Seizures and Epilepsy
Content
Chapter 426 – SEIZURES AND EPILEPSY Susan S. Spencer Definition The term epilepsy includes includes disorders or syndromes with widely variable pathophysiologic findings, clinical manifestations, treatments, treatments, and prognoses. Individuals with epilepsy are identified by the tendency for and occurrence of recurrent seizures. A seizure is a paroxysmal, hypersynchronous, excessive neuronal discharge of variable extent. However, the word seizure seizure is is not synonymous with the word epilepsy. epilepsy. Any Any brain can generate a single or even multiple seizures under appropriate provocative circumstances. It is the tendency to have recurrent seizures, not necessarily with provocation, that makes the diagnosis of epilepsy. More than one seizure must occur before the diagnosis of epilepsy is made. The clinical appearance and electroencephalographic (EEG) correlates of recurrent seizures allow classification of the seizure as either partial onset or generalized onset. An individual with epilepsy may have one or multiple specific types of seizures. Knowledge of demographic variables, the circumstances in which the seizures occur, and the results of diagnostic examinations are combined with the type of seizures to allow identification and classification of an epileptic syndrome (see Table 426-3 ). d iagnosis of a specific epileptic syndrome carries real meaning with respect to 426-3 ). The diagnosis pathophysiology, duration of treatment, and prognosis.
TABLE 426-3 426-3 -- INTERNATIONAL CLASSIFICATION OF EPILEPTIC SYNDROMES (CONDENSED) PRIMARY/IDIOPATHIC
Localization related Benign epilepsy with centrotemporal spikes
Autosomal dominant nocturnal frontal lobe epilepsy
Generalized Juvenile myoclonic epilepsy
Juvenile absence epilepsy
Severe myoclonic epilepsy of infancy
Progressive myoclonic epilepsies
Generalized epilepsy with febrile seizures plus
SECONDARY/SYMPTOMATIC
Localization related Mesial temporal lobe epilepsy
Neoplasm (primary, metastatic)
Infection (abscess, encephalitis, meningitis, syphilis, cysticercosis, Lyme disease, tuberculosis, fungal disease, herpes)
Vascular (stroke, transient ischemic attack, migraine, hemorrhage)
Developmental (migrational)
Perinatal
Traumatic
Degenerative (e.g., Alzheimer's disease)
Immunologic (e.g., multiple sclerosis)
Generalized West's syndrome
Lennox-Gastaut syndrome
Tuberous sclerosis
Sturge-Weber syndrome
The word epilepsy has has many implications for the individual and for society. Frequently, it carries considerable stigma and leads to psychosocial, p sychosocial, educational, and vocational obstacles and impairments. Nonetheless, substantial substantial if not complete control of seizures is now possible with medical treatment in most patients, and remission often occurs. Even in patients with a poor response to medical treatment, surgical or other interventions may control the seizures. Epidemiology Epilepsy, which is the most common chronic neurologic condition, affects individuals of all ages, with a peak incidence in childhood and in the elderly. In the United States, the incidence of all types of epilepsy is 35 to 52 per 100,000, varying by age: 60 to 70 per 100,000 per year in young children (<5 years), 45 per 100,000 in adolescents, as low as 30 per pe r 100,000 in the early adult years, but rising through the sixth and seventh decades back to 60 to 70 per 100,000 and reaching as high as 150 to 200 per 100,000 in individuals older than 75 years. The incidence in males is higher at every age. Estimates of the prevalence of epilepsy range from 4.7 to 6.9 per thousand, but its prevalence is much higher in less developed countries for all age groups. Specific Causes The cause of epilepsy remains undetermined u ndetermined in more than 50% of patients. The etiology varies with the age group and with the region of the country or the world. In childhood, most epilepsies are idiopathic, whereas in adults, most are secondary to identifiable causes. The most common cause of epilepsy worldwide in developed countries is stroke/vascular disease (10 to 17%), followed closely by head trauma, developmental/congenital disorders, infection, neoplasm, and degenerative disorders, especially Alzheimer's disease. The spectrum is dependent on age, with trauma/congenital/infectious trauma/congenital/ infectious causes most frequent in children and vascular disease/neoplasm accounting for greater than 25% of cases in patients older than 60 years. Comorbid diseases are common in patients with epilepsy. The most frequent are mental retardation (cognitive disorders and learning disabilities) and psychiatric disorders, but motor deficits are also common. The presence and severity of mental retardation are related to the risk for epilepsy: 7 to 18% in children with mild mental retardation (IQ of 50 to 70) and greater than 37% in children with severe mental retardation (IQ <50). Cognitive deficits are common in adults with epilepsy of many causes, including stroke, dementia, and neoplasm. Isolated symptomatic seizures that occur without a diagnosis of epilepsy are related to specific causes that overlap but differ from the causes of recurrent epileptic seizures and syndromes ( Table 426-1 ). 426-1 ). In young children, infection is the leading cause of acute symptomatic seizures, with trauma the second most common.
TABLE 426-1 426-1 -- SOME COMMON CAUSES OF ACUTE SECONDARY “SYMPTOMATIC” SEIZURES Metabolic Hypernatremia, hyponatremia, hypocalcemia, hypoxia, hypoglycemia, hyperglycemia (nonketotic hyperosmolar), renal failure Drug induced Theophylline, meperidine, tricyclic antidepressants, phenothiazines, lidocaine, quinolones, penicillins, selective serotonin re-uptake inhibitors, isoniazid, antihistamines, cyclosporine, interferons, cocaine, lithium, amphetamines, alcohol (withdrawal), (withdrawal), benzodiazepines (withdrawal) (withdrawal),, barbiturates (withdrawal) Infections Sepsis, encephalitis (viral), abscess (intracerebral, subdural, epidural), meningitis (bacterial) Endocrine Hyperthyroidism, hypothyroidism, peripartum Other systemic conditions Sickle cell crisis, hypertensive encephalopathy, systemic lupus erythematosus, e rythematosus, polyarteriti polyarteritis, s, eclampsia, high fever (any cause) Central nervous system neoplasms Central nervous system trauma Vascular Arrhythmia, stroke, intracerebral hemorrhage, hypotension Pathobiology Partial seizures involve a localized region or collection of cells in a specific area that display bursting behavior: the epileptic neuronal aggregate. Prolonged depolarization caused by a shift in calcium conductance results in firing of multiple sodium-dependent action potentials. The spontaneous or stimulation-induced bursting behavior produces a paroxysmal depolarization shift, which is the intracellular correlate of an interictal spike, the characteristic of EEG recordings in 426-3 ). ). patients with epilepsy (see Fig. 426-3
FIGURE 426-3 Interictal EEG in localization-related epilepsy. epilepsy. The The interictal spike discharge is demonstrated, with phase reversal across channels F8–T8, T8–P8, F10–T10, and T10–A2 that localizes the spike to T8, T10 (right anterior inferior temporal lobe). Spikes are highly correlated with the presence of partial epilepsy.
When a seizure occurs, the bursting cells in the epileptic neuronal aggregate recruit neighboring neurons by the accumulation of extracellular potassium, accumulation of calcium presynaptically, and activation of N -methyl-D-aspartate -methyl-D-aspartate receptors. The seizure is characterized by continuous highfrequency firing of neurons, with spread of excitatory activity into neighboring neurons representing propagation of the partial seizure. Propagation occurs locally and also through longer anatomic pathways and circuits. Eventually, this firing is interrupted by repolarization. Hyperpolari Hyperpolarization zation characterizes the postictal state. The occurrence of seizures depends on the interaction of inhibitory and excitatory influences, including ion channel behavior, variations in protein expression, and variable membrane receptor properties. Seizures can be precipitated by alterations in metabolic status, sleep, lighting, sensory stimulation, drugs, toxins, ion status, or synaptic activity, even in individuals without local accumulations of bursting neurons—in which case they are termed acute secondary or “symptomatic” seizures, which does not constitute epilepsy. The ways in which neurons develop the tendency to cause seizures—epileptogenesis—are seizures—epileptogenesis—are not well understood but may include neuronal loss and reorganization and alterations in receptor responses, basic membrane function, or ion channel regulation. Developmental, genetically determined features clearly play a role.
