Principles of Treatment

25 CHAPTER

Principles of Treatment

Christa B. Swisher and Rodney A. Radtke

At first glance, the medical management of a patient with seizures appears to be a straightforward process. In most settings, a patient who experiences a first seizure, accompanied by a normal brain MRI and EEG, does not warrant treatment. After a second seizure, anti-epileptic drug (AED) therapy is almost always appropriate. However, there are many factors that go into the decision to initiate AED therapy and the choice of the specific agent. These factors include lifestyle issues, psychosocial issues, acceptability of potential side effects, coadministered medications, and comorbid illnesses. In this chapter, the multiple issues that impact on the management and treatment decision in a patient with epilepsy will be addressed.

NONPHARMACOLOGIC ADJUNCTIVE TREATMENT

Sleep Deprivation

There are many reported precipitants of seizures. Patients with epilepsy commonly report that sleep deprivation results in worsening of their seizure control. In one survey, it was the second most common precipitant after stress (1). This was a common finding among all patients with idiopathic epilepsies, but more common in older than in younger patients. There does not appear to be a sex difference regarding the effects of sleep deprivation on seizure frequency (1). However, sleep deprivation is often associated with stress, therefore making it difficult to isolate the effect of sleep deprivation. An important component of adjunctive seizure control for all patients with epilepsy is minimizing sleep deprivation.

Stress, Depression, and Anxiety

Epilepsy patients report that stress is the most common precipitant for their seizures (2). In addition, studies have found that there is a correlation between higher stress levels and more frequent seizures. Anxiety and depression are frequent comorbidities in this patient population. Studies have shown that depression is significantly more common among patients with epilepsy than among the general population (2). The nature of the association between stress, depression, anxiety, and seizure control is unclear and quite complex. The mechanisms by which stress leads to increased seizure activity may be due to changes in neuroendocrine function, changes in neurotransmitter pathways, changes in gene expression, and possibly structural and functional changes in the brain (2). In addition, the presence of stress, anxiety, and depression may lead to medication noncompliance, which then can contribute to poor seizure control.

It is important for treating physicians to screen for significant life stressors and the presence of depression or anxiety. Methods of stress reduction should be discussed with the patient. If there is a concern for depression or anxiety, pharmacologic treatment or a referral to a mental health professional may be appropriate.

Alcohol

There are little data describing the effects of alcohol on seizure frequency. The relationship between alcohol and seizures is complex because alcohol has variable effects on seizures depending on the dose and duration of alcohol use (acute or chronic use). Patients with epilepsy commonly report that alcohol use results in exacerbation of their seizures. It is difficult to determine if this is a direct effect of alcohol or secondary to sleep deprivation and medication noncompliance that can often accompany the use of alcohol. There have been no data showing that minimal or moderate alcohol use results in precipitation of seizures (3), but this has been evaluated in very few studies. Chronic, heavy alcohol use can certainly lead to alcohol withdrawal seizures. In addition, the sedating effects of many AEDs may be worsened by alcohol. Given that alcohol use is typically underreported and that seizures may be precipitated by alcohol use of any degree, neurologists should council all patients with epilepsy to avoid alcohol use.

FIRST AID

Principles of First Aid

Families must be educated about providing first aid during a seizure so that they can keep the patient safe until emergency medical services (EMS) arrive. The caretaker should ensure that the patient is safe from their surroundings by clearing away any objects that could injure the person during a seizure. They should not try to restrain a person who is actively seizing. The caretaker should not place any objects in the patient’s mouth as this can result in unnecessary injury to the patient or the caretaker. It is recommended to gently turn the patient on their side to prevent airway obstruction and help prevent any emesis from being aspirated. Artificial respirations are rarely needed and should only be performed once the seizure has stopped and if the patient has not resumed breathing. Finally, the patient should not be given any food or water until they are completely back to their baseline mental status (4). The caretaker can administer a rectal benzodiazepine if the patient has been prescribed one and if they have been trained to do so. Oral medications should not be administered during a seizure.

