CHAPTER

Etiology

Amit Verma

Determining the etiology of epilepsy is an extremely important part of managing a patient’s seizures. A common question most patients have when they see a specialist is what caused their seizure. Several pieces of demographic information including age, comorbid conditions, and geographical location can help in suggesting an etiology but oftentimes it is the combination of these with imaging that eventually establishes the cause of a patient’s seizures. It is extremely important to establish the etiology because that can lead to a more defined treatment protocol for a particular patient and can help establish the prognosis for long-term treatment. In general terms, genetic and developmental etiologies are common in the pediatric age group and etiologies such as traumatic brain injury (TBI), central nervous system (CNS) infections, brain tumors, and cerebrovascular disease are more common in older individuals. With the advances in neuroimaging, it has become possible to identify lesions in patients that were otherwise not visible. However, despite these advances, it is still not possible to determine the etiology in a majority of patients.

There are several studies that have characterized the incidence and etiologies of epilepsy in specific age groups. In one community-based epidemiological study, 60% of patients with a new diagnosis of epilepsy had partial seizures (1). Cerebrovascular disease was the most common etiology accounting for 11% of cases, followed by neurological deficits from birth injuries, mental retardation, and/or cerebral palsy. Cerebrovascular disease, as expected, was more common in the older population and birth injuries were more common in children. It was also noted that the risk of developing epilepsy was high in the pediatric population, plateauing during adult years, and then increasing again in the elderly. In the British National General Practice Study of Epilepsy, etiologies were also found to vary depending on the age group (2). While vascular disease accounted for seizures in 15% of patients, that specific etiology accounted for seizures in 49% of patients if they were above the age of 60 years. Similarly, tumors accounted for seizures in 6% of patients overall, but 11% of those patients above the age of 60. These and other etiologies will be discussed in detail in this chapter.

RISK FACTORS

Risk factors for developing epilepsy are often considered synonymous with the etiology. It is worth noting however that just because a specific risk factor has been identified in a particular patient, it may still not be the actual cause for the development of seizures and epilepsy. The identified risk factor, such as a nervous system infection or alcohol use, may simply be the precipitating factor causing seizures in a patient with another underlying etiology.

ETIOLOGIES

There are many causes of epilepsy in the adult population. Common causes include traumatic brain injury (TBI), cerebrovascular disease, brain tumors, cognitive impairment, dementia and neurodegenerative disorders, alcohol- and drug abuse–related seizures, CNS infections and electrolyte disturbances (3). These etiologies will be discussed in further detail in the following sections.

Traumatic Brain Injury

TBI is an extremely common yet potentially preventable cause of epilepsy. It increases the risk of seizures both acutely and remotely, and the highest risk is associated with penetrating brain injuries. There has been increasing interest in TBI as it relates to epilepsy because of war-related injuries. The improvements in overall survival following blast and blunt trauma injuries in the battlefield have resulted in a greater number of veterans who have long-term effects of TBI.

There are several aspects of the treatment of posttraumatic epilepsy that have received significant attention. One is the research focused on using antiepileptic drugs (AEDs) to prevent the development of epilepsy even before seizures have occurred. Other studies have focused on using AEDs once a seizure has occurred. Phenytoin has been shown to prevent early seizures (in the first 7 days) after moderate-to-severe TBI but was not effective in preventing the development of epilepsy at 1 and 2 years (7). Many other agents have been studied, including valproic acid, phenobarbital, carbamazepine, and magnesium, with similar results showing that they were mostly ineffective in the prevention of developing epilepsy.

Cerebrovascular Disease

Different types of cerebrovascular diseases can be the responsible etiology for epilepsy, depending on the age group. In premature infants, periventricular hemorrhages can occur that increase the risk of seizures in later life. Birth injuries with ischemic–hypoxic injury will increase the risk of seizures as well. In younger patients, developmental abnormalities such as arteriovenous malformations (AVMs) or cerebral cavernous malformations are common causes of seizures. Occlusive cerebrovascular disease and intracranial hemorrhage are common causes of seizures in older patients.

Occult AVMs can sometimes be seen after a first-time seizure. In a population-based study, the 5-year risk of a first seizure was 8% for an AVM and 4% for cerebral cavernous malformation (8). The presence of an intracranial hemorrhage or neurological deficit raised this risk for AVMs to 23%. In the same study, the 5-year risk of developing epilepsy following the first seizure was 58% for AVMs and 94% for cerebral cavernous malformations. It is important to note that the risk of seizures is with arterial malformations, and the risk is typically low with venous malformations. Even though the risk of hemorrhage with venous malformations is low, there are sometimes small areas of dysplastic tissue that can be present, which can sometimes cause seizures.

