Neurology: A Clinician's Approach (Cambridge Medicine (Paperback)), 1st Ed.

20. Seizures and epilepsy

The first seizure

An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal, excessive, synchronous neuronal activity in the brain.1 According to a large epidemiologic study conducted at the Mayo Clinic, the annual incidence of seizures is approximately 61 in 100 000 with people at the extremes of age being at the greatest risk.2 An organized five-step approach is helpful in evaluating patients with a first-time seizure:

1. Get the best account of the seizure manifestation (ictal semiology) from a firsthand observer.

2. Determine whether the event was actually a seizure.

3. If it was a seizure, determine whether it was the first one.

4. Define the etiology of the seizure.

5. Determine whether treatment is needed, and if so, what agents are appropriate.

Ictal semiology

Generalized tonic–clonic seizures

The generalized tonic–clonic seizure (GTCS) is the most easily recognized type of seizure, and the one that most frequently leads to emergency room consultations. Because a GTCS is usually quite alarming, eyewitness accounts are often unreliable, even when provided by a physician or nurse. Sometimes, the only available information is that the patient passed out and shook. Although there is considerable heterogeneity, a GTCS in an adult generally lasts for an average of about a minute and may consist of some or all of the following phases3:

1. Partial seizure. A GTCS may be generalized from onset, or it may arise from a partial seizure (see below) in a process known as secondary generalization. If this partial seizure is a simple partial seizure, the patient may remember it after the seizure has finished. However, patients will not be able to remember a GTCS that is generalized from onset or that develops from a complex partial seizure.

2. Onset of generalization. After the partial seizure ends, secondary generalization is usually heralded by a forced head movement to one side (versive movement) or by a brief vocalization.

3. Pretonic clonic phase. In approximately half of patients, generalization begins with irregular, asymmetric clonic jerking of the extremities.

4. Tonic phase. This is a generalized and sustained contraction of all the muscles in the body, and may be accompanied by some clonic jerking.

5. Tremulous phase. This phase is characterized by fast muscle shaking, but is too rapid to be classified as clonus.

6. Clonic phase. This is the final phase of the seizure itself, characterized by slower muscle jerking, which eventually decreases in frequency before stopping.

7. Postictal state. After a GTCS, the patient lies limp, in a deep sleep. After several minutes, he awakens and is confused and may have a headache and muscle pain from the seizure.

Partial seizures

Partial seizures begin in a focal area of the brain and are the most common seizure type in adults. Because they may arise from any area of the cerebral cortex, partial seizures produce a vast array of motor, sensory, perceptual, and behavioral manifestations. Partial seizures may be divided into simple partial seizures (SPSs, also called auras) in which consciousness is preserved, and which therefore can be described by the patient, and complex partial seizures (CPSs), which are associated with an impairment of consciousness.

Simple partial seizures

Motor seizures

Simple partial seizures (SPSs) arising from the motor cortex may take the form of forced head deviation to one side, speech arrest or vocalizations, stereotyped limb or facial movements such as twitching or jerking, or coordinated, almost purposeful-appearing movements. When a motor seizure remains restricted to one area of the cortex, it produces only a single manifestation. If the electrical activity spreads to adjacent areas of the motor cortex, a Jacksonian march in which there is sequential spread of the seizure into the ipsilateral face, arm, and leg occurs over seconds. Focal motor seizures may be followed by Todd’s paralysis in which muscle weakness persists for several minutes to hours.

Sensory seizures

Simple partial seizures may affect any sensory modality. Common sensory auras include visual (seeing spots, stars, or bright lights), auditory (ringing, buzzing, or musical sounds), somesthetic (tingling, numbness, or electrical sensations), olfactory (the smell of burning rubber or other foul odors), gustatory (acidic, bitter, or sweet tastes), vestibular (vertigo), or epigastric (the sensation of rising in the abdomen, descending a rollercoaster, or having butterflies in the stomach). Auras that involve the primary sensory cortex are generally unformed and primitive, whereas those that involve the higher-level association cortex or mesial temporal structures are more detailed.

Behavioral and psychic seizures

Simple partial seizures may also produce a wide variety of behavioral or psychic phenomena. Déjà vu is the sensation of visual familiarity whereas déjà entendu is the sensation of auditory familiarity. Jamais vu and jamais entenduare feelings of unfamiliarity in the visual and auditory realms, respectively. Patients with temporal lobe SPS may also describe a dreamlike or disconnected state, or a sense that they are watching themselves (autoscopy). Depersonalization, fear, pleasure, religious ecstasy, and forced thinking are also well-described psychic auras that arise from the temporal lobes.

Complex partial seizures

Complex partial seizures (CPSs) are partial seizures that are characterized by impairment of consciousness. They frequently arise from SPSs, and may progress to GTCSs. Complex partial seizures are often accompanied by automatic, repetitive, stereotyped behaviors known as automatisms. Automatisms arising from the temporal lobe tend to be simple and include lip smacking, chewing, swallowing, grasping, fumbling, blinking, and eye fluttering. Automatisms arising from the frontal lobe are usually more complex and often appear purposeful. Orbitofrontal automatisms may have bizarre characteristics including bicycling movements of the legs, pelvic thrusting, and sexual activity mimicry.

Absence seizures

Absence seizures begin in childhood or adolescence. In some cases, they are misdiagnosed as CPSs and the correct diagnosis is not made until adulthood. Typical absence seizures last for just a few seconds, and are characterized by unresponsiveness, a fixed blank stare, eye fluttering, and facial twitching.4 Accompanying seizure manifestations may include increases or decreases in postural tone, brief clonic movements, and automatisms that resemble those of patients with CPSs. Patients with absence seizures may or may not be aware of the attack, and resume preictal activities as soon as the seizure is completed.

