Epilepsy and Other Seizure Disorders






Abstract

Epilepsy is a broad umbrella term defining a group of neurological diseases that present with recurrent episodes of seizures. As one of the most prevalent neurological disorders, epilepsy is affecting an estimated 50 million individuals worldwide. Epilepsy is caused by abnormal electrical activity of the brain, which results from uncontrolled discharges and hyperexcitability of groups of neurons. Seizures are characterized by sudden involuntary convulsions, and in some cases, small periods of unawareness that may accompany random, uncharacteristic behaviors in the patient. Epilepsy is a disorder that can present at all ages, affecting both males and females, and commonly caused by genetic predisposition, congenital abnormalities, and antenatal or perinatal injury. The overall objective in management and treatment of epilepsy is complete seizure control for an improved quality of life. Being aware of the health status of a patient diagnosed with epilepsy is critical for health professionals. It is vital that the coordination of care between health professionals’ teams exists to ensure the practitioner has all the required information about the patient before initiating any clinical procedures. Appropriate treatment planning and coordination with other health practitioners will ensure the patient’s general and dental health is adequately sustained and potential dangers minimized.



Background of Epilepsy and Other Seizure Disorders


Epilepsy, one of the most prevalent neurological disorders, is a broad umbrella term that defines a group of diseases that present with recurrent episodes of seizures, affecting an estimated 50 million individuals worldwide. They are regarded as a collection of conditions with different pathophysiologies, multiple manifestations, and diverse etiologies.1 Seizures are characterized by sudden involuntary convulsions, and in some cases, small periods of unawareness that may accompany random, uncharacteristic behaviors in the patient. While the terms epilepsy and seizures tend to be used synonymously, they, in fact, describe different but related medical situations. Any healthy brain can be provoked to generate a seizure, be it through drugs, metabolic changes, or trauma. Such self-provoked seizures are not classified as epileptic. Epilepsy is exclusive to seizures that are not self-provoked, and there is an underlying neurological reason for the episodic attacks.2 Occurrences of repeated seizures lead to the potential diagnosis of epilepsy; however, many other factors must be considered in order for a patient to be diagnosed with epilepsy, including the frequency of unprovoked seizures and risk of recurrence in patients.



Description of Epilepsy and Other Seizure Disorders


Epilepsy is caused by the abnormal electrical activity of the brain. Specifically, the disease state in the brain results from uncontrolled discharges from groups of neurons—hyperexcitability of the neurons of the cerebral hemispheres.3 The potential cause of such abnormal brain activity is vast and extensive and may be different for each patient. Some common causes include genetic predisposition, congenital abnormalities, and antenatal or perinatal injury.3 Epilepsy is a disorder that can present at all ages, affecting both males and females, with males at a slightly higher risk.3


Many patients experience warning signs before an impending seizure, such as light-headedness or nausea, usually occurring immediately beforehand. Epileptic attacks can involve several elements alongside the typical uncoordinated twitching of muscles and spastic contractions. Distorted sensory phenomena, altered consciousness, and inappropriate behavior tend to present as well. Postictal (the altered state of conscious after an epileptic seizure) symptoms may comprise headaches, confusion, muscle ache, and drowsiness.3 This tends to last between 5 and 30 minutes, but sometimes longer in the case of larger, more severe seizures. With such clinical manifestations of epilepsy, many physical and psychosocial consequences may arise. As a result of the lack of consciousness, patients may seriously injure themselves with their behaviors, potentially leading to death. Epileptic patients may also suffer from stigma and as a result educational and vocational impairments, heavily impacting their quality of life.


Seizures, epilepsies, and epilepsy syndromes have been categorized in many forms throughout the years. Classification is of importance, as it is required for correct evaluation and management of patients. Seizures are classified as generalized, simple partial, or complex partial, based on the symptoms observed during the seizure. There are fundamental physiological differences between them, which explain their wide range of clinical manifestations and varied responses to different medications. Generalized seizures involve a loss of consciousness at the onset. The entire cortex is affected concurrently; therefore, cortical neurons that maintain consciousness are unable to function. They are in most cases idiopathic and begin in childhood.4 Consciousness is retained during partial seizures. Simple partial seizures are localized to a small discrete area of the brain, and the subsequent symptoms are location-dependent, involving only a few muscles on the face, arms, or legs. Seizures arising in the visual cortex of the occipital lobe cause visual abnormalities, while those in the primary motor cortex of the frontal lobe affect hand movements. Complex partial seizures are characterized by an alteration of consciousness, often awake but unresponsive to external stimuli. Automatism, repetitive purposeless movements, such as lip smacking, hand rubbing, and squeezing, may also manifest.


Treatment of epilepsy involves a number of factors that must be considered. Many antiepileptic drugs (AEDs) exist; however, prescription is based on detailed evaluation of the epileptic patient, which indicates the positive effects of the prescribed drugs will outweigh potential side effects that may manifest. Furthermore, appropriate management of epilepsy extends beyond the prescription of antiepileptic medications; a holistic approach must be adopted—one that addresses social, educational, and psychological issues that the patient may face.