In the generalized epilepsies, in which onset of the seizure is manifested by diffuse clinical and EEG changes that involve many or all areas of the b brain, rain, an alteration in the normal oscillatory rhythms that characterize the circuits of pyramidal neocortical neurons and neurons of the nucleus reticularis of the thalamus may be the cause. The nucleus reticularis of the thalamus controls the activity of Ttype calcium currents in thalamic relay neurons through cells utilizing γ-aminobutyric acid as a neurotransmitter (GABAergic (GABAergic input). The thalamic relay neurons project to and regulate the excitability of cortical pyramidal neurons. Influences on this system, such as blockade of T-type calcium currents, prevent absence seizures. In generalized tonic-clonic seizures, the substantia nigra appears to play a role by acting through GABAergic inhibitory neurotransmission. neurotransmission. Genetics Most of the common epileptic syndromes have complex inheritance patterns that have eluded definition. Many of the epilepsies with mendelian inheritance are rare disorders related to alterations in ion channels: benign neonatal convulsions associated with mutations in the potassium channel genes KCNQ2 and and KQCNQ3; KQCNQ3; generalized generalized epilepsy with febrile seizures associated with mutations in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, and SCN3A, and SCN1B SCN1B and and with mutations in the GABA receptor gene (GABRG2); (GABRG2); severe severe myoclonic epilepsy of infancy associated with mutations in the sodium channel gene SCN1A; SCN1A; juvenile juvenile myoclonic epilepsy associated with mutations in the GABA receptor gene GABRG1; GABRG1; and and autosomal dominant nocturnal frontal lobe epilepsy associated with mutations in the neuronal nicotinic acetylcholine receptor genes CHRNA4 CHRNA4 and CHRNB2. CHRNB2. Other Other genetic epileptic syndromes for which specific mendelian genetics are now known include a variety of progressive disorders characterized by childhood seizures, developmental decline, and demonstrable structural abnormities. Such syndromes include progressive myoclonic epilepsy of Unverricht-Lundborg associated with EPM1, EPM1, which which encodes cystatin B, and progressive myoclonic epilepsy of Lafora associated with EPM2; EPM2; neuronal neuronal ceroid lipofuscinoses associated with CLN1, CLN2, CLN3, CLN5, and CLN5, and CLN8; CLN8; and and a list of developmental disorders of neuronal migration resulting in various forms and locations of aberrant cortical cellular collections. Among these disorders are lissencephaly (associated with LIS1, LIS1, which which encodes a subunit of platelet-activating factor acetylhydrolase, a microtubule-associated protein), subcortical band heterotopia (associated with doublecortin DCX, DCX, or or XLIS XLIS), ), and periventricular nodular heterotopia (associated with the filamin 1 gene FLN1, FLN1, which which encodes an actin-binding protein). There is growing appreciation of both the genotypic variability associated with a single phenotype and the phenotypic variability associated with alterations in single identified genes. Nevertheless, the rapidly evolving understanding of the genetic g enetic determinants may lead to more rational classification and treatment. Clinical Manifestations The earliest manifestation of a partial seizure can be subjective and recognized by patients as an “aura.” The most common aura is experiential: a feeling of déjà vu or jamais vu. Other auras include feelings of impending doom, fear, euphoria, or an odd sensation in the stomach, often rising toward the head. Such auras are typical in seizures beginning in the temporal lobe, but similar auras may occur with seizures originating from other lobes and are therefore not of localizing value. Rarely, the aura may be pleasant. Autonomic symptoms that may herald the onset of a seizure or be part of the clinical manifestations of a partial seizure include pallor, diaphoresis, olfactory or gustatory sensations, urge to defecate, dizziness, vertigo, nausea, and salivation. Complex sensory phenomena may accompany or precipitate seizures and must be distinguished from psychiatric disorders. Auditory hallucinations are much more likely to be psychiatric than seizure related, although seizures that originate in the Heschl gyrus area include buzzing or o r ringing in the ears. Seizures can be precipitated by hearing music (so-called musicogenic epilepsy), presumably secondary to activation of portions of the auditory cortex as a form of reflex epilepsy; in these situations, an actual auditory stimulus, not a hallucinatory phenomenon, is present. Similarly,
visual hallucinations can be complex in temporal lobe seizures but are unformed in simple partial seizures from the occipital cortex. Transient pain is rarely associated a ssociated with seizures. Vocalization is a common accompaniment of seizure activity. Frequently, the vocalization is not intelligible language but rather consists of repetitive phrases that become incorporated into the seizure activity; the vocalization may have originally been part of a reaction to the oncoming seizure. Thus, patients may repetitively repetitively state “help me, help me” or “oh God, oh God” at the onset of a seizure but have no recall of the event. Intelligible and intact language output during seizures excludes dominant hemisphere involvement in the seizure. Vertigo and dizziness are common at the onset of a seizure and are usually associated with involvement of the lateral temporal or occipital cortex. Diagnosis History The diagnosis of epilepsy is based on historical information. However, because epilepsy may involve a change of consciousness, diagnosis can be problematic. In localization-related seizures, the patient has intact consciousness at the start of the seizure and can report what transpires up to the point when consciousness is altered. With generalized seizures, patients lose consciousness immediately and can report only the postictal state. Thus, for grand mal seizures, patients may report only awakening and noting of o f muscle aching, incontinence, a bloody pillow, or disarray in their surroundings. Nocturnal seizures may not come to light until individuals share a bed with someone. Simple partial seizures that are subjective in nature may be disregarded or underreported by patients who fear the consequences of reporting them and not come to medical attention until a more severe seizure is recognized by others. Dating the onset of symptoms is dependent on asking the appropriate question. Moreover, seizures may have been misdiagnosed as hypoglycemia, panic attacks, or migraine and not be reported at all. Because patients have limited or no recall, the history from others is crucial. Observers contribute valuable information about the patient's activity, responses, and appearance (changes in color, diaphoresis, respirations, vocalization, vocalization, and muscle tone), which are essential to characterize the type of seizure and to distinguish seizures from syncope ( Chapter 427 ) 427 ) and other paroxysmal disorders affecting the nervous system. The setting in which the events occur (time of day, activity, ambient temperature, position, and sleeping or waking state) is important. Seizures, especiall especially y frontal lobe seizures, can occur predominantly or even exclusively during sleep. Seizures can occur in any position. The seizure threshold is lowered by fasting, lack of sleep, stress, fever, hyperventilation, strobe lights, withdrawal of certain drugs (e.g., alcohol, benzodiazepines, 426-1 ). ). barbiturates), and use of illegal and legal toxic substances (see Table 426-1 The history should also define any familial paroxysmal disorders. The possibility that events called “seizures” represent ischemic or other processes demands that historical features thought to relate to cardiovascular disease, movement disorders, and a family history of syncope be obtained. The psychiatric history not only influences the diagnosis but may also modify the manifestation of the seizure disorder and the history provided by the patient. In mood disorders (particularly anxiety), treatment may interact to obscure the diagnosis of o f seizures; for example, benzodiazepines suppress seizure activity, even though they are not the usual choice for chronic use. Conversely, 420 ) ) is treated with many drugs that lower the seizure threshold (e.g., tricyclic depression ( Chapter 420 antidepressants, selective serotonin re-uptake inhibitors). Physical Examination Seizures resulting from injury or from congenital, traumatic, neoplastic, immunologic, infectious, metabolic, or toxic causes may be associated with other findings that point to specific causes. Atrial fibrillation, arrhythmia, arrhythmia, or heart failure suggests cardiovascular or ischemic causes of seizures. Neurologic deficits in the distribution of a specific cerebral vessel suggest an ischemic cause.
Seizures characterized by abnormal motor activity can be confused with movement disorders, and 434 ) ) produce repetitive motor activity that is incorrectly some movement disorders ( Chapter 434 434 ) ) can be mistaken for attributed to seizures. The vocalization of Tourette's syndrome ( Chapter 434 vocalization in frontal lobe epilepsy, and vice versa. Paroxysmal dystonias and ataxias ( Chapter 434 ) 434 ) may be misdiagnosed as epilepsy with motor features. Types of Epileptic Seizures The current classification of epileptic seizures into diagnostic entities relies on clinical features and their accompanying EEG patterns. Seizures are divided into two main categories, partial and generalized, defined on the basis of involvement, at least at their start, of a localized region of the brain (partial) or the whole brain (as far as can be determined). In generalized seizures, consciousness is lost immediately. In partial seizures, consciousness may or may not be lost; by definition, partial seizures are simple, without alteration of consciousness, or complex, with altered consciousness. The specific types of seizures determine the epileptic syndrome and dictate the choice of drugs for treatment (see later). Partial Seizures Partial seizures have their origin in the gray matter of a localized area of the brain, although the size of this localized region remains unspecified. To observe any a ny change on a simultaneous EEG recording, a cortical area of at least 6 cm 2 must participate in the electrical discharge, but demonstration of such EEG phenomena is not essential for diagnosis. Partial seizures from small or deep brain foci often show no change on surface EEG recordings. The manifestations of partial seizures are as diverse as the functions of the brain. The sequence of symptoms and signs gives information on the cerebral localization of dysfunction ( Table 426-2 426-2 ). ).
TABLE 426-2 426-2 -- CHARACTERISTICS OF PARTIAL SEIZURES FROM DIFFERENT LOBES AND REGIONS TEMPORAL LOBE SEIZURES Medial temporal Aura (70–90%): epigastric sensation, déjà vu, emotions, indescribable feelings Arrest of activity (30–50%) Simple automatisms at onset; complex later, usually ipsilateral to the region where the seizure began Later, contralateral tonic motor activity secondary to spread of seizure activity—usually to the arm Confusion Consciousness may be preserved Lengthy (1–3 minutes) Lateral temporal (neocortical) Early, auditory hallucinations, vertigo Contralateral motor/sensory abnormalities Later, complex visual/auditory hallucinations Receptive aphasia Spread to medial areas results in signs/symptoms of medial temporal lobe syndrome (see above)
FRONTAL LOBE SEIZURES Rolandic Contralateral upper extremity clonic activity Postictal paralysis common Supplementary motor Mainly tonic, contralateral arm extension Fencing posture (contralateral head turning and arm extension) Speech arrest or vocalization Preservation of consciousness Brief (10–20 seconds) No postictal findings Frontopolar Contralateral tonic, often with secondary generalization Ipsilateral head and eye deviation Later, contralateral turning, axial clonic jerks Dorsolateral frontal Prominent contralateral motor, tonic or clonic Contralateral head/eye deviation Speech arrest Orbital frontal Mainly complex partial Autonomic disturbance Loud vocalization Bilateral motor and gestural automatisms, ambulation Olfactory hallucinations Cingulate Complex motor/gestural automatisms (bilateral) Autonomic signs Urinary incontinence Asymmetrical tonic activity No loss of consciousness PARIETAL LOBE SEIZURES Sensory symptoms, usually contralateral face, hand, and arm, with positive or negative phenomena Positive phenomena: tingling, need to move, feeling of movement, tongue crawling, formed visual hallucinations, nausea, pain, metamorphopsia Negative phenomena: loss of awareness of body part (asomatognosia), numbness
Then, complex partial ± secondary generalization Dominant hemisphere: language disturbance Nondominant hemisphere: metamorphopsia, asomatognosia Paracentral: generalized sensory phenomena, secondary generalization Inferior: vertigo, disorientation OCCIPITAL LOBE SEIZURES Simple partial onset with elementary visual sensations (in the contralateral field, center, or moving across the field), decreased vision (white or black), b lack), sensation of eye movement, forced blinking, oculoclonic activity, ocular flutter Contralateral head and eye deviation Then, complex partial ± secondary generalization; the spread pattern determines subsequent characteristics Infrasylvian spread causes medial temporal syndrome Lateral suprasylvian spread causes motor/sensory signs Medial suprasylvian spread causes supplementary motor syndrome The same patient may have variable suprasylvian and infrasylvian spread in individual seizures
In partial seizures, the neuronal discharge representing the partial seizure may remain confined to the region where it began (as an “aura” or more objective simple partial event), or it may spread to involve additional brain areas. Thus, a simple partial seizure of occipital lobe origin might begin with flashing lights in the contralateral visual field and then progress to involve additional occipital lobe regions ipsilaterally or contralaterally or propagate (along known anatomic pathways) to ipsilateral or contralateral temporal or frontal lobe regions (inferior or suprasylvian propagation). If consciousness is altered, it is termed a complex partial seizure. A special instance instance of propagation in the frontal lobe occurs in seizures with with onset in the the rolandic area. The initial circumscribed contralateral clonic activity propagates in the primary motor strip. This seizure activity “marches” from hand to arm to leg area ipsilaterally, a process referred to as a jacksonian march. After After the clonic clonic motor activity activity ends, patients are are often weak; a postictal or T Todd odd paralysis may last hours or even a day or two, with gradual resolution. Simple partial seizures originating from any region can become complex partial seizures, and unilateral simple or complex partial seizures can progress to involve bilateral brain areas, thereby resulting in secondary generalized seizures. Such secondary generalized seizures usually take the form of generalized tonic-clonic events rather than another type of generalized seizure in the international classification. The evolution of the clinical seizure reflects the evolution of the EEG changes, which in turn reflects the pathophysiology of the process, with a simultaneous rhythmic, localized discharge (often in the 4- to 7-Hz range) becoming higher in amplitude and lower in frequency as the seizure continues ( Fig. 426-1 ). 426-1 ). The EEG characteristics do not, however, influence the ultimate consequence, the specific seizure diagnosis, localization of the seizure, diagnosis of a specific syndrome, or selection of appropriate therapy.
