1 year (82 vs. 51%), a lower incidence


*Source: Modified from Hirsch et al. [3].*

*Note: CAE, childhood absence epilepsy; CSF, cerebrospinal fluid; EEG, electroencephalogram; and GTCS, generalized tonic–clonic seizures.*

*\*Alert criteria are absent in most CAE patients, but they may be rarely present. Alerts do not exclude CAE diagnosis but their presence should lead to a rethink of the diagnosis or to make further investigations.*

#### **Table 1.**

*Diagnostic criteria for CAE.*

of generalized tonic–clonic seizures (8 vs. 30%), and absence of relapse upon discontinuation of AEDs (0 vs. 22%).

The estimated percentage of patients developing generalized tonic–clonic seizures range from 8 to 69%, as can be seen from the literature [45, 57]. Most often, generalized tonic–clonic seizures occur 5–10 years after the onset of the absence seizure. Some patients develop a refractory syndrome known as juvenile myoclonic epilepsy [58]. However, all these observations relating to the evolution of the syndrome and/or the earlier onset of generalized tonic–clonic seizures remain controversial. Furthermore, the development of myoclonic seizures also suggests a worse prognosis. Other negative prognostic factors include: type of absence, late onset of absence seizures (after age 8), abnormal EEG background activity, multiple spikes, and presence of focal abnormalities [58, 59].

On the contrary, a favorable prognostic factor is the early remission of the seizure following the introduction of an appropriate antiepileptic treatment [60]. EEG abnormalities can persist even in adults and even in seizure-free subjects [1].

#### **11. Differential diagnoses**

Differential diagnosis includes other IGE syndromes. Epilepsy with myoclonic absences (EMA) is characterized by an alteration of contact with the environment of variable extent (from mild to complete); bilateral myoclonus (prevalent in the limbs) constitutes the constant characteristic of this type of crisis and is often associated with a tonic contracture, especially proximal. Seizures begin and end abruptly, and their duration varies from 10 to 60 seconds. The frequency is high and absences often occur 10 times a day; in 14% of cases, they can be induced by SLI or occur during slow sleep, awakening the patient. The interictal EEG is usually normal. In a third of cases, generalized PO sequences and rarer focal or multifocal PO bursts can be observed. The critical EEG is characterized by a discharge of bilateral, synchronous, and symmetric 3 Hz PO complexes. Polygraphic recordings document that myoclonias are closely correlated with the tips of the complex. The prognosis appears to be closely correlated with the presence of associated generalized tonic–clonic (CGTC) seizures (worse if present) [9].

The juvenile absence epilepsy (JEA) has the same characteristics as CAE, but the age of onset is pubertal (9–13 years), and its frequency is lower: 1–10 per day.

Seizures are often associated with CGTC and more rarely, with sporadic myoclonia. Absence-type status epilepticus (SE) is also described. The interictal EEG is normal or with short bursts or groups of PO and PPO. PO discharges, predominantly frontal, are generally faster than 3 Hz (3.5–4 Hz), the first complex is often faster, and PPOs are frequent. However, seems to be very difficult to exactly define a certain border between these CAE and JAE, and there always remains a gray area between the two syndromes [61].

However, studies relating to this syndromic group are few. In a video-EEG study, Panayiotopoulos et al. [62], reported the characteristics of the absence seizures of patients with EAG, compared to those typical of EAI: Contact breaking is less important, eyes opening during the absence is less common, crises last longer, and discharges can become fragmented [9].

Reflex absences. They are classified based on the stimulus capable of causing them. According to the ILAE classification, reflex syndromes can be caused by visual, proprioceptive, and somatosensory stimuli and there are seizures caused by music, reading, contact with hot water, etc. However, the ILAE specifically mentions only idiopathic photosensitive occipital epilepsy, primary reading epilepsy, and startle epilepsy as reflex epilepsies. Seizures are usually of a generalized type on a clinical level (absences, myoclonia, generalized tonic–clonic seizures) [9].

Juvenile myoclonic epilepsy is a syndrome that begins in the pubertal period (12–18 years) and is typically characterized by massive, bilateral, single, arrhythmic, irregular myoclonic seizures, predominant in upper limbs, without alteration of contact with the environment. Myoclonias are more frequent after waking up at night and cause objects to fall from the hands. In addition to myoclonic seizures, subjects present CGTC (preceded by myoclonic seizures) in 85% of cases and absence seizures in approximately a third of cases. The critical EEG is characterized by generalized bursts of PP at 10–16 Hz, of medium voltage, followed by short sequences of slow waves at 1–3 Hz. Absence seizures are short and generally not associated with automatisms and from an EEG point of view, they correlate with discharges of irregular PO and PPO complexes at 3–4 Hz (with inscriptions of components at 2–7 Hz). The interictal EEG is characterized by normal background activity, with the possibility of recording short groups of generalized and irregular PO and PPO complexes [1].

The epilepsy with eyelid myoclonia should be considered if there are rhythmic and fast (>4 Hz) jerks of the eyelids, with an upward deviation of the eyeballs and with possible subtle head extension; seizures can be very frequent and can be triggered by eye closure and photic stimulation [63].

#### **12. Neurocognitive aspects in CAE**

The impact of absence epilepsy on neurocognitive functions can vary widely. While some individuals may not experience significant cognitive difficulties, others may exhibit varying degrees of impairment in cognitive domains such as memory, attention, and executive functions.

Even in the absence of visible seizures (ictal events), individuals with absence epilepsy may exhibit abnormal electrical brain activity during interictal periods. These interictal discharges can disrupt cognitive processing and contribute to neurocognitive impairments [64].

Furthermore, cognitive difficulties may depend on cortical microdysplasias for example, on the characteristics of absence seizures themselves (aura, ictal phase, perictal phase) or on anticonvulsant pharmacological treatment [65].