Occlusive cerebrovascular disease or stroke is the most common cause of seizures in adults over the age of 60 (9). Stroke is a common enough cause in older patients that a detailed and thorough cerebrovascular workup is warranted when they present with seizures. It has also been found that the risk of a major stroke following a first-time seizure after the age of 65 is approximately 2 to 3 times the general population. Stroke can be associated with both an increased risk of acute seizures and remote seizures. A history of stroke is associated with a significant increase of the lifetime risk of developing epilepsy (10). Risk factors for stroke such as elevated total cholesterol and left ventricular hypertrophy are also associated with an increased risk of seizures. The incidence of early seizures following stroke has been found to be between 2.4% and 5.4%. The risk of remote seizures has been found to be between 3% and 4.5%. Early postischemic seizures, size of stroke, and cortical signs during the stroke increase the risk for subsequent development of epilepsy. Secondarily generalized seizures are very common in the setting of an acute stroke. Status epilepticus can also be a presenting symptom of stroke. In a status epilepticus study, approximately 50% of adult cases were caused by a stroke (11). Status epilepticus after stroke is associated with higher functional disability, and early-onset status epilepticus after stroke is associated with a higher mortality than late-onset status epilepticus. Several studies have shown that larger infarcts and hemorrhagic transformation are associated with a higher risk of developing seizures.

The treatment of seizures and in the setting of a stroke carries many challenges. Seizures are often considered a contraindication to the use of tissue plasminogen activator (TPA) in the setting of an acute stroke. The use of anticoagulation becomes worrisome because of the risk of bleeding in the setting of a seizure. Many injuries can occur during a seizure, and the increased risk of bleeding may contribute to not only increased morbidity but also possibly mortality. Many of the AEDs can also influence the efficacy of anticoagulants and may require frequent monitoring of prothrombin time (PT) and international normalized ratio (INR).

Brain Tumors

The most common seizure type associated with brain tumors is focal seizures and secondarily generalized tonic–clonic seizures. The specific semiology is consistent with the location of the tumor. Certain tumors such as hypothalamic hamartomas may be associated with specific seizure types like gelastic seizures. Tumors arising from the medial temporal region may be associated with olfactory auras, and their semiology is consistent with temporal lobe epilepsy.

The treatment of seizures associated with brain tumors is related to the treatment of the brain tumor. Complete resection of the tumor often results in resolution of the seizures. One specific exception is the removal of meningiomas. Despite removal of these tumors, there is still a high risk of development or persistence of seizures. This is related to the cortical injury that occurs because of the meningiomas.

Cognitive Impairment

Cognitive impairment is often thought to be a strong risk factor for the development of epilepsy. Often cognitive impairment, especially in the pediatric population, is associated with other injuries such as perinatal hypoxia, metabolic disorders, neuronal migration disorders, and brain malformations. A common pediatric condition that is associated with cognitive impairment is Lennox-Gastaut syndrome (LGS) (12). This syndrome comprises patients with multiple seizure types, cognitive impairment, and EEG findings that show slow spike wave activity. LGS is often diagnosed between the ages of 2 to 8 years, and 80% of these patients will continue to have seizures as adults. In these patients, the cognitive impairment typically worsens with age.

Dementia and Neurodegenerative Disorders

Dementia due to cerebrovascular disease carries the same risk of developing seizures as those related to the underlying cerebrovascular disease. There has been an increased risk of seizures and development of epilepsy in patients in the later stages of Alzheimer’s disease. Patients who were eventually proven to have Alzheimer’s disease on autopsy had a 10-fold increased risk of unprovoked seizures. The seizures that occur in the late stages of Alzheimer’s disease are often generalized tonic–clonic. Even though there may be temporal lobe atrophy in these patients on neuroimaging, the seizures are often not of temporal onset. The diagnosis of Alzheimer’s disease or a diagnosis of dementia is associated with a six-fold increased risk of unprovoked seizures (13).

Alcohol and Drug Abuse-Related Seizures

Although the most common description for alcohol-related seizures is in the setting of alcohol withdrawal, seizures associated with alcohol use may occur in the setting of intracranial hemorrhage, subdural hematomas, acute CNS infection, stroke, metabolic disturbance, or TBI. The term alcohol-related seizures is often reserved for seizures that result as a direct consequence of alcohol use, especially alcohol withdrawal. Alcohol withdrawal seizures are most often generalized tonic–clonic, typically occurring between 6 and 36 hours after the last drink and are often multiple. Chronic daily drinking can cause seizures as well. In patients who present with alcohol-related seizures, it is important to obtain a head computed tomography (CT) to rule out acute injury. Patients who present to emergency departments often do not have any accompanying relatives or friends and can have subdural hematomas or other trauma-related findings (14).