FIGURE 426-1 Partial seizure. An seizure. An electroencephalogram shows the first 10 seconds of a complex partial seizure discharge, with 5-Hz rhythmic theta activity in channels recorded in the right temporal scalp (Fp2–F8, F8–T8, T8–P8, Fp2–F10, F10–T10).
Some seizures that begin in the association cortex have bizarre or extremely brief clinical manifestations, without postictal deficits. deficits. This sequence may occur in frontal lobe seizures, which may not be immediately appreciated as bona fide seizures. The stereotyped nature of the clinical events, with identification of EEG changes if present, may be the only way to make an appropriate diagnosis. The diagnosis can be even more challenging if the seizure spreads to different cortical regions during different seizure episodes, thereby producing variable constellations of clinical findings. Partial seizures can also occur as a series of single events without intervening normal behavior, termed “complex or simple partial status epilepticus.” Simple partial status epilepticus appears as typical, repetitive, simple partial seizures, whereas complex partial status epilepticus is characterized by persistent confused behavior, quite different from what is observed in individual complex partial events, even though it is a result of repeated complex partial seizure events. EEG findings may be normal in a simple partial seizure, and they may remain normal during simple partial status epilepticus, but the diagnosis is usually evident from the clinical features. In complex partial status epilepticus, EEG recordings show continuous abnormalities that are not of the same nature as seen in single seizures in that individual. The most common are a slow background with superimposed rhythmic high-amplitude sharp waves or o r repetitive rhythmic seizure discharges. Complex partial status epilepticus is most frequent with frontal lobe seizures but can occur in
temporal lobe seizures as well. The factors that precipitate complex partial status epilepticus are not well defined, nor are the implications for treatment or prognosis. “Nonconvulsive status epilepticus” is a cause of confusion or impaired mental status in patients with various neurologic diagnoses (i.e., trauma, stroke) in the acute intensive care unit setting. Clinical suspicion should prompt an EEG study, which is essential for diagnosis. Generalized Seizures The international classification of epileptic seizures recognizes six distinct types of generalized seizures: tonic-clonic, absence, tonic, atonic, clonic, and myoclonic. All can involve both hemispheres at their onset, but one type of generalized seizure (tonic-clonic) may evolve by “secondary generalization” of a partial seizure. The subcortical structures that presumably contribute to these seizures are not entirely defined. The distinctive EEG patterns observed with generalized seizures differ from the lateralized EEG patterns of partial seizures and can be produced by stimulation of subcortical structures, particularly certain thalamic nuclei. Generalized Tonic-Clonic Seizures A generalized tonic-clonic tonic-clonic seizure iis s also termed a grand mal seizure or seizure or convulsion. convulsion. It It is the most dramatic and common of the generalized seizures and arguably the most dramatic event in clinical medicine. Tonic-clonic seizures disrupt any situation in which they occur and frighten even the most informed or experienced bystanders. They may begin with a “cry” as a result of abrupt air movement across the glottis from sudden tonic muscle contraction. The patient becomes diffusely stiff, usually with limb and body extension and a nd often with arching of the back. Breathing is suspended, cyanosis occurs, and urinary incontinence is common. EEG recordings show generalized high-amplitude rapid spiking, although interpretation is impeded by the intense muscle artifact. After 15 to 60 seconds, the tonic activity gives way to clonic, rhythmic jerking of all four extremities, and the EEG spiking is also interrupted. The rhythmic contractions gradually become slower in frequency until the event stops; the patient is apneic, comatose, and diaphoretic and within 60 seconds begins stridorous breathing with foaming and gasping. Patients who have generalized tonic-clonic seizures in public often prompt bystander resuscitation efforts, although such patients begin spontaneous respiration within 1 minute or o r so. Postictal stupor lasts a variable length of time. The patient generally sleeps for 2 to 8 hours and then complains of severe headache, sore muscles, a bitten tongue, and inability to concentrate for a day or more. After generalized tonic-clonic seizures, some individuals have severe memory loss that gradually improves, sometimes over a period of weeks. When the generalized tonic-clonic convulsion ends, the EEG findings mirror the patient's clinical appearance. At first it is nearly flat and then shows very slow recovery through different stages of less marked slowing of background rhythms, with normal rhythms resuming within 24 to 48 hours. Generalized tonic-clonic seizures can occur secondarily from a partial-onset seizure as the sole type of seizure or with other generalized seizures in certain inherited, generalized epileptic syndromes. Generalized tonic-clonic tonic-clonic seizures are also what is seen 426-1 )—termed )—termed in response to many metabolic, toxic, traumatic, or ischemic insults (see Table 426-1 acute symptomatic seizures—but seizures—but these do not qualify for the diagnosis of epilepsy. Absence Seizures An absence seizure, which is the second most common type type of generalized seizur seizure e and is synonymous with the term “petit mal,” describes a momentary lapse of awareness. The patient has no perception of any aspect of the event and may or may not realize that some time was lost, although individuals often lose their place in reading or their train of thought. Simultaneous with the “absence,” the EEG recording shows a high-amplitude, 3-Hz spike and wave discharge, rarely lasting longer than 2 to 10 seconds, that occurs in both hemispheres but is predominantly frontal ( 426-2 ). ). The discharge and the event involve both hemispheres at once; there are no focal or Fig. 426-2 localized EEG discharges or lateralized behavioral manifestations. Because consciousness is
immediately lost at the onset, there is no aura. There are also no residual postictal symptoms. Because these seizures begin in childhood, school teachers are often the first to notice them. The “absence” may be accompanied by brief eye blinking or myoclonic movement, particularly if the event (as judged by EEG recordings) extends beyond 10 seconds. These seizures can occur many times a day but are not associated with progressive neurologic disease. They can also occur in a more continuous form, with resultant confusion, another cause of “nonconvulsive status epilepticus.”
FIGURE 426-2 Absence seizure. seizure. The The 3-Hz spike and wave pattern of absence epilepsy emerges from a normal electroencephalographic (EEG) background and abruptly stops with resumption of normal activity. Shorter bursts of this type or single spike and wave forms are interictal; when they are longer, clinical absence seizures accompany the EEG findings. The discharge is strictly regular, bilateral, and most prominent in frontal leads (Fp1–F7, Fp1–F3, F2–C2, Fp2–F4, Fp2–F8).
ATYPICAL ATYPICA L ABSENCE ABSENCE SEIZURES. SEIZURES. Some patients with extensive bilateral brain disease have a variation of this generalized seizure type designated “atypical absence.” The event is similar in terms of the brief loss of contact, but the spike and wave discharge observed on a simultaneous EEG recording is slightly slower in frequency and longer in duration; d uration; there is also more motor, autonomic, or automatic activity. “Atypical absence” seizures are usually part of symptomatic generalized epileptic syndromes (see later). Myoclonic Seizures
Myoclonic seizures are brief episodes of sudden motor contraction, often flexion of the upper extremities, that appear as muscle jerks. These movements can be focal, with one arm involved, or bilateral and massive, with involvement of both upper extremities and the trunk. There is no acknowledged loss of consciousness, but the episodes are so momentary that consciousness is difficult to evaluate. Myoclonic seizures often appear in the setting of other generalized types of seizures in degenerative or inherited syndromes with bilateral cerebral involvement, and they may also be associated with abnormal cerebral function. Myoclonic seizures most commonly occur in the morning, just after awakening, and they can crescendo in frequency to culminate in a generalized tonic-clonic seizure. Generalized discharges accompany myoclonic seizures but may be difficult to distinguish from muscleEEG a rtifact. artifact. Atonic and Tonic Tonic Seizures Atonic forms of generalized seizures are are also associated w with ith generalized EE EEG G abnormalities. These brief motor events are characterized by a sudden increase or decrease in muscle tone, often causing falls and injuries. Such seizures frequently occur in children with diffuse central nervous system (CNS) disease and multiple types of seizures. Diagnostic Studies 419 ) ) is the most important diagnostic study in epilepsy. Most The electroencephalogram ( Chapter 419 patients with epilepsy do not have a seizure recorded on a routine 30- to 40-minute EEG study, but interictal abnormalities abnormalities on a routine EEG study can be highly suggestive of an epileptic disorder. Spikes or sharp waves in a restricted distribution associated with a localization-related seizure ( Fig. 426-3 ) 426-3 ) or in a generalized distribution associated with generalized epilepsy (see Fig. 426-2 ) 426-2 ) rarely occur in the normal population. Spikes may not be present on a single interictal EEG recording, but interictal spikes are seen in more than 80% of individuals with localization-related epilepsy if three or more interictal EEG studies are performed. The generalized spikes or spike and wave complexes or polyspikes associated with generalized seizures are more frequent and therefore easier to see on routine EEG recordings, especially if hyperventilation and photic stimulation are used. The highest likelihood of detecting abnormal interictal activity on an EEG recording is in the 24-hour period after a seizure. Focal slowing and asymmetry may also be demonstrated, but such findings are not necessarily associated with epilepsy; however, they do establish a localized region of brain dysfunction or injury. By comparison, diffusely increased or decreased background activity can occur with a variety of medications and does not help in the diagnosis of epilepsy. Brain magnetic resonance imaging (MRI), which can demonstrate the structural correlate of most diagnoses associated with secondary “symptomatic” seizures, should always be performed in patients with new-onset seizures. Functional imaging techniques, including single-photon emission computed tomography (SPECT) for determination of blood flow and positron emission tomography (PET) for analysis of metabolism, are useful, especially in individuals with uncontrolled seizures. Regions of the brain that generate frequent seizure activity also demonstrate interictal hypoperfusion and hypometabolism, findings that can help establish a diagnosis of intractable epilepsy and localize a region for surgical treatment. 111 ) ) can point to other systemic disorders or causes of Metabolic and toxic screening ( Chapter 111 seizures. Endocrine disorders are not usually a cause of epilepsy but will worsen its clinical picture. Lumbar puncture is not helpful unless un less there is a possibility of hemorrhage, infection, or immunologic disease as the underlying cause. These entities typically have systemic manifestations that suggest a need for lumbar puncture.
With the history, EEG recordings, and MRI, a definitive diagnosisisofinsufficient epilepsy and its cause canbut be made in up to 50% of patients. In other patients, the information or inconsistent,
the physiologic and CNS abnormalities surrounding the actual event allow it to be placed provisionally into a specific diagnostic category nearly 80% of the time. Intensive 24-hour EEG and videotape monitoring in an inpatient epilepsy unit, while withdrawing the patient from medications and using provocative maneuvers such as sleep deprivation, can increase diagnostic sensitivity. The serum prolactin level is elevated two-fold or more within 5 minutes after generalized tonic-clonic and some complex partial seizures; it rises to a maximum at 15 minutes and declines to baseline by 1 hour. This level can be a useful adjunct to diagnosis. An EEG recording during a spontaneous event can distinguish syncope and cerebral ischemia, which are manifested as diffuse rhythmic slowing, from epileptic events, which are characterized by rhythmic sharp, slow, spike or spikewave discharges. However, some seizures, especially simple partial seizures and seizures arising in deep medial locations such as the medial frontal lobe, do not cause a change in the scalp EEG findings, even when recorded simultaneously with the clinical event. Differential Diagnosis 420 ), ), movement disorders ( Syncope ( Chapter 427 ), 427 ), various psychiatric disorders ( Chapter 420 Chapter 434 ), 429 ), and cerebrovascular insufficiency ( Chapter 431 431 ) ) 434 ), sleep disorders ( Chapter 429 ), may be confused with epilepsy ( Table 426-4 ). 426-4 ). The neurologic manifestations of classic migraine ( 421 ) can resemble a partial seizure, and some seizures are followed by headaches. The Chapter 421 ) sequence of events, the consistency of the headache, and resolution of the neurologic features without progression to more severe seizure activity suggest a diagnosis of migraine. However, distinction between migraine and epilepsy can be difficult, and individuals with migraine have an increased prevalence of epilepsy.