Myoclonic seizures

Myoclonus is a sudden, involuntary, brief jerk of a muscle or group of muscles which is discussed in further detail in Chapter 14. Although myoclonic seizures tend to occur in children, they may also begin in adolescents or young adults as part of juvenile myoclonic epilepsy (see below). The progressive myoclonic epilepsies are a group of uncommon degenerative disorders, which include adult-onset neuronal ceroid lipofuscinosis, Lafora body disease, Unverricht–Lundborg disease, and myoclonic epilepsy with ragged red fibers (MERRF).

Atonic seizures

Atonic seizures are associated with mental retardation and Lennox–Gastaut syndrome (see below). They are sudden drop attacks in which the patient suddenly loses tone and falls to the ground. They are frequently included in the differential diagnosis of falls and syncope, but should be omitted because they do not occur in cognitively normal adults.

The differential diagnosis of seizures

Syncope

The main condition that is confused with GTCS is syncope, a sudden, brief loss of consciousness that results from reduced cerebral blood flow (Chapter 9). It is usually preceded by lightheadedness, diaphoresis,

Table 20.1 Factors that help differentiate between seizure and syncope

Table 20.1

and anxiety. Syncope may be confused with seizure because it is accompanied by multifocal jerking movements in 50–90% of patients.5 These myoclonic movements usually last for only 3–10 seconds, and are brainstem release phenomena rather than abnormal, synchronous cortical discharges. Syncopal patients regain consciousness and coherence within a few seconds, often in response to elevation of their feet, which restores cerebral blood flow. Patients with GTCSs require minutes to hours to recover from an event. Features that help to differentiate between seizures and syncope are found in Table 20.1. The most reliable of these is the presence of a postictal state, which strongly favors seizure.

Migraine and transient ischemic attack

Simple and complex partial seizures have a broader differential diagnosis than GTCSs. Among neurological conditions, the two that are often difficult to distinguish from partial seizures are migraine aura and transient ischemic attack (TIA). Prior history of migraine or risk factors for cerebrovascular disease may help to differentiate among the three conditions. In the absence of a relevant past medical history, the time course with which symptoms develop is the most important piece of information: with some exceptions, seizures develop over seconds, migraine auras develop over several minutes, and TIA symptoms are maximal at onset.

Movement disorders

Motor seizures may be confused with movement disorders, especially myoclonus and hemiballismus (Chapter 12). With the rare exception of epilepsia partialis continua in which partial seizures occur continuously, movement disorder symptoms tend to be relatively continuous activities while seizures are usually discrete events that are spaced widely apart in time. For example, intermittent flinging of the arm that lasts for days on end is more likely to be hemiballismus than a focal motor seizure. The most important exception to this rule is paroxysmal kinesigenic dyskinesia, a condition that is often misdiagnosed as a seizure disorder. Paroxysmal kinesigenic dyskinesia is characterized by sudden and episodic choreoathetotic or dystonic movements that last from seconds to minutes at a time, are precipitated by movement, and are often preceded by an aura. They tend to respond to treatment with carbamazepine.

Sensory symptoms

The differential diagnosis of sensory seizures depends, obviously, on the affected sensory modality. In all cases, think carefully about dysfunction of the sensory end organ (e.g. the eye in patients with visual symptoms) before concluding that the problem is coming from the brain. Patients with olfactory or gustatory phenomena, for example, may have primary otorhinolaryngological disorders or exposure to some toxin or medication that leads to their abnormal smells or tastes. Auditory hallucinations usually occur in the context of psychotic disorders. Somatosensory deficits secondary to seizures should not be fixed, unlike disorders such as radiculopathy, compression neuropathy, and multiple sclerosis.

Psychiatric disorders

Psychic and affective partial seizures must be differentiated from psychosis and depression, a task that usually requires the assistance of a psychiatrist. Malingering and conversion disorders (see below) are relevant considerations in all patients with paroxysmal disorders. Despite careful history and observation, an EEG recorded during an event is often the only reliable way to determine whether a behavior or perception is a seizure.

Narcolepsy

Narcolepsy is a disorder characterized by the tetrad of excessive daytime sleepiness, cataplexy (sudden loss of body tone, often precipitated by laughter or other emotional states), hypnagogic hallucinations (those that occur upon going to sleep), and sleep paralysis. Although differentiating narcolepsy from seizures is almost always straightforward, rare patients with cataplexy as their first or only symptom may be referred to a neurologist for seizure evaluation. The diagnosis should be obvious from history alone. A multiple sleep latency test (MSLT) helps to establish the diagnosis in unclear cases. Treatment should include referral to a sleep specialist. Modafinil (200 mg qd–bid) and methylphenidate (10 mg bid) are helpful in managing excessive daytime sleepiness, while REM-suppressing medications such as extended-release venlafaxine (75–150 mg qd) or fluoxetine (20–40 mg qd) are most often used for cataplexy.

Parasomnias

Parasomnias are a group of sleep disorders characterized by unusual movements or behaviors that arise from sleep. Well-known examples of parasomnias that may be confused with seizures include:

• Somnambulism (sleepwalking). Although more common in childhood, some adults may engage in sleepwalking.

• Sleep terrors. These arousals characterized by screaming, yelling, and sometimes violent behavior are more common in children.

• Periodic limb movements of sleep. Sudden involuntary limb movements during sleep may awaken the patient, or more commonly, their bed partner.

• Rapid eye movement (REM) sleep behavior disorder. This disorder, characterized by acting out one’s dreams, commonly precedes the development of a synucleinopathy such as Parkinson’s disease or dementia with Lewy bodies (Chapter 13).

The diagnosis of a parasomnia is often straightforward from history alone. In confusing cases, a sleep study with video recording assists in making the diagnosis. Referral to a sleep specialist is indicated for most patients with parasomnias.