When to Call Emergency Medical Services

The decision regarding when to summon emergency help for a seizure largely depends on the individual situation. EMS should be summoned for anyone suffering their first seizure. Although the seizure may be quite brief, it is important to be evaluated by a physician to possibly identify the cause of the seizure. Neuroimaging is often required to rule out an acute neurologic event, such as an intracerebral hemorrhage. In someone with a known seizure disorder, the decision to call for emergency help is usually based on a few basic rules of thumb that are outlined in Table 25.1 (4). Emergency response services should always be called if a seizure has lasted longer than 5 minutes. The observer of a seizure should be encouraged to time the seizure duration as estimates of seizure duration are almost universally overestimated due to the highly stressful situation. The vast majority of seizures last 1 to 2 minutes, and if a seizure lasts more than 5 minutes it is a situation that may become life threatening. When a seizure has lasted more than 5 minutes, the patient is considered to be in status epilepticus and requires immediate evaluation and treatment. Additional indications for calling emergency personnel are listed in Table 25.1. EMS are most commonly summoned for a second seizure that occurs before return of normal mental status or when an injury may have occurred during the seizure.

TABLE 25.1 Indications to Call Emergency Personnel for a Seizure

If this is the individual’s first seizure

If the seizure lasts more than 5 minutes

If a second seizure occurs before normal mental status returns

If there is prolonged unresponsiveness after the seizure

If an injury was sustained during the seizure

If the individual becomes aggressive after a seizure

If there is a comorbid health concern (pregnancy, diabetes)

WHEN SHOULD AN ANTIEPILEPTIC DRUG BE INITIATED?

Management of the First Seizure

Seizure Recurrence After a First Seizure

The most important piece of information needed when deciding if an AED needs to be initiated is knowing the risk of seizure recurrence after the first seizure. A systematic review determined that the overall risk of seizure recurrence in all age groups following the first seizure was 46% (5). There were two factors that consistently discriminated low-risk patients from high-risk patients: an abnormal EEG and the presence of a neurologic abnormality (ie, mental retardation, cerebral palsy, and neurologic deficit). A normal EEG and the absence of a neurologic abnormality placed patients in the low-risk group (24% seizure recurrence risk). The presence of an EEG abnormality and a neurologic abnormality placed patients in a high-risk group (65% seizure recurrence risk). Partial seizures appeared to be associated with an increased risk of seizure recurrence, but this finding was inconsistent across studies (5).

Based on these results, the majority of patients who present with their first seizure have less than a 50% chance of seizure recurrence, since the majority of patients will have a normal EEG and no neurologic deficits. To avoid long-term AED treatment in a large number of patients that will never have another seizure, general practice is to not initiate AED therapy after a first seizure in the absence of EEG or neurologic changes (6).

Starting an Antiepileptic Drug After a First Seizure

Several prospective trials have evaluated seizure risk over time after a first seizure in various patients groups. The 1-, 3-, and 5-year seizure recurrence risk for patients with either an abnormal EEG or neurologic disorder/deficit is 35%, 50% and 56%, respectively. If both an EEG abnormality and neurologic disorder/deficit are present, the 1-, 3-, and 5-year seizure recurrence risk is 59%, 67%, and 73%, respectively. In both patient groups, treatment with an AED significantly lowered these seizure recurrence risks. Therefore, it is recommended that an AED be initiated after the first seizure only if an EEG abnormality or neurologic disorder/deficit is identified (6).

Seizure Recurrence After Two or More Seizures

In adults, the overall risk of seizure recurrence after a second seizure is over 65% (5). The risk of a third seizure after having two unprovoked seizures is higher in patients with remote symptomatic seizures when compared to patients with idiopathic or cryptogenic seizures. Interestingly, the presence of an EEG abnormality, the presence of a neurologic disorder/deficit, and seizure type were not independently associated with a higher risk of seizure recurrence in this patient population (6). A study of pediatric patients found similar results and identified a 72% recurrent seizure risk after having two unprovoked seizures (6). Given these results, it is recommended that antiepileptic medications be started in all adult or pediatric patients after two unprovoked seizures (6). There are some exceptions to this recommendation. Patients with benign rolandic epilepsy often do not require AED therapy. In addition, patients who have seizures as the result of an identified precipitant may not need AED treatment, especially if this trigger can be easily avoided. It is unclear if patients with an extremely long time period between the first and second seizures require AED therapy.