It is important to consider a genetic generalized epilepsy in a patient presenting with an alcohol-related seizure. Alcohol use can often precipitate seizures in patients with juvenile myoclonic epilepsy. In these patients, the first seizure typically occurs in the setting of sleep deprivation and alcohol use. A history of myoclonus and generalized spike-wave discharges recorded on EEG can confirm the diagnosis.

Several recreational and prescription medications have been associated with an increased risk of seizures. Prescription stimulant medications such as dextroamphetamine, methamphetamine, methylphenidate, and pseudoephedrine and recreational drugs such as cocaine and ecstasy are commonly implicated in causing seizures. The risk with prescription stimulant medications that are used to increase alertness in a variety of neurological disorders is often considered very low and seizures mostly occur in the setting of overdose. The risk of seizures in cocaine-intoxicated patients can be up to 9%, and it appears that the risk is higher after smoking crack than after snorting cocaine. Overdosage with ecstasy can cause seizures, coma, and death. Opioids such as heroin rarely cause seizures, and if a patient presents with seizures after heroin use, other etiologies should be considered. Phencyclidine or Angel dust overdose can also cause seizures, status epilepticus, and myoclonus.

Marijuana has recently gained notoriety as a legal recreational drug in some states. With its increasing availability, renewed attention has been focused on its use in patients with epilepsy. In animal studies, cannabidiol has been found to be consistently anticonvulsant. Human data are currently lacking, but studies are underway to assess its utility in various types of epilepsies.

There are a variety of reasons why CNS infections can increase the risk for seizures. Increased intracranial pressure, inflammation, and subsequent occlusion of blood vessels, inflammation of the cortical region and mass effect can cause seizures. Viral, bacterial, fungal, and parasitic infections can result in seizures.

A variety of viruses can cause inflammation of the brain. West Nile, Japanese, Eastern equine, and herpes simplex type I (HSV-1) encephalitides are commonly associated with seizures. HSV-1 encephalities often affects the perisylvian region with hemorrhages in the temporal region. EEGs in these patients often demonstrate periodic discharges in the temporal region. With encephalitides related to other viruses, the EEG often shows either focal or generalized periodic discharges.

Bacterial infections that are associated with seizures include Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumonia, and others. Seizures can occur in up to 40% of patients acutely, and the seizures are often generalized tonic–clonic. Brain abscesses can result from emboli from a distant source such as an infected heart valve or as a result of sepsis. Most abscesses occur at the cortical–subcortical junction and frequently cause seizures. CNS tuberculosis is a common cause of seizures in developing countries. Patients who have CNS tuberculosis often have cranial nerve involvement and are either immunocompromised or from developing countries.

The most common parasitic infection that is associated with seizures is neurocysticercosis. The responsible parasite is Taenia soulim. It is a very common cause of seizures in developing countries, accounting for up to 30% of epilepsy cases. Seizures can occur at any stage of the cycle of the parasite. Calcified cysticerci are associated with astrocytic gliosis, which is thought to be the etiology of the seizures. Diagnosis is made by neuroimaging and cerebrospinal fluid (CSF) serology. Treatment of neurocysticercosis can result in reduced risk of subsequent seizures.

Electrolyte Disturbances

Seizures secondary to electrolyte disturbances are common. Common electrolyte disorders that can result in seizures include hyponatremia, hypomagnesemia, uremia, and hepatic failure. Hyponatremia and hypomagnesium are possibly the most well characterized (15).

Hyponatremia may have different etiologies. Severe hyponatremia defined as serum sodium levels less than 120 mEq per liter can result in neurological symptoms especially if it occurs acutely. Patient may develop cerebral edema and seizures, and in severe cases this may lead to death. Hyponatremia is sometimes also be seen with AED therapy, especially carbamazepine, oxcarbazepine, and eslicarbazepine acetate. The risk of clinically significant hyponatremia, which is defined as less than 125 mEq per liter, is approximately 7% to 8% with carbamazepine and oxcarbazepine and approximately 1.5% with eslicarbazepine acetate. Seizures have also been reported with uremia and less frequently with other metabolic disturbances.