Was this really the first seizure?

Determining whether a seizure was actually a patient’s first one is essential to guide further evaluation and treatment. When asking a patient about prior seizures, keep in mind that a person who has a GTCS will remember only the postictal state and not the seizure itself. Ask the patient, therefore, if they have ever awoken with a confused feeling, unexplained injuries, tongue lacerations, or loss of urine. Because most people are not familiar with seizures other than GTCSs, when determining whether a seizure was really a patient’s first, it is important to inquire directly about specific SPS and CPS phenomena, staring spells indicative of absence seizures, and myoclonic seizures.

Determining seizure etiology

Because a seizure is a symptom of brain dysfunction rather than a disease unto itself, determining its underlying cause is an essential but surprisingly overlooked part of the evaluation. Seizure etiologies may be divided broadly into two groups: those that are caused by identifiable and often reversible metabolic or structural processes, and those that have no identifiable cause and are therefore labeled idiopathic. In the search for a seizure etiology, all patients require a careful and complete medical and neurological history. Laboratory studies, neuroimaging, and EEG are also important elements of the evaluation.

Laboratory testing

Laboratory testing is very similar to that which is performed for the confused patient (Chapter 1) and should include a complete blood count, chemistry studies with calcium, magnesium, and phosphorus levels, liver function tests, a toxicology screen, and urinalysis. Although many patients with seizures have minor laboratory abnormalities, these are often not the proximate cause of the seizure. Lumbar puncture should be performed on all patients with fever, a history of immunosuppression, or other reason to suspect meningitis or encephalitis. Although GTCSs by themselves may cause CSF pleocytosis, the number of cells rarely exceeds 1–2 cells/mm3 and any value exceeding 10 cells/mm3 should prompt more careful evaluation for meningitis or encephalitis.6

Neuroimaging

All patients with a first-time seizure should undergo a neuroimaging study: approximately 10–15% of patients will have an abnormal, responsible finding.7 In the acute setting, noncontrast head CT is sufficient to evaluate for structural lesions that require urgent attention such as brain hemorrhages, tumors, abscesses, and cysts. Slowly growing tumors, encephalitis, and ischemic stroke are seizure etiologies that may not be detected by CT scan. MRI with diffusion-weighted imaging and contrast enhancement are indicated if one of these processes is suspected.

Electroencephalography

EEG is perhaps the most valuable diagnostic tool in evaluating a patient with a first-time seizure: it helps to differentiate epileptic seizures from conditions that mimic them, to classify seizure types, and to tailor therapy. The vast majority of patients with a first-time seizure will have their EEG between seizures (an “interictal” EEG), rather than during a seizure. Abnormal interictal epileptiform discharges (Figures 20.1 and 20.2) are present in approximately 30–50% of these patients, but also in approximately 2% of normal subjects.7,8 The yield of EEG is increased by sleep deprivation, by performing multiple studies, and by performing the study within 24–48 hours after the seizure.9EEG obtained with sphenoidal electrodes may offer greater sensitivity to focal seizures originating from the temporal lobes.10

Specific seizure etiologies

Electrolyte abnormalities

Many electrolyte abnormalities are minor and not the direct cause of seizures. The following are rough guidelines to electrolyte levels that might be expected to cause seizures:

• Hyponatremia <120 mEq/l

• Hypocalcemia <6.0 mg/dl

Figure 20.1

Figure 20.1 Interictal EEG in a patient with a recent partial-onset seizure. Note the sharp wave with phase reversal at the F8 lead (arrow), placing the likely seizure focus in the right anterior temporal lobe. Image courtesy of Dr. Julie Roth.

Figure 20.2

Figure 20.2 Interictal EEG in a patient with primary generalized epilepsy. Note the generalized sharp discharges (arrow) followed by slow waves. Image courtesy of Dr. Julie Roth.

• Hypomagnesemia <0.8 mg/dl

• Hypophosphatemia <1.0 mg/dl

Careful correction of these electrolyte abnormalities should reduce the chances of seizure recurrence.

Uremia and dialysis disequilibrium syndrome

Both acute and chronic renal failure leads to the accumulation of toxic metabolites and uremic encephalopathy (Chapter 1).11 Patients with uremic encephalopathy may have both generalized and partial seizures, although GTCSs are more common. Uremic seizures are often accompanied by myoclonus. There is no single blood urea nitrogen, creatinine, or glomerular filtration rate that predicts seizures: the diagnosis must be made clinically. Dialysis is the definitive treatment of seizures secondary to uremia, but some patients with recurrent seizures require anticonvulsants, as seizures may recur even after an adequate dialysis schedule is arranged. In addition to uremia, patients in renal failure are at risk for seizures secondary to dialysis, the so-called dialysis disequilibrium syndrome (DDS), which may include encephalopathy, seizures, blurred vision, loss of consciousness, or coma. It is usually a self-limited condition that is best avoided by gentle dialysis.

Glucose imbalance

Because glucose is the brain’s primary energy source, hypoglycemia is an obvious substrate for neurological dysfunction including seizures. The glucose level at which seizures occur varies from patient to patient: in diabetics, seizures may occur at relatively higher glucose levels than in healthy patients, while nondiabetics may be free of seizures and other neurological dysfunction, even at blood sugar levels of 40 mg/dl. Nonketotic hyperglycemia may also precipitate seizures (sometimes taking the form of continuous focal seizures, i.e. epilepsia partialis continua). Because ketosis raises the seizure threshold, ketotic hyperglycemia is not a direct cause of seizures.

Hepatic encephalopathy

Hepatic encephalopathy and associated seizures are discussed in greater detail in Chapter 1.