In 2013, a double-blind randomized clinical trial conducted on 446 children affected by CAE showed a high rate of attention deficits in patients before treatments and even if seizures were well controlled. Despite average intellectual ability, 35% of untreated children demonstrated the presence of clinically significant attention problems. Attention deficits in children with CAE have an important impact on learning and achievement. Although children may become seizure-free with a normalized EEG, attention deficits persist even with the use of the most efficacious medication. Furthermore, in this study, valproic acid affects attention more than either lamotrigine or ethosuximide [66].

Various areas of cognitive domains may be compromised in CAE patients. Below, we will analyze some of the cognitive domains affected by alterations or impairment.

To explain CAE comorbidities, several studies have evaluated the intellectual functioning of affected subjects in relation to healthy patients or other types of epilepsy. For assessing cognitive problems in children, intelligence tests are considered a first-line instrument. The results of intelligence quotient (IQ ) tests were largely analyzed in various studies. Despite being within the normal range, the average IQ scores in current studies were significantly lower than those in healthy controls [65, 67, 68]. IQ appeared to be related to the frequency and extent of seizures [69]. The common hypothesis in multiple studies is that IQ could reflect the impact of seizures, considering lower age of onset and not well-controlled seizures, as negatively affecting cognition and language skills [70, 71]. Lower IQs in CAE children [72] are even related to social difficulties and behavioral problems. Performance analysis by testing found lower IQ scores in CAE subjects compared to those with partial or generalized seizures.

There is some evidence that a reduction of sleep spindle density in N2 sleep phase can represent a good EEG marker in predicting cognitive impairment in children with CAE [73].

The study of ASMs role on cognition has been widely debated in CAEs. Some studies have reported a significantly beneficial effect of AEDs, through seizure control, on various cognitive functions such as motor fluidity, memory, and attention [74]. However, Nolan et al. in 2003 [70] showed that the use of more than two anticonvulsant drugs was associated with lower IQ scores.

#### *Childhood Absence Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.114001*

Pavone et al. conducted a study on 16 children suffering from an epileptic syndrome defined by clear diagnostic criteria: epilepsy with absences. All patients had negative neuroimaging and were under pharmacological treatment with ethosuximide, valproate, or both [65]. The researchers excluded all children with generalized tonic–clonic seizures. The abilities of these patients were compared with a control group of the same number. The study showed that global cognitive abilities appeared average (with total IQ between 71 and 120), although significantly deficient compared to the control group.

Visuospatial skills were moderately deficient in subjects with absence seizures. Furthermore, a selective deficit in non-verbal memory was observed, while language functions were generally preserved.

Studies conducted on surface-based morphometry in CAE patients have shown that the average intellectual functioning of these children reflects the neuropathology underlying CAE and is linked to plasticity and reorganization of brain development. In fact, CAE patients did not have cortical morphometric measures in line with age or related to other variables such as age of onset, seizure frequency, or AED intake. In particular, an increase in sulcal depth was found at the level of the superior temporal gyrus, the somatosensory region, and the left frontal lobe [75]. This suggests widespread neurocognitive deficits in patients with absence seizures involving multiple brain systems.

Several studies investigating verbal IQ in children with CAE, such as those conducted by Jones et al., Caplan et al., or Henkin et al. [8, 76, 77] revealed worse performances than normal children especially in verbal fluency [78].

Children affected by absence epilepsy often experience attention-related problems [69].

During absence seizures, individuals often experience a sudden and temporary loss of awareness or consciousness. This means their attention to their surroundings, ongoing activities, and conversations are interrupted [79].

Attention appears particularly vulnerable to epileptic activity [80]. At the same time, seizures themselves are typically very brief (usually lasting only a few seconds), these interruptions can disrupt attention and concentration, especially if they occur frequently throughout the day [81].

A study by Cerminara et al. [82] assessed the attentional characteristics of children with CAE using tests that measure attention and discovered that patients with CAE had lower scores in the areas of vigilance, selective attention, and impulsivity compared to healthy controls.

Neuroimaging studies demonstrate significant changes in brain networks underlying attention, such as, for example, decreased activity in the anterior insula of the medial frontal cortex [1, 80].

Regarding how treatment affects attentional abilities, several studies agree that VPA can cause a worsening of attentional abilities more than other antiepileptic drugs [83].

Visual memory is impaired in children with CAE, as evidenced by multiple studies [75], while others have found no significant differences with children with other epileptic syndromes [84]. The presence of epileptic seizures in children and adolescents for several years can lead to problems with consolidating knowledge, which can negatively impact school results [85].

A deficit of executive functions is frequently found in subjects with epilepsy, as demonstrated by several studies [72, 84], even in CAE children compared to healthy controls [86]. The affected children showed difficulties in those domains of frontal

executive functions such as decision-making skills, problem-solving, and planning, in particular, the difficulty they had concerned knowing how to change responses based on external requests.

#### **13. Comorbidities**

Studies focused on CAE have shown the presence of learning disabilities in this group of patients. Frequent absence seizures, if uncontrolled, can interfere with the learning process, particularly in school-aged children. These seizures can disrupt the continuity of lessons and affect the ability to retain information [8].

Vanasse et al., in a 2005 study [87], demonstrated that even children suffering from generalized seizures, specifically absence seizures, had difficulties in reading. Many children struggle to acquire the phonological strategies that underlie learning to read.

The involvement of both the temporal and frontal lobes in the phonological reading processes has largely been demonstrated; about this, patients with complex partial epilepsy show difficulties in reading skills [88, 89].

Despite seizures per se, duration, age of onset, and other factors influencing cognitive abilities, and variables such as familial factors or neuropsychological comorbidities are often significant in influencing underperformance at school in epileptic children [77].

Attention deficit hyperactivity disorder (ADHD) may co-occur with epilepsy in some cases, especially in children. The presence of both conditions can complicate diagnosis and management.

ADHD is the most common disorder in preschool and school-age children with epilepsy [90]. It has a negative impact on the quality of life and represents a significant risk factor for academic performance [91].