TABLE 426-4 426-4 -- PAROXYSMAL DISORDERS IN THE DIFFERENTIAL DIAGNOSIS OF EPILEPTIC SEIZURES
Vascular/perfusion disorders Vascular/perfusion Migraine, syncope, transient global amnesia, transient ischemic attack, arrhythmia/hypoperfusion
Movement disorders Tics, paroxysmal dystonia, paroxysmal choreoathetosis, paroxysmal ataxia
Sleep disorders Night terrors, sleep walking, sleep myoclonus
Psychiatric disorders Panic disorder, dissociative disorder, psychogenic (nonepileptic) seizures, multiple personality disorder
Other Breath-holding spells, paroxysmal vertigo
Myoclonic seizures must be distinguished from myoclonus ( Chapter 434 ), 434 ), a term that refers to muscle jerks that are unassociated with epilepsy, such as those in uremic encephalopathy. Myoclonus resembles myoclonic seizures, but myoclonus is not accompanied by the EEG changes of a generalized seizure. 434 ), ), paroxysmal Paroxysmal movement disorders such as paroxysmal dystonia ( Chapter 434 choreoathetosis, and paroxysmal ataxia can be confused with epilepsy. Autosomal dominant nocturnal frontal lobe epilepsy is a predominantly motor event that occurs in the middle of the night;
its paroxysmal movements can be confused with a movement or sleep disorder. Video EEG monitoring may be necessary for diagnosis. d iagnosis. Patients with panic attacks and dissociative disorders ( Chapter 420 420 ), ), including multiple personality disorder, can experience events that mimic simple or complex partial seizures. With such nonepileptic events, secondary gain is usually evident, and similar behavior may have occurred for an extended period. Nevertheless, the peculiarities of such attacks, as well as the neurologic manifestations of some patients, may require continuous video EEG monitoring for diagnosis, especially because frontal lobe seizures may also be associated with similar peculiar behavior. An erroneous diagnosis of nonepileptic seizures poses a risk for inappropriate discontinuation of medication, with resulting status epilepticus. Moreover, psychiatric disorders and epileptic seizures may coexist in the same patient. Treatment Treatment Medical Treatment The goal is to find the drug or drugs that suppress all seizure activity without side effects. Even for a single seizure, prophylactic treatment with antiepileptic drugs delays the time to the next seizure,[1] although most experts recommend treatment after a single seizure only for patients in whom the likelihood of recurrent seizures is especially high. The presence of abnormal EEG changes, abnormal neurologic findings, a lesion on MRI, or a history of significant brain injury increases the risk for recurrent seizures sufficiently to consider treatment after only one seizure. If a seizure occurs in the setting of an acute correctable metabolic or other provocation, longterm treatment is not indicated. After two unprovoked unprovoked seizures, the the risk for recurrence recurrence is 70%. Initiation Initiation of tr treatment eatment is typical typically ly indicated except in specific benign and self-limited syndromes, such as febrile seizures and benign epilepsy with centrotemporal spikes. Specific drugs are effective for specific types of seizures, and some drugs can worsen other 426-5 ). ). Knowledge of individual drugs as they relate to age, sex, types of seizures ( Table 426-5 comorbid conditions, drug interactions, sedation, tolerance, mood, and withdrawal is critical in the drug selection process. Drugs that cause enzyme induction (e.g., carbamazepine, phenytoin, phenobarbital, oxcarbazepine, topiramate) or inhibition (e.g., valproic acid) can be difficult to manage when additional medications are used for independent conditions, such as oral contraceptives. For these settings and in the elderly, gabapentin and levetiracetam are particularly useful because they have no appreciable drug interactions. The newer drugs are more expensive, whereas phenobarbital costs only pennies per dose and is preferable in many undeveloped countries and for individuals with limited resources. As early as the the 1980s, a randomized comparison comparison study of carbamazepine, phenytoin, primidone, and phenobarbital for newly diagnosed partial seizures, with or without secondary generalization, found that all four drugs had similar efficacies but that the side effects of primidone and phenobarbital made carbamazepine and phenytoin preferable. [2] In a more recent meta-analysis of randomized clinical trials of antiepileptic drugs as monotherapy in newly diagnosed epilepsy, none of the newer antiepileptic drugs showed more efficacy than the traditional drugs, although tolerability was better in some situations. However, methodologic concerns may limit the applicability of these data to general treatment considerations. In trials comparing carbamazepine with lamotrigine monotherapy, for example, efficacy was equivalent, but more carbamazepine-treated carbamazepine-treat ed patients withdrew from the trial because of side effects. [3] In other [4]
[5] [5]
than topiramate and carbamazepine. randomized trials, valproate asis good as or betteradvantage The overall data indicate thatwas there not indisputable of any single agent in terms of
efficacy of monotherapy in patients with newly diagnosed epilepsy, so side effects, toxicity 426-6 ), ), and the type of seizure are of major importance in guiding therapy. For profiles ( Table 426-6 example, carbamazepine, oxcarbazepine, phenytoin, topiramate, lamotrigine, gabapentin, levetiracetam, and zonisamide could all be considered for initial treatment of partial epilepsy, with lamotrigine representing a potentially cost-effective alternative to carbamazepine.[6] Final selection would depend on age, gender, weight, psychiatric status, employment, concomitant medications, and pregnancy concerns relevant to the individual. Similarl Similarly, y, treatment of absence seizures would be equally appropriate with valproic acid, lamotrigine, and ethosuximide, so the accompanying seizure types, gender, age, and other aspects of the clinical setting would guide drug selection. Treatment with the initial drug controls seizures completely in more than 50% of patients with newly diagnosed epilepsy. After failure of the first monotherapy, only 14 to 20% of patients p atients with partial seizures will be successfully controlled with any alternative single drug. In combination therapy, drugs with differing mechanisms of action are used, but side effects are additive, and selection of combinations is not straightforward. Sometimes combining drugs with similar mechanisms is facilitative. Unfortunately, after failing monotherapy trials, less than 10% of patients have complete control of seizures with dual therapy. Medical intractability occurs more often in patients with frequent seizures, multiple types of seizures, abnormal neurologic findings, a brain lesion, onset in the first year of life, or abnormal EEG findings consisting of either spike and slow wave activity or multifocal abnormalities. However, the most valuable predictor of medical intractability in epilepsy is the etiology. Patients with seizures secondary to mesial temporal sclerosis associated with mesial temporal lobe epilepsy or developmental (migrational) substrates are most difficult to manage medically; only 40 to 50% of such patients are controlled as compared with a seizure-free rate of 65 to 80% in patients with newly diagnosed epilepsy of vascular or neoplastic cause. Antiepileptic drugs and concomitant use of other drugs may alter serum llevels. evels. Antiepil Antiepileptic eptic drug levels (see Table 426-6 ) 426-6 ) can establish the optimal therapeutic ranges for the individual, thereby allowing assessment of treatment failures as being caused by noncompliance, drug interactions, or incorrect prescribing. Phenytoin, carbamazepine, oxcarbazepine, topiramate, and phenobarbital induce hepatic enzymes, which may necessitate increasing the dose of other drugs. Similarly, enzyme inhibitors such as valproic acid or macrolide antibiotics can cause cau se toxic levels of antiepileptic drugs. Carbamazepine induces the enzymes that metabolize it, so the initial dose needs to be increased later. Valproic acid inhibits clearance of lamotrigine, thereby allowing use of approximately half the dose of lamotrigine that would otherwise be needed to achieve the same serum level. Treatment of Refractory Epilepsy Epilepsy When seizures fail to respond to antiepileptic drug treatment, potential causes to be considered include incorrect diagnosis, incorrect drug selection, lack of compliance, factors that lower the seizure threshold, factors that reduce medication effects because of enhanced e nhanced metabolism or 426-7 ). ). However, an reduced absorption, and factors that directly activate the CNS ( Table 426-7 estimated 15% or more of patients with partial-onset seizures are unresponsive to medical treatment, and resection of a cerebral region identified to be the origin of intractable partial seizures offers the possibility of cure. Removal of an epileptogenic region requires accurate identification of the region, as well as documentation d ocumentation of a lack of functional consequences after its removal. Video EEG monitoring with seizure recording from scalp electrodes, MRI protocols with special attention to areas commonly associated with refractory seizures (e.g., the medial temporal(perfusion), and frontal are lobes), and functional neuroimaging, including PETboth (metabolism) andareas SPECT routinely used. Neuropsychological evaluation, for localizing
of dysfunction and for establishing the level of functional activity in tissue being considered for possible resection, is an essential component of the evaluation. Good performance on measures of verbal memory, generally believed to rely on o n the dominant medial temporal lobe, may be used as an indicator of excessive risk of memory loss from contemplated resection of dominant medial temporal lobe structures when seizures localize to that region. Sometimes, EEG localization localization of the area of seizure onset o nset requires implantation of intracranial or subdural electrodes or grids, which are also used for electrical stimulation to map cortical function in the nearby regions of the brain. Surgical Interventions In a randomized trial, resective surgery for intractable medial temporal lobe epilepsy achieved a 58% seizure-free rate at 1 year versus 8% in the control group. [7] Although 20% of patients relapse with long-term follow-up, reintroduction of antiepileptic antiepileptic drugs can control the seizures in some patients. When intractable epilepsy is associated with multifocal seizures, when the onset of seizures occurs in functionally critical brain regions, or when localization is not possible, resection cannot be attempted. Alternative surgical interventions, including corpus callosum section or multiple subpial transection, may be of benefit. These usually palliative procedures functionally disconnect epileptogenic tissue from other brain regions, thereby preventing propagation of seizures andand resulting smaller, partial events. Callosotomy thecost major commissure stopsin generalized seizures in most patients, severs but at the of interhemispheric considerable morbidity. Multiple subpial transection involves vertical cuts in the cortex to a depth of about 4 mm, placed 4 to 5 mm apart, in the identified region or regions of seizure generation to sever the horizontal connections that allow the seizure to propagate while maintaining the vertical, functional columns. Electrical Stimulation Electrical stimulation stimulation is now used to treat medically refractory epilepsy when surgery is not indicated. Programmed, intermittent intermittent stimulation of the vagus nerve in the neck with implanted leads attached to a battery placed subcutaneously in the upper part of the chest can reduce the frequency of seizures in approximately a third of patients by about 30%. Electrodes implanted to stimulate cortical epileptogenic locations are under study. Epilepsy Management Issues in Women with Epilepsy Hormonal cycling, pregnancy, and the long-term effects of certain antiepileptic drugs influence the management of epilepsy in women. Estrogen lowers the seizure threshold, whereas progesterone raises it, and changes in hormone levels during the menstrual cycle may aggravate seizures perimenstrually, less often at midcycle. In many women these changes do not cause difficulty with control of the seizure, se izure, but some women have seizures more frequently or even only with their menses (i.e., catamenial epilepsy). Although levels of antiepileptic drugs may fluctuate with the menstrual cycle, altering drug doses at mid or end cycle is generally difficult. Catamenial Catamenial epilepsy is sometimes improved by the administration of an oral contraceptive pill; Depo-Provera may also reduce perimenstrual seizures. Enzyme-inducing antiepileptic drugs, particularly phenytoin, carbamazepine, phenobarbital, primidone, and topiramate, reduce estrogen levels by enhancing its metabolism, so oral o ral contraceptives with higher doses of estrogen may be necessary, or alternative methods of contraception may be preferable. Pregnancy itself has no consistent effect on the frequency of seizures, and the response varies