Posttraumatic seizures

Although figures vary from study to study, a rough estimate of seizure risk following head trauma is 5% for patients with closed head injuries and 50% for those with penetrating head injuries.12 Not surprisingly, the seizure risk is greater in patients with severe injuries than in those with mild injuries. Posttraumatic seizures may be divided into early seizures, which occur within 1 week of head injury, and late seizures, which occur more than 1 week after head injury. Because early seizures are not necessarily associated with a higher risk for developing posttraumatic epilepsy, anticonvulsants are not clearly indicated.13,14 Neurosurgeons, however, commonly prescribe phenytoin as prophylaxis for all patients with severe head injuries in the first week after injury, as the consequences of seizures including increased intracranial pressure may be severe in this population.12 Patients with late seizures are at increased risk for developing epilepsy, even 10 years after the injury, and should be treated with anticonvulsants.13

Alcohol withdrawal

Alcohol withdrawal may lead to seizures, which are almost exclusively GTCSs. Almost all seizures occur within 72 hours of the last drink, with a peak between 6 and 24 hours after alcohol discontinuation.15Do not assume that all seizures in a patient who is withdrawing from alcohol are due to the withdrawal itself, as comorbid conditions including head trauma, electrolyte abnormalities, and meningitis may also precipitate seizures. Unless seizures are frequent or status epilepticus ensues, patients with alcohol withdrawal seizures do not necessarily require acute treatment. Long-term prophylaxis is rarely, if ever, indicated.

Other medications and toxins

A variety of medications including certain antidepressants, antipsychotics, stimulants, anesthetics, and antibiotics may precipitate seizures. It is a good policy to review the manufacturer’s prescribing information to determine whether a new medication played a role in lowering a patient’s seizure threshold and then to discontinue the offending medication as necessary. Intoxication with drugs of abuse, particularly stimulants and hallucinogens, and withdrawal from benzodiazepines are also important causes of seizures.

Meningitis and encephalitis

Patients with meningitis and encephalitis are obviously at risk for seizures. Any patient with a new seizure and a fever should undergo lumbar puncture after a space-occupying lesion is excluded by head CT. Chapter 1 contains a more detailed discussion of meningitis and encephalitis.

Neurocysticercosis

Infection of the brain parenchyma by the parasite Taenia solium is the most common cause of seizures in many Latin American and African countries. Cysts of all stages, including calcified cysts, may precipitate seizures. Other manifestations of neurocysticercosis include headaches, focal neurological disturbances, and in some cases, hydrocephalus due to obstruction of the ventricular system. The diagnosis of neurocysticercosis is usually established by finding cysts on a neuroimaging study in a patient from an endemic part of the world (see Chapter 23). When the diagnosis is in doubt, enzyme-linked immunoelectrotransfer blot assay plays a confirmatory role. Treat patients with seizures and enhancing cysts with a combination of anticonvulsants and albendazole (15 mg/kg/day) and prednisone (60–80 kg qd) under the guidance of an infectious disease specialist.

Neoplasms

Although precise numbers are difficult to establish, between 3 and 15% of epilepsy is due to brain tumors, with middle-aged patients having the greatest chance of a neoplastic etiology.2 Approximately 35% of patients with brain tumors will eventually have a seizure: the relative likelihood is greatest with low-grade gliomas, then with meningiomas, followed by high-grade gliomas, and is least for metastatic tumors.16 Tumors are more likely to be the source of seizure when postictal deficits are prolonged. The study of choice to evaluate for brain tumor is MRI with and without contrast (Chapter 23). When evaluating patients with known cancer who develop seizures, it is important to keep in mind sources of seizures other than metastasis, including meningitis from immunosuppression, paraneoplastic limbic encephalitis, radiation necrosis, scarring from surgical resection sites, and hemorrhage due to coagulopathy. Because chemotherapy used to treat the tumor often decreases anticonvulsant levels, levetiracetam (which has few drug–drug interactions) is often the agent of choice for patients with brain tumors. Despite common practice, anticonvulsant prophylaxis is not required for all patients with brain tumors, unless they have already had a seizure.17

Stroke

Cerebrovascular disease is the most commonly identifiable source of epilepsy in adults, and is especially common in the elderly. One prospective study showed that approximately 9% of patients with a stroke will have a seizure, usually within 24 hours of the stroke.18 In the acute setting, the likelihood of seizure is predictably greater for patients with hemorrhagic strokes than for those with ischemic strokes. Seizure risk from hemorrhage decreases considerably, however, as intracranial blood is reabsorbed, while patients with ischemic strokes remain at higher risk for seizures months to years later.18

Arteriovenous malformations

Arteriovenous malformations may cause a variety of symptoms including intracranial hemorrhage, stroke, and seizure. They are discussed further in Chapter 23.

Neurodegenerative diseases

Up to 15% of patients with Alzheimer’s disease (AD) may have seizures, usually GTCSs.19 It is not clear how frequently the seizures are the direct consequence of AD, but in many patients, there may be no other identifiable risk factor. Other neurodegenerative diseases including Creutzfeldt–Jakob disease and frontotemporal dementia may also produce seizures.

Eclampsia

Preeclampsia is a condition specific to pregnancy consisting of the triad of hypertension, proteinuria, and edema. It may occur at any time between week 20 of gestation and 6 weeks postpartum. The only cure for preeclampsia is delivery of the baby. Eclampsia is the occurrence of seizures in a woman with preeclampsia. These are usually GTCSs, may be severe, and may threaten both mother and baby. Multiple studies indicate that magnesium sulfate is the preferred therapy to prevent preeclampsia from developing into eclampsia and to prevent seizure recurrence in women who have already had an eclamptic seizure.2022 Therefore, treat women with severe preeclampsia or eclamptic seizures with 6 g IV magnesium sulfate followed by an IV drip of 2–3 g/hour. Because high levels of magnesium may cause respiratory depression, neuromuscular transmission failure, or kidney dysfunction, it is important to hold the infusion for any decline in respiratory rate, loss of deep tendon reflexes, or decrease in urinary output.