There is evidence pointing to a complex relationship between ADHD and seizure disorders. Some literature studies have demonstrated the presence of ADHD, anxiety, and depression disorders in children affected by CAE [8, 92]. A close association between these pathologies has recently been postulated. The mechanisms underlying attention deficits are still unknown and appear to be different between generalized and focal epilepsies [93].

ADHD and selective attention deficits are more prevalent in children with CAE than in typically developing children. ADHD is reported to be comorbid in children with childhood epilepsy in about 12–17% of cases [94]. In several studies, comorbid ADHD was diagnosed in about 40% of CAE patients [95, 96].

In particular, some findings suggest that recurrent seizures and treatment may not be the main etiological factor underlying ADHD [97] and that attention deficit and hyperactivity symptoms start before the diagnosis of epilepsy [95, 97]. From most recent studies, it is therefore clear that the early diagnosis of ADHD in comorbidity with epilepsy is useful to correctly plan a pharmacological treatment.

Furthermore, a significant proportion of patients affected by epilepsy, between 10 and 15%, manifests intellectual disability [65].

The comorbidity between intellectual disability and epilepsy is well-documented and relatively common. Studies have shown that individuals with intellectual disabilities have a higher risk of developing epilepsy than the general population. Individuals with intellectual disabilities may have a higher predisposition to epilepsy due to underlying structural brain abnormalities or genetic factors [98]. As discussed,

#### *Childhood Absence Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.114001*

epilepsy can potentially lead to intellectual impairment, particularly if seizures are frequent, severe, or difficult to control.

In this regard, for example, a syndrome has been described as a phenotype of the 15q13.3 microdeletion syndrome, characterised by absence seizures and intellectual disability [99].

Regarding behavioral problems, there is an ongoing debate as to whether these problems are an integral part of epilepsy syndrome or whether they develop due to factors associated with the disease [100].

Some researchers argue that behavioral problems are intrinsic to certain epilepsy syndromes. They believe that abnormal electrical activity in the brain during seizures or interictal periods can directly affect mood and behavior [101].

In addition, the resulting psychosocial disruption of diagnosis in patients' lifestyles or therapeutic interventions with AEDs can also cause behavioral effects [102]. Some AEDs may lead to mood swings, aggression, or other behavioral changes [103].

In this regard, we recall a 1997 study, in which Elaine et al. hypothesized that patients suffering from absence epilepsy could have more serious psychosocial disorders than patients suffering from chronic non-neurological pathologies [104].

In the study, two groups of patients were compared: one group was made up of young adults who had been diagnosed with CAE, and the other group was affected by juvenile rheumatoid arthritis. The study found that patients suffering from CAE had many more psychosocial problems than those suffering from arthritis. Patients with CAE, in fact, had greater scholastic difficulties, increased need for scholastic support, major behavioral problems, and relationship difficulties with peers and family members.

Psychiatric and emotional disorders were reported in both groups but were more common in subjects with CAE. Furthermore, remission of epileptic seizures did not lead to an improvement in the psychosocial condition, although subjects whose seizure remission was not observed showed a remarkable worsening and a higher risk of psychiatric and emotional disorders.

Furthermore, the presence of these comorbidities can contribute to causing difficulties in socialization and poor academic results in patients with CAE.

Individuals with epilepsy may also have comorbid psychiatric disorders, such as depression, anxiety, or ADHD [105]. At least 50–60% of patients with epilepsy develop psychiatric disturbances.

Depression is one of the most common psychiatric disorders in people with epilepsy. The physical and emotional impact of seizures, as well as the social stigma associated with epilepsy, can contribute to feelings of sadness and hopelessness [106].

Depressive and anxiety syndromes are the most frequent disorders in adults with epilepsy [107], and there is much literature evidence that epilepsy and depression share a bidirectional relationship, although the nature of this relationship remains unclear at present [108].

Anxiety disorders, including generalized anxiety disorders and specific phobias, are more prevalent in individuals with epilepsy. The unpredictability of seizures can lead to heightened anxiety [109, 110].

A study on 45 subjects with CAE and 41 healthy controls, between the ages of 6 and 16 years specifically examined anxiety and depression symptoms, revealing that children with CAE demonstrated higher rates of anxiety and depression symptoms and greater general psychosocial problems, while intractability, disease duration, and medication effects were not associated with higher rates of affective problems [99], although an iatrogenic role in this context cannot be ruled out.

However, Ott et al., in 2001 [111], administrating the Diagnostic Interview for the Evaluation of Psychopathological Disorders in Children and Adolescents (K-SADS-PL) reported mood disorders, specifically anxiety and depression disorders, in 12% of 48 children suffering from complex partial seizures and in 18% of 40 children suffering from CAE.

Caplan et al., in a 2005 study [92] conducted on 171 children, of which 100 with complex partial epilepsy, 71 with absence epilepsy, and 93 healthy children, demonstrated that 33% of children affected by complex partial epilepsy and absence epilepsy suffer from affective disorders, especially anxiety disorders. Individuals with epilepsy, particularly those with comorbid psychiatric disorders, may be at a higher risk of suicide [112].

In conclusion, we can state that although CAE is historically considered a benign disorder, children affected may present several difficulties in psychosocial adaptation [1].

An early diagnosis and evaluation of comorbidities can favor the implementation of specific interventions such as cognitive-behavioral therapy, school and educational approaches, and psychological support [1] that help to contain and reduce negative prognostic outcomes related to neurodevelopmental disorders.

#### **14. Iatrogenic effects of treatment**

Antiepileptic drugs (AEDs) are a common cause of cognitive and behavioral effects in children with CAE.

Cognitive functions, including vigilance, attention, psychomotor speed, memory, and mood, are also the domains affected. Despite iatrogenic effects, epilepsy treatment may positively affect patients' cognitive performances by stopping or decreasing seizures [113, 114].

Some common cognitive side effects associated with certain AEDs include memory problems, attention and concentration, language and verbal skills [114].