Epidemiology of Epilepsy


The prevalence of epilepsy is defined as the proportion of those diagnosed with the condition relative to the entire population. The incidence of epilepsy is the rate of diagnosing new cases of the disease within a specified timeframe. The disease is not evenly distributed, appearing more prevalently in developing countries, particularly among individuals of low socioeconomic status, which may be caused by limited access to health treatment, higher incidence of road accident injuries, decreased availability of preventative health measures, and exposure to certain endemic factors such as malaria.5


Many studies report the prevalence and incidence of epilepsy to be slightly more pronounced in males, but these differences are statistically insignificant. The prevalence of the disease increases with age in developed countries, while in developing countries it is most prevalent in teenagers and young adults. The incidence is high in infancy and early childhood. Approximately 80% of people with epilepsy in developing countries do not receive appropriate treatment.5


Epidemiological differences associated with race are poorly understood, as research comparing ethnic differences within regional populations has not been extensively conducted. The accuracy of epidemiological studies may be inaccurate due to underreporting, as cultural beliefs regarding the causes of the condition lead to heavy stigmatization in certain populations.5



Etiology and Pathogenesis of Epilepsy


Epilepsy is a noncommunicable condition that may be etiologically described as idiopathic, symptomatic, or cryptogenic (Fig. 7.1). Idiopathic forms, which make up approximately 60% of incidences of the disease, have a genetic basis and symptoms manifest early in life. The genetic disorders may be directly related to neuronal dysfunction or may be the result of cortical developmental abnormalities, cavernous and arteriovenous malformations, or neurocutaneous syndrome. The syndrome-specific effects may be the result of a single gene or may follow a complex pattern of inheritance, due to multiple genes and environmental factors.6



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Fig. 7.1 Etiology of epilepsy.


Symptomatic epilepsies are predominantly acquired following damage to the brain from injuries, tumors, or strokes. Infection of the brain by bacterial, viral, and parasitic organisms may also result in an epileptic disease state, such as in meningitis, encephalitis, or neurocysticercosis. Cryptogenic epilepsies are those to which a cause cannot be readily identified, but which may be eluded upon further investigation.6


The incidence of epilepsy is close to 30% in people suffering from brain tumors, whether benign or malignant.7 The epilepsy risk is dependent on variables such as the presence of cerebral hemispheric dysfunction, hemorrhagic lesions, multiple metastases, and tumor type, grade, or location.8 A tumor located in the temporal cortex, around the central sulcus or in supplementary areas, is associated with the highest risk for epilepsy development. High-grade malignant tumors grow rapidly and destroy nearby neurons rather than stimulate epileptogenesis; the slow progression of low-grade tumors results in more time for the disease to develop. The comparatively high metabolic rate may lead to hypoxia and interstitial acidosis, which may contribute to disease progression.5 ,​ 8 ,​ 9


Brain injury has been identified as one of the most vital risk variables for epilepsy development, with up to 20% of epilepsy cases attributed to damage to the brain. The risk of epilepsy is largely dependent on the extent of the injury. Mild brain injuries, characterized by loss of consciousness, amnesia, confusion, and focal temporary neurological deficit, double the epilepsy risk, while a severe brain injury involving intracranial hemorrhage or brain contusion results in a sevenfold higher risk. The risk is highest in the first year following the injury but remains significant even a decade later. The age of the person at the time of the injury is also a factor. Those aged over 15 are more likely to develop epileptic symptoms, as are those with a family history of the disease.6


Epilepsy may develop after brain injury as a result of direct cerebral damage or as a consequence of a number of interrelated processes such as edema, ischemia, iron deposition from extravasated blood, or accumulation of glutamate leading to excitotoxicity. Viral meningitis is a common cause of fever-associated seizures. Epilepsy risk is six times higher in those who convulse during meningeal acute illness. Herpes simplex virus is the most common viral epileptogenic agent. The risk is greatest during the first 5 years following infection but remains persistent for 20 years due to the possibility of reactivation of the virus. This may be related to a series of changes such as an increase in proinflammatory cytokines or activation of the immune system.6 ,​ 9


Epilepsy also arises as a consequence of bacterial brain abscesses resulting from head trauma, blood-borne infections, or complications following brain surgery. The risk is greatest in the 3 years following abscess formation. Streptococcus, Staphylococcus, and gram-negative bacilli are the species typically involved.6



Genetic Component of Seizure Disorders


Although 70 to 80% of cases of epilepsy in the United States have a genetic basis, there is not one uniform genetic disorder responsible for each case of epilepsy.10 ,​ 11 Genetic syndromes involved in epilepsy may be the result of copy number variants, deletions of genes, or single-gene mutations.10 ,​ 11 ,​ 12 SCN1a and PCDH19 are two genes that, when mutated, can manifest into a variety of epileptic outcomes that can differ in relation to seizure type, severity, prognosis, and age of onset.10 ,​ 11 ,​ 12 ,​ 13 ,​ 14