Idiopathic seizures

The majority of adults with new-onset seizures have no specifically identifiable etiology.2 These patients presumably have an underlying genetic basis or unidentified environmental exposure that is responsible for their seizures.

Table 20.2 Anticonvulsants and specific applications

Table 20.2

Treatment of the first-time seizure

Provoked seizures

Provoked seizures are those that are caused by a specific, identifiable abnormality, and which do not recur when that abnormality is corrected. Common causes of provoked seizures include electrolyte disturbances and alcohol withdrawal. By definition, provoked seizures should not be treated as they have a low likelihood of recurrence.

Benefits and risks of anticonvulsants

Choosing to prescribe anticonvulsants for a patient after a single seizure is often a difficult decision. The main benefit of prescribing anticonvulsants is greater security for both patient and doctor that seizures will be controlled. This benefit, however, must be balanced against the potential for the anticonvulsant to cause side effects such as sedation and dizziness, and the cost of the medication. While each patient must be approached individually, understanding the risk for seizure recurrence is helpful in deciding when to start anticonvulsants. For an adult with a single unprovoked seizure, the 2-year risk for seizure recurrence is approximately 50%.23,24 The probability of seizure recurrence increases to 60–70% if there is a history of prior neurological injury, developmental abnormalities, abnormal imaging studies, or EEG with epileptiform features.23 Although a 50% risk for seizure recurrence would seem to warrant anticonvulsant therapy, the side effects of taking these medications must be weighed against their protective effects. Most neurologists, including myself, do not usually prescribe an anticonvulsant for a patient with a single seizure, normal EEG, and normal imaging results. Obviously, this rule must be flexible. For example, it makes sense to have a lower threshold to start an anticonvulsant in a patient whose livelihood depends on the ability to drive.

After a second seizure, the 2-year risk for further seizures increases to approximately 70%.24 Because this risk of a second seizure is so high, I almost always prescribe anticonvulsants after a second seizure. Possible exceptions to this rule include patients with nondisabling nocturnal seizures or elderly nursing home residents who are at high risk for side effects from anticonvulsants.

Choosing an anticonvulsant

In most cases, there is little difference in efficacy among the various anticonvulsants, and the choice of agent is usually based on the anticipated side effects, interactions with other medications, cost, and speed with which the medication can be titrated to effective levels. Obviously, there is no single anticonvulsant that can be labeled as the “best” or “first choice” for all applications. Table 20.2, however, contains a summary of common applications in which certain anticonvulsants may be preferred based on expert consensus25 and personal experience, while Table 20.3 contains a summary of the dosing and side effects of commonly used anticonvulsants.

Table 20.3 Common anticonvulsants

Table 20.3

a Reference ranges are also available for the newer anticonvulsants, but are used less frequently in clinical practice.

b Side effects of all medications include dose-related sedation, dizziness, and ataxia.

Anticonvulsants in patients with renal dysfunction

Many hospitalized or otherwise chronically ill patients have renal dysfunction, which plays a significant role in anticonvulsant selection. In addition, patients with renal dysfunction often undergo hemodialysis, which may remove anticonvulsants entirely, partially, or not at all. Table 20.4 contains a summary of dose adjustments for common anticonvulsants in patients with renal dysfunction and in those who are undergoing hemodialysis.

Counseling after the first seizure

Patients react to a new seizure diagnosis in a variety of ways including fear, depression, nonchalance, defiance, and even rage. It is absolutely essential to address any concerns that the patient and their family might have about seizures. It is important to discuss seizure manifestations (especially for patients with partial seizures) and what to tell schools or workplaces about the seizures. It is also essential to tell family members that they should not put a spoon or other object into

Box 20.1 Phenytoin dosing and levels

The usual initial dose of phenytoin is 300 mg/day. In some patients, it is necessary to achieve a therapeutic level quickly: these patients require loading with intravenous phenytoin or fosphenytoin (20 mg/kg). Therapeutic levels of phenytoin are typically in the range of 10–20 µg/ml, although many patients achieve excellent seizure control at levels <10 µg/ml and some patients continue to seize despite levels >20 µg/ml. Because phenytoin is highly protein bound, the serum level may be misleading, and it is important to determine free phenytoin levels. If rapid measurement of free phenytoin levels is not readily available, then the true phenytoin level may be approximated by the equation:Corrected phenytoin level = measured phenytoin level (0.2 × albumin) + 0.1

Make the following adjustments as necessary:

• For patients with total levels <5 µg/ml, reload phenytoin orally (three doses of 300 mg, each separated by 3 hours) or intravenously and increase the total daily dose by 100 mg.

• For patients with levels between 5 and 10 µg/ml, increase the total daily dose by 100 mg.

• For patients with continued seizures despite levels between 10 and 20 µg/ml, increase the total daily dose by 30–50 mg. This small increase is necessary because, at higher doses, phenytoin metabolism assumes zero-order kinetics at which point no more phenytoin is metabolized and drug levels rise precipitously into the toxic range.

Table 20.4 Anticonvulsants in patients with renal dysfunction26

Table 20.4

CrCl = creatinine clearance.

a patient’s mouth during a seizure: a person cannot swallow their own tongue, but they certainly can swallow a foreign body or aspirate it. Instruct family members that the safest place for a patient during a GTCS is on the floor, placed on their side to prevent aspiration. Let family members know than any GTCS that lasts >5 minutes is potentially dangerous and requires medical assistance. It is often helpful to instruct patients and their families to look at their watches as soon as a seizure begins, because seizure duration is often overestimated. It is the physician’s duty to know the individual state’s laws about driving restrictions for patients with seizures and to inform patients of these laws or report seizures as necessary. Lastly, it is important to instruct patients that they should only swim with a companion and should take showers rather than baths to prevent accidental drowning.