Certain AEDs may affect language abilities, leading to difficulties with speech or comprehension.

New antiepileptic drugs generally produce fewer cognitive effects, although topiramate may impair attention, memory, and language.

Most studies agree that high doses of antiepileptic drugs and polytherapy compromise concentration, motor skills, and memory functions [65].

The effects of valproate have not yet been carefully studied in children, but we know that the drug has mild effects on cognitive abilities [101, 115].

A more recent study reports that valproic acid does not cause consequences on cognitive abilities if the ammonia level is controlled [116] and that ethosuximide does not cause cognitive deterioration, although the available data are still sketchy [116].

In some cases, cognitive side effects may be dose-dependent, meaning that higher doses of medication are more likely to cause cognitive impairment [66].

A targeted therapy evaluating the benefits and potential side effects of AEDs is recommended, searching for the best way to control seizures with minimal cognitive side effects [102].

#### **15. Conclusion**

CAE is a common epilepsy syndrome whose diagnosis is not difficult, and it should be considered in every child with normal development and multiple daily

#### *Childhood Absence Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.114001*

absence seizures associated with 3 Hz generalized spike-and-wave. Seizures are usually drug-responsive, and it is possible to retain first-line monotherapies: ethosuximide followed by valproate. CAE may be associated with impairments in executive function, attention, and concentration, and it may be correlated with learning disabilities, language disorders, and neuropsychological problems such as anxiety and depression. According to this perspective, taking care of patients with CAE may require a multispecialty approach especially when it is necessary to treat cognitivebehavioral disorders or drug-resistant seizures.

### **Author details**

Luigi Vetri1,2, Carola Costanza3 \*, Margherita Siciliano2 , Francesco Precenzano2 , Beatrice Gallai4 and Marco Carotenuto2

1 Oasi Research Institute-IRCCS, Troina, Italy

2 Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, University of Campania "Luigi Vanvitelli", Caserta, Italy

3 Department of Sciences for Health Promotion and Mother and Child Care "G. D'Alessandro", University of Palermo, Palermo, Italy

4 Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy

\*Address all correspondence to: ccostanza@oasi.en.it; marco.carotenuto@unicampania.it

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 6**

## Perspective Chapter: VNS Nerve Stimulation in Epilepsy through Lifespan

*Isabella D'Andrea-Meira*

#### **Abstract**

Vagus nerve stimulation (VNS) has emerged as a significant therapeutic intervention for individuals with drug-resistant epilepsy (DRE) throughout their lifespan. DRE is a debilitating condition characterized by recurrent seizures that do not respond to traditional antiepileptic drugs, imposing substantial physical, cognitive, and emotional burdens on patients. VNS involves the implantation of a device that delivers electrical impulses to the vagus nerve, a major nerve connecting the brain to various organs. The mechanism of action is complex and not yet fully understood, but VNS has been found to modulate abnormal electrical activity in the brain, reducing the frequency and severity of seizures. This non-pharmacological approach offers a valuable alternative for patients who have exhausted conventional treatment options, improves their quality of life, and provides hope for seizure control. Importantly, VNS has demonstrated efficacy across different age groups, from children to adults, making it suitable for lifelong management of DRE. Furthermore, long-term studies have shown sustained benefits and safety of VNS, with potential positive effects on cognitive function and mood regulation. As a result, VNS represents a promising adjunctive therapy that can significantly impact the lives of individuals with drug-resistant epilepsy, offering them renewed hope and the potential for a better future.

**Keywords:** epilepsy, vagus nerve stimulation, neuromodulation, drug resistant epilepsy, network

#### **1. Introduction**

Epilepsy is a neurological disorder characterized by a persistent tendency to generate epileptic seizures [1]. Epilepsy manifests with a variety of symptoms, ranging from temporary confusion and loss of awareness to convulsions and unconsciousness.

While most patients achieve seizure control with antiseizure medications (ASMs), approximately 30% of individuals experience drug-resistant epilepsy (DRE), defined as failure of adequate trials of two tolerated, appropriately chosen, and used ASMs schedules to achieve seizure freedom [2–4]. It significantly impacts patients' daily lives, cognitive function, and psychosocial well-being. Managing DRE requires a

multidisciplinary approach to address the diverse underlying etiologies and provide individualized treatment plans.

Surgical intervention has gained recognition as an effective alternative for individuals with pharmacoresistant epilepsy and is often considered when drug therapy fails to control seizures adequately. The goal is providing a chance for improved seizure control and enhanced quality of life [5, 6].

While surgical interventions have shown promising results, they may not be suitable for everyone. Non-surgical treatments offer alternatives for individuals who are not candidates for surgery or prefer less invasive approaches. One such non-surgical option is vagus nerve stimulation (VNS), which involves implanting a device that delivers electrical impulses to the vagus nerve, a major nerve in the neck. VNS can help reduce seizure frequency and intensity, although it may not eliminate seizures entirely [7].

Vagus nerve stimulation (VNS) is a non-pharmacological therapy that has been approved for the treatment of refractory epilepsy. The purpose of this chapter is to review the current literature on the use of VNS for the treatment of epilepsy and to discuss its mechanism of action, efficacy, and safety along lifespan.

#### **2. Vagus nerve stimulation**

VNS is a non-pharmacological treatment option, making it suitable for individuals who may not respond well to medications or are unable to tolerate their side effects. It can also be used in conjunction with medication, maximizing the chances of seizure control and improving overall outcomes for people with epilepsy.

In recent years, technological advancements have further improved the effectiveness and convenience of VNS therapy [8]. Newer devices offer increased customization and programming options, allowing healthcare providers to tailor treatment to each patient's unique requirements [9]. Additionally, some VNS devices are equipped with responsive neurostimulation capabilities, meaning they can detect and respond to the early signs of seizures, potentially aborting them before they manifest [9].