not only among women but also among pregnancies in individual women. Generalized tonicclonic seizures during pregnancy may pose a risk to the developing fetus. Whether complex partial seizures have similar negative effects on fetal development is not known. Simple partial seizures do not pose any risk unless they progress to a complex partial or generalized tonicclonic event. Although most of of the antiepilept antiepileptic ic drugs double the risk (to 4 to 6% 6%)) of major m malformations alformations in the developing fetus, it is usually important to maintain an effective antiepileptic drug level for each patient during pregnancy. Valproic acid is the most teratogenic of the commonly used antiepileptic drugs, with a substantial risk for spina bifida; it should be avoided in pregnancy and possibly in all women of childbearing age. Carbamazepine is also associated with an increased risk for spina bifida, but less so. The teratogenic effects of newer antiepileptic drugs are still unclear. With use of a single drug at the lowest possible dose, more than 90% of women with epilepsy have normal pregnancies and deliver de liver normal babies without complications. Most antiepileptic drugs reach breast milk only in low concentrations, so breast-feeding is possible. Occasionally, however, somnolence from absorption of even small amounts of antiepileptic drugs by the nursing infant may interrupt successful feeding. Women of childbearing age and particularly women with epilepsy should routinely take 1 to 3 mg of folate per day. Long-term bone loss in women taking antiepileptic drugs, especially those that induce cytochrome P-450, is treated prophylactically with supplemental calcium and vitamin D. Syndromes Epileptic Syndromes The syndromic diagnosis of epilepsy (see Table 426-3 ) 426-3 ) uses the classification of the type or types of seizures, as well as information about the setting in which seizures occur, the patient's neurologic and cognitive status, age at onset, family history, and results of diagnostic studies, including imaging. Selection of specific drug treatment depends on the types of seizures present (see Table 426-5 ). 426-5 ). The need for lifelong treatment, the risk of genetic transmission, the likelihood of concurrent neurologic diseases, the risk of comorbid conditions, and the long-term prognosis are critical factors that can be addressed only with knowledge of the specific epileptic syndrome. The first issues in syndromic diagnosis are whether the epilepsy is related to a localized brain region or is generalized and whether it has an identified cause (symptomatic of or secondary to a detectable brain lesion) or not (idiopathic). Sometimes epilepsy is presumed to be symptomatic but no clear cause can be identified; these cases are called cryptogenic. Thus, the syndromic classification of epilepsies first divides syndromes into localization related versus generalized (see Table 426-3 ) 426-3 ) and into symptomatic versus idiopathic. Other variables are then used to define the specific syndromes within these groups. Although most generalized epilepsies are idiopathic (and genetic) and most localization-related epilepsies are symptomatic with an identifiable brain lesion or cause, idiopathic epilepsy syndromes can be associated predominantly or exclusively with partial onset seizures (localizations related), and symptomatic epilepsy syndromes can be associated predominantly or exclusively with generalized seizures. Generalized Epileptic Syndromes Benign neonatal convulsions, which occur in previously healthy newborns on about day 5, may be partial or generalized tonic seizures. Mutations in two potassium channel genes (KCNQ2, KCNQ3) have KCNQ3) have been associated with this syndrome. Potassium channel regulation may be age dependent and therefore account for the age-related appearance of the seizures. The EEG recording is abnormal and shows rhythmic slow wave activity or spiking with seizures. The
seizures are refractory to treatment, are recurrent over a brief interval, and disappear within a month. About 90% of such infants subsequently have normal development, whereas 10% have subsequent seizures in this idiopathic, generalized epileptic syndrome. In generalized epilepsy with febrile seizures plus, febrile seizures occur in combination with a variety of other nonfebrile types of seizures, including myoclonic, absence, atonic, tonic-clonic, and partial seizures. Mutations in at least four different ion channel genes, including voltagegated sodium channels (SCN1A, SCN2A, SCN3A) and SCN3A) and GABA receptors (GABRG2), (GABRG2), have have been identified. In the syndrome of severe myoclonic epilepsy of infancy, which is also associated with various SCN1A mutations, SCN1A mutations, myoclonic seizures are associated with other types of seizures, including absence, atonic, and partial seizures. The seizures are difficult to treat and are associated with developmental and cognitive decline after 1 to 2 years of normal development. Childhood absence epilepsy begins in early to mid childhood, usually with autosomal dominant inheritance, and is characterized by absence seizures, rarely with other types of generalized seizures. It is self-limited in about 40% of cases. It occurs in the setting of otherwise normal brain structure and function. The seizures are accompanied by a characteristic 3-Hz spike and wave EEG discharge, which appears in short bursts between seizures se izures and in continuous runs during 426-2 ). ). Earlier onset may be associated with a tendency to remit, whereas seizures (see Fig. 426-2 onset after 12 of age is more likely to be accompanied by generalized tonic-clonic seizur seizures es and persist intoyears adulthood. Juvenile myoclonic epilepsy usually starts in the second decade with generalized tonic-clonic and myoclonic seizures. Mutations in GABA receptors, including GABRG1, GABRG1, can can be found. Seizures typically occur in the morning, immediately after awakening. A proportion of these patients have had absence seizures se izures as well. The EEG recording may be similar to the 3-Hz spike-wave of absence epilepsy, but the spike-wave pattern can be faster. The seizures are especially linked to sleep deprivation and tend to appear in college students. Lifetime treatment is generally needed. West's syndrome is a catastrophic, usually secondary generalized epileptic syndrome that appears before the age of 12 months and ceases by the age of 5 years, often to be replaced by other symptomatic generalized epilepsy syndromes such as Lennox-Gastaut (see later). 444 ) ) and hypoxia are among the common causes, but West's Tuberous sclerosis ( Chapter 444 syndrome can also be idiopathic. The syndrome comprises a triad of so-called infantile spasms (synonymous terms include myoclonic spasms, jackknife convulsions, salaam seizures), developmental arrest, and an EEG pattern called hypsarrhythmia (a markedly abnormal EEG pattern with high-amplitude slowing and superimposed multifocal spikes, polyspikes, and spike and slow wave complexes). Associated abnormalities often include developmental delay, porencephaly, atrophic lesions, calcifications, and agenesis of the corpus callosum. Lennox-Gastaut syndrome, a secondary or cryptogenic generalized epilepsy found in children with mental retardation, is characterized by the occurrence of multiple generalized types of seizures, including atypical absence, generalized tonic-clonic, tonic, atonic, and partial seizures. The EEG pattern is a spike-wave variation but slower than the 3 Hz associated with absence seizures, more characteristically between 2 and 2.5 Hz. It often appears after West's syndrome has resolved. Febrile seizures are acute secondary seizures that are a re not considered epilepsy because seizures occur only when provoked by fever. The seizures begin after 6 months of age and generally do not continue beyond the age of 6 years. Usually, the febrile seizure diathesis is left
untreated because the prognosis is benign. When seizures occur in the setting of a neurologic abnormality or are prolonged or complicated, the risk for later epilepsy is increased. Localization-Related Localization-Relat ed Epileptic Syndromes Benign rolandic epilepsy, which is also called benign epilepsy with central temporal spikes, is an age-related partial seizure disorder with onsetorbetween and 13 years of age; it is characterized by almost exclusively nocturnal partial motor sensory3seizures with facial or oral onset and with frequent secondary generalization. The family history is positive for epilepsy diagnoses in nearly 50% of cases. The EEG recording shows spiking in the central/temporal region. In some cases, the disorder may not require treatment because it usually remits spontaneously (97%) and is not associated a ssociated with any known brain abnormality. Autosomal dominant dominant nocturnal front frontal al lobe epilepsy is characterized by clusters clusters of brief seizures seizures that occur during sleep and are manifested by turning prone, vocalization, and violent thrashing lasting 10 seconds, followed by immediate return to sleep. The syndrome is caused by mutations in genes for neuronal nicotinic acetylcholine receptors (CHRNA4, CHRNB2); the CHRNB2); the inheritance pattern appears to be autosomal dominant with variable penetrance. Seizures begin in childhood and persist, but they are not associated with other clinical manifestations or evidence of structural or functional brain abnormalities. Lobar epilepsies are epileptic syndromes that begin in the temporal, parietal, occipital, and frontal lobes. Each of these lobes has subdivisions and regions, which can result in different clinical manifestations and EEG findings. Causes include neoplastic, traumatic, developmental, infectious, and ischemic diseases. Clinical characteristics are consistent with seizures originating 426-2 ). ). in each specific cortical location (see Table 426-2 Mesial Temporal Lobe Epilepsy Mesial temporal lobe epilepsy is the most common partial (lobar) epilepsy in adults. It is characterized by recurrent simple and complex partial seizures that originate in mesial temporal/limbic temporal/limbi c structures, as documented by EEG seizure recordings obtained from implanted electrodes placed in the medial temporal regions. Various components of the mesial temporal limbic network (including the hippocampus, entorhinal cortex, amygdala, neocortical areas of the frontal and temporal lobes, and dorsal medial thalamus) are probably involved in the pathogenesis of these seizures. Mesial temporal sclerosis, also called hippocampal sclerosis, is characterized by neuronal loss and gliosis, mostly in the CA1 and CA3 regions of the hippocampus, with mossy fiber reorganization seen as sprouting of neuropeptide Y and dynorphin interneurons into the inner third of the dentate molecular layer. Whether the neuronal loss is secondary or primary and whether neuronal reorganization has a critical role in the epileptogenic process are not known. The seizures of mesial temporal lobe epilepsy begin at 5 to 15 years of age. Seizures have mostly complex partial manifestations with altered consciousness, typically beginning with an aura of a rising epigastric sensation or a feeling of déjà vu, followed by oral and alimentary automatisms and later by contralateral arm dystonia and ipsilateral arm automatisms. The seizures are lengthy (lasting minutes), rarely generalize, and typically occur three to five times a month. Auras without following seizures are common. Up to 70% of patients have a risk factor, such as lengthy and complicated seizures before the age of 4 years, frequently associated with fever or with encephalitis, meningitis, or trauma. However, the characteristic seizures generally begin some years later. Most cases are sporadic, but there are familial forms of mesial temporal lobe epilepsy. Hippocampal atrophy and increased hippocampal T2 signal are best seen on coronal MRI, and widespread hypometabolism is seen in the temporal lobe on PET. Material-
specific (verbal or visual) memory impairment corresponds to primary involvement of the dominant or nondominant hippocampus. EEG recordings show temporal lobe spikes interictally (see Fig. 426-3 ), 426-3 ), as well as rhythmic 4- to 7-Hz discharges over the appropriate temporal lobe during seizures (see Fig. 426-1 ). 426-1 ). Less than 40% of patients with newly diagnosed mesial temporal lobe epilepsy will be controlled with medications, although familial cases are more easily managed medically. Up to 80% of patients with medically refractory seizures become seizure free, usually without medications, after resection of the responsible anterior temporal lobe and hippocampal structures. Status Epilepticus Epilepticus Status epilepticus is a medical emergency in which seizures occur continuously or repeatedly without intervening resumption of consciousness. Although the standard diagnostic criteria require a duration of 30 minutes, even 5 minutes of g generalized eneralized tonic-clonic seizures cause hypoxia, lactic acidosis, muscle breakdown, and CNS toxicity as a result of excessive excitatory neurotransmitters, neurotransmitter s, and longer durations cause p progressively rogressively more severe long-term morbidity and mortality. Immediate intervention with parenteral agents to stop the seizures is mandatory. Prompt attention to defining the cause of the status epilepticus must also be given. Stabilization of airway and vascular status and initiation of assessment of the diagnostic possibilities are immediately followed by the use of intravenous benzodiazepines (e.g., lorazepam, 0.1 mg/kg given at 2 mg/min). Diazepam (10 mgatintravenously) an alternative. seizures continue for 10 to 15 minutes, intravenous phenytoin 20 mg/kg (or is fosphenytoin in aIfsimilar phenytoinequivalent dose) should be administered. If seizures do not respond within an additional 15 minutes, barbiturates (phenobarbital, 20 mg/kg intravenously) or a continuous drip of midazolam (0.1 to 2 mg/kg/hr), pentobarbital (0.5 to 3 mg/kg/hr), or propofol (2 to 4 mg/kg/hr) can be used. In refractory cases, the next step is general anesthesia for 24 hours. TABLE 426-5 426-5 -- ANTIEPILEPTIC DRUG SELECTION BY SEIZURE TYPE Useful Combinations (Any A + Any B)
Other Useful Alternatives (Monotherapy or Polytherapy)
First or Alternative Monotherapy (Alphabetical Order)
A
B
Partial seizures (complex or simple) with or without secondarily generalized seizures
Carbamazepine (CBZ)
CBZ
GBP
Acetazolamide (ACZ)
Gabapentin (GBP)
LTG
LEV
Chlorazepate (CLZ)
Lamotrigine (LTG)
OXC
TPM
Clonazepam (CLN)
Levetiracetam (LEV)
PHT
VPA
Phenobarbital (PB)
Oxcarbaz aze epine (OXC)
ZNS
Primidon one e (PRM)
Phenytoin (PHT)
Topiramate (TPM) Valproate (VPA) Zonisamide (ZNS)
Felbamate (FBM)
Useful Combinations (Any A + Any B)
First or Alternative Monotherapy (Alphabetical Order)
Other Useful Alternatives (Monotherapy or Polytherapy)
A
B
Tonic clonic seizures, tonic Carbamazepine seizures, atonic seizures
CBZ
LEV
Acetazolamide
Lamotrigine La
LTG
TPM
Chlorazepate
Levetiracetam Le
OXC
VPA
Clonazepam
Oxcarbazepine
PHT
ZNS
Felbamate (FBM)
Phenytoin
Phenobarbital
Topiramate
Primidone
Valproate Va Zonisamide
Absence seizures
Ethosuximide (E (ETH) TH)
LTG
ACZ
Acetazolamide
Lamotrigine Valproate
VPA
CLN ETH
Clonazepam Phenobarbital
Topirimate
TPM
Primidone
Myoclonic seizures
Clonazepam
CLZ
Phenobarbital
Valproate
VPA
ZNS
Zonisamide Levetiracetam
LEV
TABLE 426-6 426-6 -- CHARACTERISTICS OF MAJOR ANTIEPILEPTIC DRUGS
Name
Total mg/day (Usual Schedule)
Therapeutic Range (μg/mL)
Prominent Side Effects
Other Effects Other Issues
Carbam Car bamaze azepin pine e 400 400–16 –1600 00 (bid)
4–12
Diplopia, fatigue, hyponatremia
Mood stabilizer
Enzyme inducer
Gabapentin
600–6000 (tid, qid)
2–12
Fatigue
Treatment of pain
No drug interactions
Lamotrigine
100–600 (bid)
4–18
Insomnia, headache, tremor, anxiety
Mood stabilizer
Risk for StevensJohnson syndrome; slow start-up
Leve Leveti tirracet acetam am
50 500– 0–30 3000 00 (bid)
3–63
Mood change, irritability, lethargy
No drug interactions
Oxcarbazepine
300–2400
6–40
Diplopia,
Mood
Total mg/day (Usual Schedule)
Name
Phenobarbital
Therapeutic Range (μg/mL)
Prominent Side Effects
Other Effects Other Issues
(tid)
hyponatremia, sedation
stabilizer
60–240 ((h hs) 15–40
Fatigue,
Joint pain
Enzyme inducer
depression, sedation Phenytoin
200–600 (bid)
10–20
Fatigue, hirsutism, gingival hypertrophy
Treatment of some pain
Enzyme inducer
Topiramate
50–600 (bid)
2–12
Anorexia, weight loss, kidney stones, speech disturbance, distal paresthesias
Headache prophylaxis, mood stabilizer
Enzyme inducer
Valproate
500–6000 (tid)
50–100
Weight gain, hair loss, tremor
Headache prophylaxis, mood stabilizer
Enzyme inhibitor, parkinsonian effects in elderly
Zonisamide
100–600 (hs)
10–40
Anorexia, kidney stones, dizziness, distal paresthesias
Mood stabilizer
TABLE 426-7 426-7 -- CONSIDERATIONS IN REFRACTORY EPILEPSY
Incorrect diagnosis Nonepileptic disorder (see Table 426-4 426-4 ) )
Seizure type
Incorrect drug selection
Lack of compliance
Other drugs causing reduced levels of antiepileptic drugs Other medications that exacerbate seizures Interferons
Lithium
Phenothiazines
Antidepressants
Isoniazid
Theophylline
Antihistamines
Illicit drug use Cocaine
Amphetamines
Drug withdrawal Alcohol
Barbiturates
Benzodiazepines
Comorbid conditions exacerbating epilepsy Diabetes mellitus
Sleep disorder
Psychosis
Pregnancy
Other central nervous system–activating factors Heat (hot tubs, saunas, fever, exercise)
Sleep loss
Fasting
Stress
Hyperventilation
Prognosis After a single, single, first seizure, only 25% of patients patients have a recurrent seizure. seizure. Risk factors factors for recurrence include the presence of a brain lesion or injury or abnormal EEG findings. The risk for future recurrence rises to 70% after a second seizure. The prognosis with treatment for individuals with two or more unprovoked seizures is excellent. The majority of patients without risk factors who have been seizure free for 5 years can be successfully withdrawn from medications. Remission Remission is less likely for adults with more frequent seizures, a greater number of seizures before diagnosis, multiple types of seizures, or abnormal EEG or neurologic findings. Most remissions occur early, and response to treatment can also be predicted early: only 60% of patients p atients who do not achieve control of seizures with medical treatment in the first year will ever remit, and only 10% of patients uncontrolled after 4 years can anticipate successful response to any medical regimen. In population-based studies, idiopathic epilepsy has little effect on mortality rates, but secondary “symptomatic” epilepsy increases mortality rates two- to six-fold. Most of the increase in mortality among patients with epilepsy has been related to the underlying cause, but seizure-related causes of death include status epilepticus, injury, and SUDEP (sudden unexplained death in epilepsy). The pathophysiology of SUDEP, which occurs more often in individuals with frequent seizures and generalized tonic-clonic seizures, is unknown, although pulmonary edema is usually found on autopsy and hypoventilation is considered a likely mechanism. There is speculation that ion channel defects may cause both the epilepsy and cardiac abnormalities that predispose to SUDEP. The decreased mortality after successful control of seizures is related, in part, to a reduced risk for SUDEP.
Epilepsy Therapies
The goals of all epilepsy therapies are to achieve seizure freedom without adverse effects of treatment. Choosing between the numerous options available av ailable for epilepsy treatment can be daunting for physicians and patients alike. The last two decades have seen the release of a number of newer AEDs into clinical use, many of which offer improved tolerability and safety profiles. Another advent is vagus nerve stimulation (VNS), the first device using the novel approach of electrical stimulation in epilepsy approved by the Food and Drug Administration (FDA). Centers offering expert evaluation for epilepsy surgery have also become more widely available. Guidelines for choosing among epilepsy therapies are currently lacking. Until evidence based guidelines are developed, optimal therapeutic triage must be highly individualized by synthesizing available data, clinical wisdom, and the patient's preference. All AEDs have the potential to cause dose-related neurotoxic adverse effects. Fortunately, these may be obviated in most patients by dose reduction or substituting for a better tolerated AED. ANTIEPILEPTIC DRUG THERAPY
Table 4 4 itemizes itemizes specific AEDslevels, with accompanying information onThere clinical uses, typical dosing and blood and cardinal adverse effects. arespectrum currentlyof no clear evidence-based algorithms to guide the temporal sequencing of different AED trials. Nonetheless, common treatment principles underlie the choosing, dosing, sequencing, and monitoring of AED therapy in epilepsy care. Here are several basic principles: •
Choose AED therapy appropriate for the epilepsy syndrome.
•
Consider paent characteriscs and co-morbidies when choosing AEDs.
•
Employ AED monotherapy at the lowest lowest eecve dosage dosage to achieve seizure freedom.
•
Reserve AED polytherapy (combining two or m more ore AE AEDs) Ds) for refractory paents and
minimize total drug load to limit adverse eects.
•
Treat according to the paent's clinical response, not the AED level.
•
•
Monitor for long-term long-term comp complicaons licaons of older AED therapy and and con consider sider withdrawal withdrawal of therapy when appropriate. Choose aordable AED therapy.