Epilepsy

Epilepsy is a disorder of the brain characterized by the occurrence of at least one epileptic seizure and an enduring predisposition to generate epileptic seizures.1 For some patients, the diagnosis of epilepsy can be made after a single seizure and an EEG showing characteristic epileptiform discharges. For others, the diagnosis is established only after a second seizure occurs. The first job in treating a patient with epilepsy is to define the source of the epilepsy by using a combination of ictal semiology, EEG findings, and neuroimaging or laboratory studies. In general, epilepsy may be divided into symptomatic forms in which the source of the epilepsy is known, idiopathic forms in which there is no identifiable structural lesion but rather a presumed genetic source, and cryptogenic in which the epilepsy is likely symptomatic but the underlying source is not known. Defining the syndrome allows appropriate tailoring of treatment and consideration of surgical intervention for patients with seizures that are likely to be medically refractory.

Epilepsy syndromes

A variety of epilepsy syndromes produce characteristic patterns of seizures and respond to specific therapies. In adults, some of the more common epilepsy syndromes include the following.

Temporal lobe epilepsy

Temporal lobe epilepsy (TLE) commonly begins in childhood or adolescence. Typical simple partial seizures include an epigastric rising sensation, olfactory hallucinations, déjà vu, or ictal fear. Complex partial seizures are often associated with automatisms such as lip smacking, chewing, swallowing, or sniffing. Secondary generalization of partial seizures is common but not universal. Temporal lobe epilepsy may be difficult to treat medically, and is

Figure 20.3

Figure 20.3 4–5 Hz generalized polyspike-wave complexes seen in a patient with juvenile myoclonic epilepsy. Image courtesy of Dr. Julie Roth.

a frequent source for surgical referrals in the adult population.

Juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) usually begins in adolescence, but may go undiagnosed until early adulthood. Many patients have absence seizures in youth. Myoclonic jerks in the arms, usually after awakening in the morning, are the most common initial feature in adolescence. Later in the course, GTCSs develop and are often the events that bring the patient to clinical attention. In many cases, the features of the syndrome may be identified only retrospectively by careful history. Interictal EEG characteristically shows 4–6 Hz spike-wave complexes (Figure 20.3). Although it is considered a benign form of epilepsy, most patients with JME require lifelong treatment, generally with valproate or lamotrigine, in order to prevent seizure recurrence.

Autosomal dominant nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) may begin in children or young adults and is inherited in an autosomal dominant fashion. It is characterized by brief motor seizures that awaken the patient from non-REM sleep. Bizarre automatisms secondary to frontal lobe involvement accompany the seizures, which often leads to this syndrome being diagnosed as a parasomnia or as a psychogenic disorder. This syndrome responds to traditional anticonvulsants.

Reflex epilepsies

Reflex epilepsies are a group of epilepsy syndromes in which sensory stimuli such as flashing lights, the voice of a specific person, or a piece of music precipitate seizures. Avoiding the stimulus is helpful in preventing seizure recurrence, but, in many cases, the stimulus is so frequent that the patient may require anticonvulsants.

Refractory epilepsy

Almost all adults with epilepsy are treated with medications and the first anticonvulsant leads to seizure freedom approximately 70% of the time.27 Up to 30%, therefore, will have refractory seizures. The challenge in managing this group of patients is to determine the reason for poor seizure control. It is good practice to start from scratch by retaking the patient’s history, defining ictal semiology (usually with the help of an observer), asking about precipitating factors, reviewing EEG and neuroimaging findings, and inquiring about responses to past medication trials. Usually, the explanation for refractory seizures may be divided into one of the following:

1. Complex partial seizures are misdiagnosed and treated as absence seizures or vice versa. This is most often a problem in children and adolescents. Carbamazepine and phenytoin are quite effective for CPSs, but may worsen absence seizures. Ethosuximide, used exclusively for patients with absence seizures, worsens CPSs. For patients with refractory staring spells, the duration of postictal confusion is the most reliable clinical way to distinguish between CPSs and absence seizures: postictal confusion lasts for minutes in CPSs and seconds (or not at all) in absence seizures. Although automatisms are more likely to be present in CPSs, they may also accompany absence seizures. EEG may differentiate between CPSs and absence seizures if any doubt remains after the history. Patients with absence seizures have characteristic 3 Hz spike-wave discharges

Figure 20.4

Figure 20.4 3 Hz generalized spike-wave complexes in patient with absence seizures. Image courtesy of Dr. Julie Roth.



(Figure 20.4), often elicited by hyperventilation whereas those with CPSs are more likely to have focal spikes or sharp waves.

2. Avoidable precipitants lower the seizure threshold. Factors that lower the seizure threshold include excessive alcohol intake, sleep deprivation, and stress. Lifestyle modifications, easier in principle than in practice, may reduce seizure frequency.

3. The patient is not taking their medication. Factors that lead to medication noncompliance include frequent dosing, high monetary expense, and undesirable side effects. Some patients with large numbers of medications often skip one or more of them. Others are simply not “pill people.” If you suspect medication noncompliance, ask the patient to bring his pill bottles to his appointments so that you may count his remaining medication. Checking serum drug levels may also help to establish medication noncompliance (Table 20.3).