#### **2.1 The Vagus nerve**

The vagus nerve is the longest cranial nerve, originating from the brainstem and extending down to the abdomen. It is composed of both motor and sensory fibers, which allow it to carry signals in two directions: from the brain to different organs (motor function) and from organs back to the brain (sensory function) [10].

The vagus nerve's sensory fibers carry important information from the visceral organs back to the brain. These sensory signals help maintain homeostasis, allowing the brain to monitor and regulate various physiological processes.

In the vagus nerve, there are three main types of fibers: A fibers, B fibers, and C fibers. These fiber types differ in their diameter, conduction velocity, and the type of information they transmit. It's important to note that while A fibers and B fibers are myelinated and transmit signals relatively quickly, it is in these fibers that the VNS acts preferentially. C fibers are unmyelinated and conduct signals more slowly.

#### **2.2 VNS and epilepsy history**

The use of electrical stimulation for therapeutic purposes dates back to the ancient Greeks, who used electrical eels to treat headache and gout. In the modern era, the first

#### *Perspective Chapter: VNS Nerve Stimulation in Epilepsy through Lifespan DOI: http://dx.doi.org/10.5772/intechopen.111956*

application of electrical stimulation for therapeutic purposes was in the 18th century, when Benjamin Franklin used electricity to treat paralysis resulting from stroke [11].

The first documented attempt to use electrical stimulation for epilepsy was made in the late 19th century by English neurologist John Hughlings Jackson. He experimented with electrical stimulation of the vagus nerve to observe its impact on seizures [12]. It wasn't until the late 20th century that VNS gained significant traction as a viable treatment option for epilepsy. In the 1980s, researchers started investigating the therapeutic potential of VNS in animal models, which showed promising results in reducing seizure activity [13, 14].

The use of VNS specifically for epilepsy was first reported in the 1980s when a team of researchers at the University of Alabama in Birmingham implanted a VNS device in a patient with refractory epilepsy [15]. The patient experienced a significant reduction in the frequency and severity of seizures, and subsequent studies confirmed the device's efficacy in reducing seizure frequency in patients with refractory epilepsy [16].

Thereafter, prospective randomized clinical trials were carried out, and approval for use in patients with refractory epilepsy occurred in 1994 and 1997 in Europe and the United States, respectively [17]. Approval by ANVISA (National Health Surveillance Agency) for use in Brazil occurred in 2000. Recently, the neuromodulation committee of the Brazilian League of Epilepsy published recommendations for the use of the vagus nerve stimulator and stimulation deep brain [18].

The development of VNS devices has undergone significant improvements since the first clinical trials in the 1980s. The first-generation VNS device, developed by Cyberonics Inc., was implanted in the chest and connected to the vagus nerve via a lead wire. This device delivered fixed-frequency stimulation and required frequent adjustments to optimize therapeutic effects. Over the years, advancements in technology have led to the development of more advanced VNS devices. These newer devices allow for better customization of stimulation parameters and offer improved patient comfort and convenience.

Since then, VNS has been increasingly used as an adjunctive treatment for individuals with epilepsy, particularly those who do not respond well to medication. The therapy has demonstrated efficacy in reducing seizure frequency, improving quality of life, and providing an alternative option for patients who may not be suitable candidates for other forms of epilepsy surgery [7, 19].

In recent years, VNS has also shown potential for the treatment of other neurological and psychiatric conditions, such as depression and anxiety disorders. Ongoing research continues to explore the full range of therapeutic applications and optimize the effectiveness of VNS as a treatment option.

#### **2.3 VNS mechanism of action**

The mechanism of action of VNS is complex and not fully understood, but it is thought to involve a combination of effects on the central nervous system (CNS), autonomic nervous system (ANS), and immune system.

The afferent fibers of the vagus nerve transmit signals from the body to the CNS, providing sensory information about various physiological processes. The efferent fibers of the vagus nerve, on the other hand, transmit signals from the CNS to various organs and tissues in the body, regulating their function. The vagus nerve plays an important role in regulating many physiological processes, including heart rate, blood pressure, respiration, digestion, and immune function.

The mechanism of action of VNS involves various pathways, including the locus ceruleus, solitary tract, raphe nuclei, and cortical areas. The vagus nerve projects to various regions of the cerebral cortex, including the prefrontal cortex. Activation of the vagus nerve through VNS can lead to increased cortical excitability and the modulation of neural networks involved in cognition and emotional processing.

The locus ceruleus receives direct projections from the vagus nerve and is densely innervated by its fibers. This suggests that the locus ceruleus is a key player in mediating the effects of VNS on epilepsy [20]. The activation of the vagus nerve during VNS leads to the stimulation of the locus ceruleus, triggering a cascade of events that may contribute to its therapeutic effects [20, 21]. One of the major neurotransmitters released by the locus ceruleus is norepinephrine [22]. Norepinephrine has been shown to have both antiepileptic and proconvulsant properties, depending on the specific brain region and receptor subtype involved.

Furthermore, the locus ceruleus is interconnected with other brain regions implicated in epilepsy, such as the hippocampus and the cortex [23]. These connections allow for the integration of signals from the locus ceruleus with the broader epileptic network. Through its projections, the locus ceruleus can influence the excitability of these regions, potentially dampening epileptic activity. So, it contributes to the overall modulation of neuronal excitability and seizure activity by modulating the activity of inhibitory and excitatory neurotransmitters, as well as interacting with key brain regions involved in epilepsy.

Regarding neurotransmitters, studies have shown that VNS can modulate the release of neurotransmitters such as gamma-aminobutyric acid (GABA) and glutamate, which play critical roles in regulating neuronal excitability and seizure activity [24]. By increasing GABAergic inhibition and decreasing glutamatergic excitability, VNS helps to restore the balance of neurotransmission, thereby reducing the likelihood of seizures.

VNS has been found to influence EEG synchrony in individuals with epilepsy. Abnormal EEG synchrony, characterized by excessive synchronization or desynchronization, is often observed in epilepsy. VNS has been reported to modulate this abnormal synchrony and promote more balanced and coordinated neural activity. The exact mechanisms through which VNS achieves this effect are not yet fully understood, but it is thought to involve the modulation of neurotransmitters and neural networks involved in seizure generation [25, 26].