SCN1a mutations can lead to the development of a variety of epileptic conditions including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome (DS).12 ,​ 14 DS and GEFS+ follow a dominant inheritance pattern or can be de novo mutations.14 SCN1a is a gene on chromosome 2q24 that forms part of a group of nine genes encoding a functional subunit of voltage-gated sodium ion channel 3. Consequently, mutations in the SCN1a group result in a defective sodium ion channel.12 ,​ 14 The sodium ion channel is responsible for the depolarization of the plasma membrane when an action potential propagates through a neuron.14 As the gene can be mutated at any point along its chain, the mutation can be excitatory or inhibitory of central nervous system activity.14


Eighty-five percent of SCN1a mutations result in Dravet syndrome. DS is usually the manifestation of a sodium ion channel that has completely lost its function and is associated with intellectual impairment, mental regression, and early onset of seizures.11 ,​ 14 Thus, it is a more severe condition when compared to GEFS+ as symptoms other than just seizures are involved. In addition, the degree to which the seizures affect the quality of life of the individual is more severe.12 ,​ 14


Over 50% of the mutations of DS are either frameshift, nonsense, or splice site mutations.14 Frameshift mutations are the addition or deletion of one or more base pairs during transcription, causing misreading of the genetic code during translation. Nonsense mutations result in a premature stop codon, completely stopping the translation process. Splice site mutations alter where the splicing will occur during translation, resulting in completely different introns and exons and consequently a totally different protein.


Ten percent of SCN1a mutations lead to GEFS+1, an autosomal-dominant disorder.10 GEFS+ is commonly the outcome of a missense mutation, in which an error of a single nucleotide results in a different amino acid on the mRNA strand. The resulting protein forms a semifunctional sodium channel.12 ,​ 14 A defective voltage-gated sodium ion channel may not close once a neuron is depolarized, which leads to hyperexcitable neuronal pathways. Hyperexcitable brain activity can cause spontaneous seizures.10 ,​ 12 Seizures may manifest in individuals with GEFS+, but the overall disease is generally less severe than DS as it is not associated with mental disability or refractory seizures.14


Protocadherin 19 (PCDH19) is a gene on chromosome Xq22.3, which encodes for a transmembrane protein important for neuronal development and the formation of connections between synapses within the brain.13 During brain development, the transmembrane protein is highly expressed as neuronal pathways are being formed.13 Mutations in this gene may result in the development of Epilepsy and Mental Retardation Limited to Females (EFMR).


Typically, X-linked inheritance refers to a gene located on the X chromosome. Therefore, males have an increased risk of developing the associated phenotype associated with the gene mutation, as they inherit only a single copy of the mutated allele, unlike females who possess two copies of the X chromosome. This inheritance pattern is commonly seen in color blindness, which affects more males than females. Interestingly, PCDH19 displays X-linked inheritance patterns opposing this standard pattern, and affects only heterozygous females.13 The disease can be carried through families by asymptomatic male carriers. The reason for this phenomenon is still unknown, but may be the result of a non-paralogous protocadherin gene or other compensatory or rescue factor present on the Y chromosome of males.13 Epilepsy associated with a PCDH19 mutation is usually associated with intellectual retardation, and brain developmental defects as neuronal development and the formation of synaptic connections are compromised.13



Diagnostic Evaluation of Epilepsy and Seizures


The constitution of what defines epilepsy and seizures involves brain dysfunction, which may manifest as a result of numerous factors. One such definition of an epileptic seizure is “a transient occurrence of signs and symptoms due to abnormal excessive or synchronous neuronal activity in the brain.”15 As it is difficult to identify excessive neuronal activity directly, diagnosis of the seizure-related disease states relies on professional clinical judgment and findings based on medical history, physical examination, and investigation. It is challenging to accurately assess these conditions, as it is not always possible to obtain accurate information regarding the patient’s medical history and to ascertain why such a disorder may manifest.15


A more practical definition used in a clinical setting sees epilepsy as a disease when two unprovoked seizures are occurring more than 24 hours apart, or one unprovoked seizure and a probability of recurrent seizures over the next 10 years.15 Understanding of the classification of seizures and epilepsy is crucial for evaluating a patient’s medical history during diagnosis (Fig. 7.2).15 Partial seizures are localized to an area of the brain and may spread. If a patient is conscious, then the diagnosis of a simple partial seizure can be made. Contrary, a generalized seizure does not have a focal onset and awareness by the patient is lost immediately.16 Generalized seizures are further classed as absence, petit mal, grand mal, myoclonic, atonic, or tonic seizures. It is of importance for a clinician to be aware of conditions that may stimulate seizures, initially addressing if the episode represents a seizure and whether it was provoked.15


Dec 13, 2021 | Posted by in NEUROLOGY | Comments Off on Epilepsy and Other Seizure Disorders
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