4. The patient may not have epileptic seizures. The differential diagnosis of seizures, including syncope, movement disorders, and psychiatric disorders, is discussed above. Approximately 20% of patients who are referred to epilepsy centers for refractory epilepsy actually have psychogenic pseudoseizures.28 These are most often the manifestations of conversion disorders, but in some cases may be secondary to malingering. Pseudoseizures may allow patients to miss work and family responsibilities, to avoid legal actions, and to gain attention and affection. Features that suggest pseudoseizures include gradual onset and offset of seizure activity, preserved awareness in the presence of bilateral motor activity, and development of multiple different seizure types in a short time frame. Patients with pseudoseizures have events almost exclusively when there is an audience available to witness them. Elements of borderline, histrionic, and dependent personality disorders are present in many patients with pseudoseizures. These traits, however, cannot be used to make the diagnosis. Although serum prolactin levels drawn within 10–20 minutes of an event may be elevated in a patient with an epileptic seizure, they are not diagnostic of a pseudoseizure if normal.29 The only reliable way to make the diagnosis is with video-EEG monitoring showing a lack of epileptiform changes accompanying the events. Be aware, however, that mesiofrontal and orbitofrontal seizures may appear bizarre and quite similar to pseudoseizures, and the associated electrical changes may be missed by video-EEG monitoring.30 For patients with mesiofrontal or orbitofrontal seizures, it is the stereotyped nature of the events that usually helps to differentiate them from pseudoseizures, which often vary considerably from event to event. The presence of pseudoseizures does not exclude coexisting epilepsy, as approximately 10% of patients with a diagnosis of pseudoseizures will also have epileptic ones.31 Treating psychogenic pseudoseizures is frequently more challenging than treating epileptic seizures because patients often resist the psychiatric treatment that will actually improve their symptoms. Patience and frank but gentle discussion about the nature of the events are more helpful than evasiveness and a string of invasive tests and ineffective or potentially toxic placebos.

5. The patient may have seizures that are not adequately prevented by their current medical regimen. If a patient continues to have seizures and appears to be tolerating their medication, try to increase the dose to the higher end of the therapeutic range. Measuring drug levels may be helpful to determine whether the anticonvulsant dose is adequate. If the patient does not tolerate the first medication or seizures persist despite a higher dose, try another first-line anticonvulsant (see Table 20.2). Adding a second first-line agent to the first one (polytherapy) is an alternate approach that has both merits and drawbacks (see Table 20.5 and Box 20.2). The question often arises as to the appropriate duration of an anticonvulsant trial. A good rule of thumb is that a medication should be tried for five to ten times the average interval between seizures prior to its initiation.32 Despite adequate medical therapy, many patients with refractory seizures may require surgical evaluation (see below).

6. The patient has a refractory epilepsy syndrome that will respond poorly to any medical or surgical treatment. The classic example of this is Lennox–Gastaut syndrome (LGS), characterized by a panoply of different seizure types, most commonly atypical absence, tonic, and atonic seizures. Patients with LGS are usually mentally retarded and may also have myoclonic seizures, GTCSs, and partial seizures. The interictal EEG signature of LGS is the 2–2.5 Hz spike-and-wave

Box 20.2 Antiepileptic drug interactions

Interactions between antiepileptic drugs may become problematic in patients receiving polytherapy. The following is a brief summary of common and important drug interactions.

The older anticonvulsants phenobarbital, phenytoin, and carbamazepine all induce hepatic P450 enzymes, which in turn decrease the levels of carbamazepine, valproate, lamotrigine, topiramate, and zonisamide. It is therefore important to monitor clinical effects and medication levels closely in patients who are receiving polytherapy with these agents. Interactions may be especially complex when two of the older medications are combined.

Carbamazepine induces its own metabolism (and therefore decreases its own level), a process that usually stabilizes 20–30 days after initiating or changing the dose.33

Phenobarbital, phenytoin, and carbamazepine induce the uridine glucuronyl transferases, which metabolize lamotrigine. Patients taking one of these medications may, therefore, require higher doses of lamotrigine.

Valproate inhibits the metabolism of phenobarbital, phenytoin, carbamazepine, and lamotrigine. The reduced metabolism of lamotrigine is particularly important, as it may lead to toxicity. For patients already taking valproate, lamotrigine should therefore be started at half the typical starting dose and titrated half as quickly. In addition, valproate displaces phenytoin from its protein-binding sites, leading to an increase in the free serum concentration of phenytoin.

Table 20.5 Suggested polytherapy combinations

Table 20.5

complex (Figure 20.5). Although seizures develop in early childhood, patients with LGS commonly survive into adulthood and are often admitted to inpatient epilepsy monitoring units during stretches of poor seizure control. Unfortunately, seizures tend to be refractory to standard treatments, and creative combinations of medical and surgical therapy are usually required. Most patients need high doses of traditional and experimental anticonvulsants supplemented by benzodiazepines. Medications used specifically for LGS, but rarely for other indications, include felbamate and rufinamide. A variety of surgical therapies including corpus callosotomy and vagus nerve stimulation may be helpful. Some patients benefit from the ketogenic diet.

Epilepsy surgery

Because seizure control with a third anticonvulsant after two unsuccessful medication trials is unlikely, consider epilepsy surgery evaluation for patients with poorly controlled seizures despite adequate trials of two first-line anticonvulsants.34 Presurgical evaluation is usually done by a multidisciplinary group including a neurologist, neurosurgeon, clinical psychologist, and epilepsy nurse. The evaluation of potential candidates begins with MRI of the brain to look for surgically correctable structural abnormalities and inpatient video-EEG monitoring to localize the seizure focus. If a relevant seizure focus is found,

Figure 20.5

Figure 20.5 2 Hz generalized discharges characteristic of Lennox–Gastaux syndrome. Image courtesy of Dr. Julie Roth.

testing proceeds with evaluation of language and memory (including a Wada test, transcranial magnetic stimulation, and neuropsychological evaluation) to minimize the chance that resection will produce adverse behavioral consequences. Surgical options include curative surgeries, which involve resection of a seizure focus (e.g. temporal lobectomy), and palliative surgeries, such as corpus callosotomy and multiple subpial transections, which are used in patients with severe refractory seizure disorders including LGS. Among curative surgeries, patients who undergo temporal lobectomy have a better long-term outcome than those who undergo occipital and parietal resections.35Frontal lobe resection is the least likely to be successful. While corpus callostomy and multiple subpial transections do not usually result in seizure freedom, they may decrease seizure frequency enough to have a positive impact on a patient’s quality of life.