VNS has been shown to have modulatory effects on brain metabolism, particularly in regions associated with mood regulation, cognition, and seizure control. It is believed that VNS influences brain metabolism through its impact on neurotransmitter systems, neuroplasticity, and the autonomic nervous system. VNS has been shown to affect brain metabolism through its impact on cerebral blood flow and glucose utilization [27–29]. Research studies using neuroimaging techniques have demonstrated that VNS can increase regional cerebral blood flow and enhance glucose uptake in certain brain regions involved in seizure generation and propagation. This increased metabolic activity in these regions may promote the normalization of neuronal function and decrease seizure activity.

Finally, VNS is thought to modulate the immune system, which plays an important role in many physiological processes, including inflammation, wound healing, and tissue repair. VNS has been shown to reduce inflammation in animal models of arthritis and other inflammatory conditions, suggesting that it may have therapeutic potential for these conditions [30, 31].

*Perspective Chapter: VNS Nerve Stimulation in Epilepsy through Lifespan DOI: http://dx.doi.org/10.5772/intechopen.111956*

Neuroplasticity is also important in seizure control. The proteome of postsynaptic density (PSD) is a protein complex located in the postsynaptic membrane, responsible for the structure, function, and plasticity of excitatory synapses in the central nervous system. It also known that neuronal activity regulates the protein composition of PSD. Researchers identified increased these protein content due to VNS showing the contribution to the plasticity of excitatory synapses [32].

The mechanism of action of VNS is intricate and not yet comprehensively understood. However, it is believed to involve a combination of influences on the central nervous system (CNS), autonomic nervous system (ANS), and immune system. To completely understand the mechanisms underlying the therapeutic effects of VNS, further research is required.

#### **2.4 VNS surgical technique**

I will describe a general overview of the surgical technique; please note that specific details and variations may exist depending on the patient, surgeon, and the device being used.

Here is a general description of the surgical technique for implanting a vagus nerve stimulation device:

#### *2.4.1 Preoperative preparation*

Before the surgery, the patient is typically evaluated and prepared for the procedure. This may involve conducting preoperative tests, reviewing the patient's medical history, and discussing any potential risks or complications.

#### *2.4.2 Anesthesia*

The surgery is usually performed under general anesthesia, ensuring that the patient is unconscious and does not feel any pain during the procedure.

#### *2.4.3 Incision*

The surgeon makes a small incision, typically on the left side of the chest, just below the collarbone. The exact location of the incision may vary based on the surgeon's preference and the patient's anatomy (**Figure 1**).

#### *2.4.4 Pocket creation*

A small pocket is created under the skin to hold the VNS device. This pocket is usually made in the upper chest area, but it can also be placed in the abdomen if necessary.

#### *2.4.5 Lead placement*

The surgeon carefully dissects down to the vagus nerve, usually located in the neck area. Two small electrodes, or leads, are wrapped around the vagus nerve. One lead is placed closer to the brainstem, while the other is positioned closer to the chest (**Figures 2** and **3**).

**Figure 1.** *Description of the cervical and thoracic incision.*

**Figure 2.** *Vagus nerve exposure.*

*Perspective Chapter: VNS Nerve Stimulation in Epilepsy through Lifespan DOI: http://dx.doi.org/10.5772/intechopen.111956*

#### **Figure 3.** *Lead placement.*

#### *2.4.6 Tunneling*

The leads are then tunneled beneath the skin from the neck area to the pocket created in the chest. The surgeon uses specialized instruments to carefully guide the leads to the desired location.

#### *2.4.7 Connection*

The leads are connected to the VNS device, which is placed in the pocket. The device is usually about the size of a silver dollar and contains a battery, electronics, and programming capabilities.

#### *2.4.8 Closure*

The incision is closed using sutures or surgical staples, and a sterile dressing is applied to the wound site.

#### *2.4.9 Programming*

After the surgery, the VNS device needs to be programmed to deliver the appropriate electrical impulses. This is typically done during a follow-up visit, using a handheld programming device that communicates with the implanted device.

It's important to note that VNS surgery carries certain risks and potential complications, including infection, bleeding, vocal cord dysfunction, device malfunction, and side effects related to nerve stimulation. The patient will be closely monitored after the procedure, and postoperative care instructions will be provided to aid in the healing process.

The specific details of the surgical technique may vary based on the patient's individual circumstances, the surgeon's expertise, and the specific VNS device being used.

#### **3. Efficacy and safety through lifespan**

#### **3.1 VNS and children**

Epilepsy affects people of all ages, including children. Despite pharmacological treatment, a significant proportion of pediatric patients continue to experience seizures and suffer from the adverse effects of medication. In such cases, alternative treatment options like vagus nerve stimulation (VNS) have emerged as a viable option.

#### *3.1.1 Seizure reduction*

VNS has demonstrated efficacy in reducing seizure frequency and intensity in children with epilepsy. Several clinical trials and observational studies have reported a significant reduction in seizure frequency by approximately 50% or more in a substantial proportion of pediatric patients [33–35].

Epilepsy has a complex etiology, and while it can be caused by a variety of factors, including brain injury, infections, or tumors, genetics play a significant role in the development of certain types of epilepsy. Advances in genetic research have led to the identification of numerous genes associated with various epilepsy syndromes. Research on the efficacy of VNS in genetic etiologies is still relatively limited, but several studies have explored its potential benefits in specific conditions.

Vagus nerve stimulation (VNS) has been the subject of investigation for several monogenic disorders, including Rett syndrome, Angelman syndrome, and Dravet syndrome. Initial research indicates that VNS could potentially improve respiratory function, heart rate variability, and overall behavioral functioning in individuals with these disorders [36, 37]. In the case of Angelman syndrome, researchers have reported improvements in communication skills, behavior [38].