CONSIDERATIONS WHEN DECIDING TO START TREATMENT

When a patient and physician are deciding if an AED should be initiated, there are several points to consider regarding the benefits and risks of treatment. The most important risks of ongoing recurrent seizures are death, physical injury to the patient or others, brain injury, driving restrictions, and adverse psychosocial consequences.

Risk of Death

There are two main causes of death specific to the epilepsy patient population: sudden unexpected death in epilepsy (SUDEP) and trauma related to seizures. Epilepsy patients have a 2.6-fold increased risk of premature death when compared to the general population. SUDEP is the most frequent cause of epilepsy-related deaths (7). The incidence of SUDEP is about 9 per 1000 patient-years in patients with refractory epilepsy (7). A single mechanism to explain SUDEP has not been identified. Potential mechanisms are arrhythmia, respiratory insufficiency, autonomic dysfunction, and cerebral dysfunction (7). It is likely that a combination of these abnormalities leads to SUDEP. Effective treatment of seizures reduces the risk for SUDEP, and this data provides strong support for the initiation of an AED after two unprovoked seizures.

Risk of Physical Injury

Several retrospective studies and one prospective study have evaluated the risk of injury in patients with epilepsy. The largest study of almost 1000 adults and children (>5 years old) found that patients with epilepsy have a significantly higher probability of accidents and injury than controls (27% vs. 17%) (8). Although many of the injuries in this patient population are minor, more concerning injuries including submersion injury, burns, fractures, head injuries, motor vehicle accidents, dental trauma, and soft tissue injury do occur. Submersion injury, which is associated with a high mortality, is 7.5 to 13.9-fold higher in the pediatric epilepsy patient population when compared with age-matched controls (8). The risk of fracture in adults and children is elevated twofold (8). This is discussed in more detail in Chapter 36, Bone Health. The risk of motor vehicle accidents is only slightly higher in epilepsy patients when compared with controls but limited difference is likely in part due to the driving restrictions placed on patients with uncontrolled seizures (8).

Risk of Neuronal Damage

Numerous animal and human studies have found an association between recurrent seizures and neuronal injury, although direct causality has not been established. Findings in humans that support the hypothesis of seizure-induced neuronal damage include hippocampal neuronal loss, elevation in makers of neuronal injury, cognitive and memory decline, behavioral problems in children, hippocampal atrophy, and cerebral and cerebellar volume loss (9). While individual seizures are not likely to result in any evident neuronal injury, the cumulative effects of uncontrolled seizures can be identified in many patients over time.

Psychosocial Consequences of Epilepsy

There are numerous psychosocial difficulties that affect children and adults with epilepsy. Although treatment with AEDs does not definitively reduce the risk of these issues, consideration of these factors may be important when deciding whether to initiate treatment. It should be noted that some of these psychosocial difficulties are directly related to side-effects of the AEDs themselves. The most frequently encountered psychosocial difficulties in patients with epilepsy are stigma, loss of control, depression, memory deficits, reduced quality of life, anxiety, cognitive deficits, and emotional problems. Inability to drive often adds to a sense of loss of control and often compromises employment opportunities.

DECIDING WHICH ANTIEPILEPTIC MEDICATION TO INITIATE

Once it has been decided that AED therapy will be initiated, there are many factors to take into consideration for AED selection. There are numerous AEDs to choose from, and AED selection should be tailored to each individual patient. Many new AEDs have been approved by the FDA, making this selection process even more complex. A list of factors to consider during AED selection is shown in Table 25.2.

The type of epileptic disorder will play a large role in determining the type of AEDs selected. There is never one sole AED indicated for a certain type of epileptic disorder. However, there are some general recommendations to help guide the selection process. Some AEDs have been found to only be effective in the treatment of partial-onset seizures. Other AEDs are felt to have broad-spectrum efficacy against both partial-onset and generalized epilepsy. Other factors to take into consideration with initial AED selection are medication safety, cost, patient preferences, side effects, ease of use, and possible interactions with other medications.

TABLE 25.2 Factors Affecting AED Selection