Vagus nerve stimulation

The vagus nerve stimulator (VNS) is a pacemaker-like device, which is implanted under the left clavicle. Stimulation of the vagus nerve reduces seizure frequency and aborts seizures, possibly by activating neuronal networks in the thalamus and limbic system.36 Meta-analysis of VNS efficacy data shows that approximately 45% of patients who undergo implantation achieve a 50% reduction in seizure frequency.36 Common side effects of VNS include hoarseness, throat pain, and cough, all of which may be remedied by adjusting device parameters.

Withdrawing anticonvulsants

Slow anticonvulsant tapering over 2–3 months may be appropriate for patients with long periods of seizure freedom. In patients who are seizure free for at least 2 years, the chance to remain seizure free over the next 2 years is approximately 80% in patients who continue to take anticonvulsants and 60% in those who discontinue them.37 Ideally, candidates for medication withdrawal should have normal neurological examinations, neuroimaging studies, and EEG results at the time of medication withdrawal. Factors that predict successful anticonvulsant discontinuation include longer periods of seizure freedom, use of a single anticonvulsant to achieve seizure freedom, and a lack of tonic–clonic seizures. It is important to involve the patient in the discussion about medication withdrawal: some are eager to discontinue their anticonvulsants, while others enjoy a greater peace of mind if they continue to take them.

Status epilepticus

Status epilepticus is defined as seizure activity that lasts for at least 30 minutes. This definition, however, has limited clinical utility, as seizures that last for even as little as 5 minutes are unlikely to resolve on their own and should be treated as status epilepticus.38 Status epilepticus is divided into convulsive and nonconvulsive types. Convulsive status epilepticus (repetitive GTCSs) is a true medical emergency and will be the focus of this section. Nonconvulsive status epilepticus is discussed further in Chapter 1. Because it is easy to panic when dealing with a patient in convulsive status epilepticus, it helps to have a systematic approach to reduce uncertainty and to guide appropriate management, as follows.

Step 1: life support

Protecting the airway (with mechanical intubation if necessary) and obtaining intravenous access are the first steps in managing status epilepticus. Although some anticonvulsants may be given intramuscularly or rectally, most anticonvulsants used for status epilepticus require intravenous access. When establishing access, draw blood for laboratory studies including a complete blood count, chemistry panel, liver function tests, anticonvulsant levels, and toxicology screens.

Step 2: abort seizures

Phase 1: benzodiazepines

Intravenous lorazepam (0.1 mg/kg) will abort status epilepticus in approximately two-thirds of patients.37 If the patient lacks intravenous access at seizure onset, alternative benzodiazepine choices include diazepam (20 mg rectally) or midazolam (10–20 mg intramuscularly).39 Administer a second dose of lorazepam if the first dose fails to abort seizure activity within 5 minutes.

Phase 2: fosphenytoin

Treat patients who do not respond to lorazepam with intravenous fosphenytoin (20 mg/kg at a rate of 150 mg/minute). Fosphenytoin is preferred to phenytoin because it produces less local irritation at the infusion site, can be administered safely through peripheral intravenous lines, and can be infused three times faster than phenytoin.

Phase 3: intravenous anticonvulsants that require intubation

Patients with status epilepticus that is refractory to lorazepam and fosphenytoin will require transfer to an intensive care unit and stronger medications that necessitate intubation. The options at this stage of treatment are:

• phenobarbital 20 mg/kg IV

• midazolam 0.2 mg/kg loading dose followed by 0.05–2.0 mg/kg/hour continuous infusion

• propofol 1–2 mg/kg loading dose followed by 2–10 mg/kg/hour continuous infusion

Additional anticonvulsants that may be considered at this stage include intravenous valproate (30 mg/kg over 10 minutes) and intravenous levetiracetam (20 mg/kg over 14 minutes).

Phase 4: pentobarbital coma

If phenobarbital, midazolam, or propofol fail to control status epilepticus, the next line of treatment is pentobarbital coma. Patients must be attached to continuous bedside EEG telemetry, as the induced coma will suppress the motor manifestations of status epilepticus that are normally used to monitor treatment success or failure. Pentobarbital is loaded at a dose of 5 mg/kg followed by IV infusion of 1–10 mg/kg/hour, titrated gradually upwards to a burst-suppression pattern on EEG (Figure 20.6). Pentobarbital coma is typically

Figure 20.6

Figure 20.6 Burst suppression in a patient with status epilepticus being treated with pentobarbital coma. Image courtesy of Dr. Julie Roth.

maintained for 24 hours, at which point the medication is weaned gradually, using the EEG for guidance.

Step 3: determine the underlying etiology of status epilepticus

Once seizure control is established, focus on determining the etiology of status epilepticus. Obtain collateral history if possible, with special attention to a prior history of epilepsy and anticonvulsant use. Common precipitants of status epilepticus include medication noncompliance, infections (especially meningitis and encephalitis), metabolic disturbances, drug overdose, and cardiac arrest. If a clear cause of status epilepticus is not identified from the initial history and laboratory studies, expand the evaluation to include neuroimaging and CSF analysis.

Step 4: prevent further episodes

Correcting the proximate cause of status epilepticus is obviously the first step in preventing further episodes. Some patients with provoked seizures may not require new medications. Patients with known epilepsy need augmentation of their anticonvulsant regimens. Medication noncompliance and other seizure precipitants must be addressed if relevant.

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