Regarding Dravet syndrome, VNS has been investigated as an adjunctive treatment option, and studies have reported a reduction in seizure frequency and severity, as well as improvements in overall quality of life and cognitive function [39, 40]. In tuberous sclerosis, VNS is one of the therapeutic options that has shown promising efficacy in the management of seizures associated with tuberous sclerosis [41, 42].

VNS has been shown to provide sustained seizure reduction over an extended period. Studies have reported a decrease in seizure frequency even after several years of VNS therapy, with some patients experiencing complete seizure control [43–45].

In conclusion, VNS has demonstrated efficacy in reducing seizures and improving quality of life among children. It provides an additional treatment option for those who have refractory epilepsy and may not respond to traditional antiseizure medications. However, the response to VNS therapy can vary, and careful evaluation and consideration of individual cases are necessary. A collaborative approach involving medical professionals experienced in DRE is crucial in determining the most appropriate treatment plan for each patient.

*Perspective Chapter: VNS Nerve Stimulation in Epilepsy through Lifespan DOI: http://dx.doi.org/10.5772/intechopen.111956*

#### *3.1.2 Safety*

When it comes to the safety of VNS in children, it's important to note that research and clinical experience in this area are more limited compared to adults. Nevertheless, several studies and clinical trials have been conducted to evaluate the safety and effectiveness of VNS in pediatric patients.

Overall, the available evidence suggests that VNS is generally safe for use in children. The most common side effects reported include hoarseness of voice, cough, throat pain, and difficulty swallowing, which are usually mild and transient. These side effects are believed to be related to the stimulation of the vagus nerve and the muscles of the larynx [44, 46–48].

Ongoing monitoring and follow-up care are essential to ensure the safety and effectiveness of VNS in children. Regular visits to the healthcare provider will allow for the assessment of any potential side effects or complications and adjustments to the stimulation parameters if needed.

#### **3.2 VNs and adults**

#### *3.2.1 Seizure reduction*

The use of VNS in adults has been used for decades since the first clinical trials. VNS therapy has shown effectiveness in reducing the frequency, severity, and duration of seizures. Research and clinical studies have provided evidence of seizure reduction in adults undergoing VNS therapy [49, 50]. The reduction in seizure frequency varies from person to person, and some individuals experience significant seizure reduction, while others may experience more modest improvements. It is important to note that VNS therapy does not guarantee complete seizure freedom but aims to decrease seizure frequency and improve quality of life.

In most published studies, the response rates for implantable VNS vary between 45% and 65% [51, 52]. Kawai et al. observed a median reduction in seizures of 25.0%, 40.9%, 53.3%, 60.0%, and 66.2% at 3, 6, 12, 24, and 36 months, respectively [52].

Over time, the benefits of VNS therapy may become more pronounced. Initially, the stimulation parameters may be adjusted to find the optimal settings for each individual, and it can take several months or longer to observe the full benefits of treatment. The response rate tends to improve over time significantly between the second and fifth year [53]. These observations could be related to neuroplasticity with neosynaptogenesis, as shown by Cramer et al. [54].

Overall, VNS therapy has demonstrated its potential to reduce seizure frequency and improve the quality of life for adults with epilepsy. However, it is important to consider the eligibility, discuss potential risks and benefits, and determine if it is an appropriate treatment option for their specific condition.

#### *3.2.2 Safety*

The implantation procedure carries some inherent risks, including infection, bleeding, and potential damage to surrounding structures. However, these risks are relatively low and can be minimized through proper surgical techniques and postoperative care [51].

The VNS device itself may cause some side effects or complications. These can include hoarseness or voice changes, coughing, shortness of breath, tingling or

prickling in the skin, neck pain, and headache. However, many of these side effects are temporary and tend to diminish over time [49].

Regarding sleep disorders, VNS has the potential to alter breathing patterns and potentially lead to more episodes of apnea or hypopnea [55]. This effect appears to be more pronounced during periods when the VNS device is active; however, it can occur during OFF periods [56].

#### **3.3 VNS and elderly**

While the use of VNS in the elderly population is generally considered safe, there is limited research specifically focused on its efficacy in this age group.

#### *3.3.1 Seizure reduction*

The evidence for VNS efficacy in elderly individuals is not as extensive. Studies have shown that VNS can lead to a reduction in seizure frequency in elderly patients with epilepsy [57]. While the specific seizure reduction rates may vary, research indicates that a significant proportion of elderly individuals experience a reduction in seizure frequency by at least 50% [57].

#### *3.3.2 Tolerability and safety*

VNS has generally been found to be well-tolerated and safe in the elderly population. Adverse effects are typically mild and transient, including hoarseness, coughing, and shortness of breath. Serious complications are rare but can occur, such as infection or stimulation-related adverse events [57].

#### *3.3.3 Potential cognitive benefits*

Some studies have suggested that VNS may have cognitive benefits for elderly patients with epilepsy, including improvements in memory and executive functions. However, further research is needed to establish a clearer understanding of the cognitive effects of VNS in this population [58–60].

#### **4. Dosing**

Programming a VNS device involves setting parameters such as the stimulation strength, pulse width, frequency, and duty cycle to optimize seizure control. Here's a description of how to program VNS for epilepsy, including setting the duty cycle:

#### **4.1 Setting stimulation strength**

This initial programming session typically takes place a few weeks after the VNS device implantation surgery, allowing for recovery and healing.

Stimulation strength refers to the intensity of the electrical pulses delivered to the vagus nerve. It is usually measured in milliamperes (mA). Typically, we should start with a conservative stimulation strength and gradually increase it over time to achieve optimal seizure control while minimizing side effects.