TABLE 4 -- Propertes of he AEDs
Specrum of
Older AEDs
Carbamazepi ne (Tegretol)
Eec
Daily Adul Dosage/Inerv
Usual Level
Adverse
(μg/mL)
Eecs
al
Idiosyncra tc
Ineractons
Toxicites
Diplopia, dizziness,
400– Paral
1600+mg
4–12+
(bid-qid)
ataxia,
Bidireconal Yes
hyponatremi
(AEDs, OC, AC, many)
a
Ethosuximide (Zaronn)
Phenobarbita
500– Absence
1500+mg
40–100+
(bid)
Paral
90–180+mg
15–40
(qd)
l
Nausea, sedaon
Yes
Undirecon al
Sedaon,
Bidireconal
psychomoto Yes
(AEDs, OC,
r slowing
AC, many)
Sedaon, Phenytoin (Dilann)
Paral
200–400+mg (qd–bid)
dizziness, 8–20+
ataxia,
Bidireconal Yes
gingival
(AEDs, OC, AC, many)
hyperplasia
Primidone (Mysoline)
500– Paral
1500+mg (bid–d)
5–12 (measure phenobarbit
Sedaon,
Bidireconal
psychomoto Yes
(AEDs, OC,
r slowing
AC, many)
al) Valproate (Depakene,
Broad
Depakote)
Newer AEDs
Felbamate (Felbatol)
Nausea,
750– 2500+mg
50–100+
(qd–d)
tremor, hair loss, weight
Yes
Bidireconal (AEDs)
gain
1800– Broad
4800+mg (bid–d)
Irritability 30–100+
insomnia, weight loss
Bidireconal Yes
(AEDs, OC, AC)
Gabapenn (Neuronn)
Specrum of Eec
Daily Adul Dosage/Inerv
Usual Level
Adverse
(μg/mL)
Eecs
al 900–
Paral
3600+mg
Paral (?
(Vimpat)
Broad)
Lamotrigine (Lamictal) Leveraceta m (Keppra)
Oxcarbazepin e (Trileptal)
Pregabalin (Lyrica)
Broad
Broad
200–600mg
300–600+mg (qd–bid) 1000–3000+ +mg (bid) 600–
Paral
3600+mg (bid)
Paral
150–600+mg (bid)
tc
Ineractons
Toxicites
Sedaon, 4–20++
(d–qid) Lacosamide
Idiosyncra
dizziness,
No
None
weight gain
?
1–20+
5–40++
Sedaon, fague
Dizziness, rash Sedaon, dizziness
10–40+
Sedaon,
(MHD)
dizziness
? (None in clinical trails)
Yes
No
Yes
None known
Bidireconal (AEDs, OC)
None
Bidireconal (AEDs, OC)
Sedaon, 2–10
dizziness
No
None
?
?
?
Bidireconal
weight gain Dizziness, somnolence,
Regabine
Paral
600–1200+
?
confusion, incoordina on
Runamide (Banzel) Tiagabine (Gabitril) Topiramate (Topamax)
Broad
Paral
Broad
400– 3200mg/d
?
Sedaon, diarrhea
Unidirecon
16–64mg
100–
Sedaon,
(bid–d)
300μg/mL
weight gain
100–600+mg
10–20+
Sedaon,
Glaucoma- Bidireconal
cognive
like
(AEDs, OC at
complaints,
reacon
high doses)
(qd–bid)
paresthesias
No
al
Specrum of Eec
Daily Adul Dosage/Inerv
Usual Level
Adverse
(μg/mL)
Eecs
al
Idiosyncra tc
Ineractons
Toxicites
, weight loss, rare nephrolithia sis Somnolence, Vigabatrin
Paral/infan 2000–
(Sabril)
le spasms
4000+mg/d
fague, ?
weight gain, behavioral
Visual eld Unidirecon decit
al
disturbances Sedaon, paresthesias Zonisamide (Zonegran)
, weight loss,
100–600+mg Broad
(qd–bid)
10–40+
rare
Unidirecon Yes
al
nephrolithia sis Notes: AED
= antiepileptic drug; + = higher doses/levels often additionally effective, as tolerated; ++ = considerably higher doses/levels sometimes additionally effective in intractable patients, as tolerated; MHD = 10, 11 Monohydroxy Mono hydroxy derivative active metabolite of oxcarbazepine. Interactions: Unidirectional indicates that other AEDs or drugs may affect this AED; bidirectional indicates that other drugs may affect this AED, and this AED affects other drugs; OC = oral contraceptives; AC = anticoagulants; an ticoagulants; many = many other non-AEDs. ? = Available information incomplete and based on pre-marketing published data from clinical trials.
Choosing an AED appropriate for the patient's epilepsy syndrome is an important tenet of epilepsy care. AEDs have different spectrums of efficacy for various seizure types within epilepsy syndromes. Some AEDs are narrow in their spectrum of o f efficacy, whereas others are broader, treating a variety of different d ifferent seizure types well. Broad-spectrum AEDs may be favored when the epilepsy syndrome diagnosis d iagnosis is ambiguous because they offer potential efficacy against most seizure types and have less potential to aggravate some epilepsy syndromes. To some degree, the spectrum of efficacy of an AED is related to its postulated mechanism of action. AEDs that chiefly antagonize sodium channel ionophores or promote
γ-aminobutyric acid (GABAergic) neurotransmission are generally most effective in partial-onset seizures, whereas drugs that combine these and other mechanisms of action action may have broader efficacy in primary generalized seizure types. Evidence from prospective, blinded, randomized clinical trials is only available for certain AEDs for monotherapy use. Gabapentin (Neurontin), oxcarbazepine (Trileptal), and lamotrigine (Lamictal) possess randomized controlled trial evidence for monotherapy treatment of partial-onset seizures, and topiramate (Topamax) has evidence for monotherapy use in new-onset epilepsy. All older AEDs and an d other newer AEDs have either comparator trial or anecdotal monotherapy evidence. All marketed newer AEDs have randomized controlled trial evidence for use as adjunctive treatment in partial-onset seizures, whereas older AEDs have comparator trial evidence. Patient characteristics and co-morbidities may affect the choice of an AED. For example, weight is an important consideration. Valproate (Depakene, Depakote), Depa kote), pregabalin (Lyrica), and carbamazepine (Tegretol) may contribute to weight gain, whereas topiramate (Topamax) and zonisamide (Zonegran) may include weight loss among their adverse effect profile. The patient with both epilepsy and migraine might favor topiramate or valproate, drugs that are efficacious for both conditions. In general, AED monotherapy is just as effective—or more effective—than polytherapy. Monotherapy limits the potential for adverse effects and drug interactions. AED dosing must be individualized to achieve optimal op timal results. Our strategy is to titrate the AED toward a target dose that has proven effective for most individuals in clinical studies and in our experience. Dose adjustment can then be made in the event of adverse drug reactions or recurrent seizures. If the endpoint of seizure freedom is preserved, maintaining a lower but clinically therapeutic AED dosage is entirely acceptable. If a patient continues to experience breakthrough seizures, raising the AED dose to the maximal dose tolerated is sometimes necessary, although recent evidence demonstrates that only o nly a minority of patients become seizure free when dosed above the usual therapeutic range, so a practical view-point of treatment futility should be realized when patients experience frequent breakthrough seizures despite adequate AED dosages. Therapeutic change should be made when seizure freedom is not maintained at AED doses effective for most patients. Overlapping AEDs in transitional polytherapy (where the baseline AED is maintained at the current dose to limit breakthrough seizures, the newly added AED is titrated to a protective dose, then the original drug is tapered and discontinued) is the preferred method when introducing a new AED monotherapy. Abruptly stopping the existing AED increases the risk of seizures (and perhaps status epilepticus), whereas introducing the new n ew AED too rapidly may induce adverse effects that taint the patient's perception of what could be an effective therapy. Many medically refractory epilepsy patients require chronic polytherapy. Overall, only a small minority of refractory patients can be rendered seizure free with AED polytherapy, but they may benefit substantially by reduction of seizure burden. Although no good evidence for specific AED polytherapy combinations exists, augmenting monotherapy with an AED offering a different or complementary mechanism of action may be considered. Great care must be taken to avoid excessive drug dosing and drug–drug interactions.
Initiating and maintaining AED polytherapy is difficult and requires oversight by a neurologist with extensive knowledge of clinical pharmacology. AED dosing should be adjusted to achieve the clinical goals of seizure freedom without adverse effects. This may indeed be a delicate balancing act for some patients because all AEDs have the potential to cause dose-related “neurotoxic” adverse effects. Fortunately, adverse effects may be obviated in most patients by dose reduction or substituting for a better tolerated AED. Philosophies on the use of AED blood level monitoring differ, but most agree that blood levels should in most cases be considered only on ly a guideline to treatment. AED levels should not be perceived as an absolute indication for altering AED dosing, divorced from clinical judgment of the patient's seizure control or adverse effects. Blood-level monitoring monitoring can help guide therapy, but so-called therapeutic levels are derived from treatment of populations. An individual patient may require a lower or higher intensity of AED therapy to achieve optimal results. For example, some patients p atients develop breakthrough seizures even at supratherapeutic or toxic levels, others may experience adverse effects within the usual therapeutic range, whereas some patients become seizure-free on levels in a subtherapeutic range. The danger of overreliance on AED blood levels is twofold: levels may lead both physicians andofpatients topatients a false sense of therapeutic adequacyTypical or may clinical lead to errant manipulation AEDs in who require no adjustments. scenarios where clinicians should obtain AED levels include the following: 1.
Aer reachi reaching ng steady-state steady-state administraon administraon of an AED, to establish a p paent's aent's individual personal baseline against which future comparisons can be made in event of breakthrough seizures.
2.
While trang individual AEDs in complex polypharmacy regimens, when drug interacons may inuence either the new adjuncve AED or baseline anepilepc and other
medicaons.
3.
Adjusng for alteraons alteraons in AED AED metab metabolism olism during aging, disease states, a and nd du during ring each trimester of pregnancy when AED levels can uctuate substanally based on altered drug absorpon, metabolism, protein binding, and clearance. With some heavily protein-bound drugs, especially phenytoin (Dilann), obtaining free drug levels is necessary to discern the biologically acve fracon of the drug, especially in chronically or crically ill paents.
4.
When trying to determin determine e the AED responsible for adverse adverse eects in a paent paent receiving polytherapy.