*Perspective Chapter: VNS Nerve Stimulation in Epilepsy through Lifespan DOI: http://dx.doi.org/10.5772/intechopen.111956*

According to clinical studies, the initial current should start with 0.25 and gradually increase by 0.25 at each visit until reaching the response dose. A computational study showed that a current of 1.75 to 2.0 should be enough to activate all vagus nerve fibers [61]. Specifically, the population-level target output current for VNS therapy is recommended to be set at 1.625 mA [62]. Patients who are gradually adjusted to output currents close to the desired level of 1.61 mA tend to experience fewer adverse events related to stimulation compared to those who are adjusted to higher or lower levels. Therefore, when determining the ideal dosage for individual patients, the primary factor to consider should be the output current. However, it's crucial to acknowledge that certain patients may require VNS output currents that deviate from the target level established for the general population, based on their specific circumstances.

#### **4.2 Adjusting pulse width and frequency**

Pulse width refers to the duration of each electrical pulse delivered by the VNS device, usually measured in microseconds (μs). A typical range for pulse width is 130–500 μs. However, biophysical data and modeling further support the use of pulse widths at or below 250 milliseconds, with lower pulse widths requiring an increase in the selected output current [62].

Frequency refers to the number of pulses delivered per second, measured in Hertz (Hz). Common frequencies range from 20 Hz to 30 Hz. Regarding the frequency of VNS therapy, there is currently insufficient robust data to advocate for the use of frequencies other than 20, 25, or 30 Hz in epilepsy to maximize clinical response. Therefore, these frequencies should be considered as the primary options [62].

Generally, these parameters are more related to the management of adverse effects. However, they may also influence the effectiveness of seizure control.

#### **4.3 Configuring duty cycle**

Duty cycle refers to the proportion of time the VNS device is actively stimulating versus the total time. It is usually expressed as a percentage. The duty cycle can be adjusted to modify the amount of stimulation delivered by the device.

A higher duty cycle means the device is actively stimulating for a larger proportion of time, which may provide increased seizure control but may also increase side effects. Conversely, a lower duty cycle means the device is stimulating for a smaller proportion of time, potentially reducing side effects but potentially compromising seizure control.

The optimal duty cycle for everyone varies, and finding the right balance often requires iterative adjustments during follow-up appointments with the healthcare professional.

There is still no robust evidence relating working time to types of seizures or response to VNS, which should be individualized for each patient.

#### **4.4 Magnet and AutoStim**

The VNS magnet is a handheld device that enables patients to deliver additional electrical stimulation to the vagus nerve when needed. It consists of a small magnet that can be placed over the implanted VNS device, triggering an immediate and short-term increase in stimulation. The VNS magnet offers patients the ability to selfmanage their symptoms and provides a sense of control over their treatment.


#### **Table 1.**

*A step-by-step guide to programming vagus nerve stimulation.*

When the VNS magnet is placed over the implanted VNS device, it activates a magnet switch within the device, leading to an increase in electrical stimulation. This temporary augmentation of vagus nerve activity can help alleviate acute symptoms or enhance therapeutic effects. The magnet switch is designed to ensure patient safety by limiting the duration and intensity of the additional stimulation. So, VNS magnet can be used during seizure events to provide immediate supplementary stimulation, potentially aborting or reducing the intensity of seizures.

Autostimulation is a feature integrated into some VNS devices that enables automatic adjustment of stimulation parameters based on real-time monitoring of heart frequency. By continuously monitoring heart rate, the VNS device can autonomously modulate the stimulation parameters, optimizing therapy delivery without requiring direct patient intervention [63].

Lo et al. showed the added effectiveness of AutoStim in children undergoing VNS treatment. Seizure reduction showed a substantial improvement, increasing from 60 to 83% after replacing the battery with AutoStim. When categorizing the results using the McHugh classification, the percentage of children achieving class I and II outcomes (≥50% seizure reduction) rose from 70 to 90% [64].

The table below shows the suggested evolution of parameters according to visits (**Table 1**).

In summary, the available evidence supports the adoption of current manufacturer dosing recommendations for VNS therapy in epilepsy. Output current is a crucial consideration when determining the optimal dose for individual patients. Further research is needed to explore the relationship between time-to-dose and time-to-response, as well as the impact of dose adjustments in non-responsive and over-responsive patients. Careful consideration of both efficacy and side effects is necessary when determining the parameters for VNS therapy in clinical practice.

#### **5. Conclusion**

The use of VNS in the management of epilepsy throughout an individual's lifespan offers significant benefits and has proven to be an effective treatment option. From early childhood to adulthood and into old age, VNS has shown promise in reducing seizure frequency and improving overall quality of life for individuals with epilepsy.

#### *Perspective Chapter: VNS Nerve Stimulation in Epilepsy through Lifespan DOI: http://dx.doi.org/10.5772/intechopen.111956*

In children, VNS has been found to significantly decrease the number of seizures, allowing for better cognitive development and academic performance. It can also lead to a reduction in medication dosages and side effects, enhancing the child's overall well-being.

During adolescence and adulthood, VNS continues to be a valuable adjunctive treatment for epilepsy. It can provide seizure control, reduce seizure intensity, and lessen the need for rescue medications. Moreover, VNS has shown potential in improving mood and reducing comorbidities such as depression and anxiety, which are often associated with epilepsy.

As individuals with epilepsy age, VNS remains a viable option for seizure management. It has demonstrated long-term efficacy and safety, helping to maintain seizure control and reduce the risk of injury that can arise from seizures. Additionally, VNS offers the advantage of being adjustable and adaptable to changing seizure patterns over time, allowing for personalized treatment.

In conclusion, VNS is a valuable treatment option for epilepsy across the lifespan. Its ability to provide long-term seizure control, reduce medication dosages and side effects, improve mood, and adapt to changing seizure patterns makes it a valuable adjunctive therapy. Further research and advancements in VNS technology will likely continue to enhance its effectiveness and expand its potential benefits for individuals living with epilepsy.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Isabella D'Andrea-Meira Paulo Niemeyer State Brain Institute, Rio de Janeiro, Brazil

\*Address all correspondence to: sadandrea@yahoo.com.br

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 3