In summary, AED levels are most useful when testing a clinical hypothesis. We discourage the use of routine or scheduled levels, an exception being chronic phenytoin therapy in institutionalized patients (where zero-order kinetics from nonlinear hepatic metabolism may lead to drug accumulation and toxicity) and during pregnancy when altered AED
absorption, metabolism, and elimination may lead to declining drug concentrations during successive trimesters. With chronic AED therapy, intermittent blood testing for monitoring of liver function tests and hematologic functions is reasonable although not of proven value. The highest risk of idiosyncratic reactions associated with AEDs such as serious rash, hepatotoxicity, and hematologic dyscrasias is during the first 6 to 12 months of o f therapy and extremely rare thereafter. Recently, the FDA has recommended assessing the HLA-B*1502 genotype prior to initiating carbamazepine (Tegretol) in patients of Asian ethnicity, given that patients of Han Chinese ancestry carrying this allele have demonstrated a heightened risk of severe allergic rash, including Stevens-Johnson syndrome or toxic epidermal necrolysis, and the drug should be avoided in such patients. It seems likely that expanded screening of selected patient populations will prove necessary as knowledge concerning heightened vulnerability for severe idiosyncratic reactions continues to grow through further research in the fields of pharmacogenomics and pharmacoepidemiology. There is mounting concern that patients on chronic maintenance therapy with older AEDs are at risk for osteopenia and osteoporosis. Any enzyme-inducing AED (carbamazepine [Tegretol], phenytoin [Dilantin], phenobarbital, primidone [Mysoline], and oxcarbazepine [Trileptal]) thedensity. potential to decrease bone density. (Depakconcern, (Depakote) ote) maygiven also lead to decreasedhas bone Chronic phenytoin exposureValproate is of particular its rare association with cosmetic adverse effects including gingival hyperplasia (which may be severe enough to warrant repeated gingivectomies), peripheral neuropathy, and irreversible cerebellar ataxia. Considering AED withdrawal in appropriate candidates or transition to another newer AED therapy without such untoward effects is often reasonable. AED cost is a crucial social issue that may trump all other medical principles in selection and maintenance of AED therapy in patients who lack adequate medical insurance. Choosing expensive AEDs that a patient cannot afford may erode the patient's adherence to treatment and trust in the physician. Insurance and financial status must therefore be considered, so that available resources (i.e., indigent federal- or state-sponsored insurance or corporate pharmaceutical assistance programs) can be summoned if a prohibitively expensive newer AED is the best therapeutic choice. Of the newer AEDs, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide are available as generic formulations. Because evidence regarding the pharmacokinetic and therapeutic equivalence of these generic formulations in epilepsy patients is not available, caution is advisable prior to switching between different AED formulations. Although there is no evidence to guide clinicians in switching between b etween AED formulations, obtaining a baseline AED level prior to a contemplated switch between AED formulations and rechecking levels once the new formulation is adjusted to its target dosage is a reasonable precaution to avoid breakthrough seizures or inadvertent toxicity. Withdrawal from chronic AEDs is a difficult consideration in the older adolescent or adult with epilepsy because seizure recurrence may impact driving and work abilities. In general, it is worthwhile to consider an attempt at withdrawing AED therapy when the patient has been seizure free for an arbitrary period between 2 and 5 years. Available data suggest that approximately 25% to 70% of patients experience seizure recurrence with AED
withdrawal. The decision to withdraw AED therapy must be discussed in the context of the patient's lifestyle and responsibilities responsibilities because driving and work considerations may be paramount and trump the medical prognosis. Neurologic consultation should be strongly considered when AED withdrawal is contemplated. EPILEPSY SURGERY
Evaluation for epilepsy surgery should be strongly considered in patients with refractory partial epilepsy. A syndrome particularly amenable to surgical intervention intervention is mesial temporal-lobe epilepsy (MTLE), characterized by medically refractory complex partial seizures, often a history of complex febrile seizures in infancy, and hippocampal sclerosis on brain MRI. Resective surgery for epilepsy has been performed for over a century, and advances in EEG and neuroimaging have increased the widespread application of epilepsy surgery. A pivotal clinical trial established the clear superiority of anterior temporal lobectomy over medical therapy for chronically refractory MTLE in carefully selected patients. Identification of potential candidates for epilepsy surgery remains the biggest challenge for tertiary care epilepsy centers. Some have estimated that nearly 75,000 potential surgical candidates in the United States remain under care in primary care settings with ongoing seizures, yet only 3000 or fewer surgical procedures for epilepsy are performed annually. Potential candidates for resective epilepsy surgery have refractory epilepsy with ongoing seizures that have been resistant to at least two to three appropriately administered AEDs. The precise seizure burden meriting an aggressive, invasive approach remains a subject of conjecture, but even one to two consciousness-impairing seizures annually may be highly disabling in patients who aspire to work and drive. The basic approach in epilepsy e pilepsy surgery involves identification and precise localization of the epileptogenic zone, the region of the brain that is necessary and sufficient to cause clinical seizures; determining whether the patient possesses appropriate functional reserve for safe removal of that seizure focus; and subsequent subsequen t operative resection of this area. A variety of investigations must be performed at specialized comprehensive epilepsy centers to determine if epilepsy surgery would be effective and safe for an individual patient. The most useful and important initial investigations investigations are a high-resolution volumetric brain MRI (with thin cut coronal plane acquisition acq uisition perpendicular to the hippocampal long axis) and inpatient prolonged ictal V-EEG monitoring that permits intimate correlation and offline, post hoc detailed analysis of the ictal behavior and EEG to localize the patient's habitual clinical seizures. Additional techniques that help localize the epileptic focus preoperatively include functional imaging techniques such as single photon emission computed tomography (SPECT) and PET, magnetoencephalography, and neuropsychological testing. An intracarotid sodium amytal test is necessary in most patients to lateralize memory functions accurately and estimate functional reserve prior to surgery. In some cases, invasive EEG recording with surgically implanted subdural or parenchymal
strips or grids of electrodes is necessary to confirm the seizure focus precisely and allow mapping of eloquent functional cerebral cortex to reduce operative morbidity. When a structural epileptogenic mesial temporal brain lesion evident on o n MRI is concordant with well-localized habitual clinical seizures by ictal V-EEG, there is a 60% to 90% chance that surgery will produce seizure freedom. Resection in neocortical neo cortical epilepsies offers a 30% to 80% chance of achieving a seizure-free outcome, depending largely on whether a MRI lesion concordant with the seizure focus is present. Surgical efficacy contrasts with a 5% or less chance that additional AED therapy will render the refractory patient seizure free. Favorable seizure outcome must be balanced with a 3% or less risk of major morbidity (i.e., hemorrhage, infection, stroke, memory, language, or hemianopic visual field deficit) incurred by surgery. Risk may be higher in extratemporal epilepsy surgery for postoperative motor, sensory, and visual deficits, depending on the location of the seizure focus. Memory or language deficits may occur oc cur in temporal lobe operations. OTHER ALTERNATIVE THERAPIES
Some patients with refractory partial epilepsy are not suitable epilepsy surgical candidates because of diffuse or unlocalizable epileptic foci, whereas others may choose not to undergo brain surgery despite suitable candidacy. In these cases, other options may still exist. The vagus nerve stimulator (VNS) is the only electrical device d evice currently approved as an adjunctive treatment for partial-onset seizures. A battery-operated generator and programmable computerized stimulator are placed surgically in a subcutaneous pocket on the left anterior chest. The device looks much like a cardiac pacemaker and has electrical leads connected to the left vagus nerve in the neck. Once implanted, the device is programmed by means of a radiofrequency wand in the physician's office and provides a small electrical current to the nerve at preset intervals and amounts. The patient also has the opportunity to trigger a stronger current to attempt to abort ab ort or lessen an oncoming seizure by means of a magnet that is passed externally over the device. The efficacy of VNS for seizure reduction is roughly comparable to that of AEDs; approximately 40% of patients experience a 50% or greater reduction in their seizures, and up to 15% of patients become seizure free. Although there are no current evidence-based guidelines for the best timing of VNS placement, we reserve VNS for patients who are not resective surgery candidates or who refuse surgery and those who have failed most older and newer AEDs. In addition to reducing seizure burden, VNS may improve a patient's quality of life by improving alertness, mood, and memory. Predictors of which patients are most likely to benefit from VNS, and the optimal dosing of the device once it is implanted, are yet to be defined in prospective clinical trials. A recently completed large, randomized controlled trial of deep brain stimulation in refractory partial epilepsy has demonstrated that 60% of patients responded with a 50% 5 0% or greater seizure reduction and nearly 20% of patients achieved 90% seizure reduction during long-term follow-up. Additional neurostimulation therapies are being evaluated, including cortical co rtical stimulation and transcranial magnetic stimulation. Two recent randomized controlled trials of transcranial
magnetic stimulation (TMS) have yielded conflicting findings concerning efficacy; one study targeting patients with MRI-visible cortical malformations demonstrated TMS efficacy for seizure reduction. Specialized diets may be a useful adjunctive treatment for epilepsy. The best studied of these is the ketogenic diet, a high-fat, low-protein, low-carbohydrate diet that induces systemic ketosis, which has an antiepileptogenic effect on the brain. The ketogenic diet is most often successfully used in children, but it may also a lso be tried in adolescents and adults. Unfortunately, unless rigid compliance is assured, the ketogenic diet produces little benefit and, in general, most adolescents and adults have limited tolerance of the diet. However, highly motivated and desperately refractory epilepsy patients may benefit from the ketogenic diet. An alternative that is often more tolerable, but not yet robustly studied, is the modified Atkins diet, a high-fat, moderate-protein, low-carbohydrate diet that induces mild ketosis. Identifying and treating seizure aggravators is an important consideration. Recent studies have suggested that obstructive sleep apnea (OSA) is a frequent co-morbidity in refractory epilepsy, and nasal continuous-positive airway pressure in patients with refractory epilepsy and co-morbid OSA may lead to seizure reduction. Primary sleep disorders such as restless legs syndrome periodic limb movements disorder fragment and is worsen seizure burden and in patients with refractory epilepsy. If amay primary sleepsleep disorder suspected, a diagnostic polysomnogram should be ordered, and aggressive treatment for the sleep disorder should be initiated. Although most complementary and alternative therapies in epilepsy have not been rigorously studied, a variety of behavioral stress reduction techniques, meditation, yoga, y oga, or naturopathic treatments may be considered. Most of these therapies have few risks and occasionally benefit individual patients. Botanical extracts for epilepsy therapy that possess potent in vitro antiepileptogenic properties and wide therapeutic windows are currently being investigated as another avenue of therapy for refractory patients. STATUS EPILEPTICUS: IDENTIFICATION AND MANAGEMENT
Status epilepticus is a prolonged, unremitting epileptic seizure that constitutes a medical emergency. Until the past decade, status epilepticus was defined as a seizure lasting 30 minutes or longer (from onset through the end of the ictal period, exclusive of the postictal recovery phase that may in itself last well over 30 minutes). However, more recent data suggest that most seizures that self-terminate do so by 3 minutes after onset, indicating that longer lasting seizures are unlikely to stop without intervention. Status epilepticus may be convulsive or nonconvulsive. n onconvulsive. Status epilepticus frequently begins with a prolonged generalized tonic–clonic or partial motor seizure, followed by a minimally convulsive or nonconvulsive phase with or o r without subtle motor features such as facial or eyelid twitching, or nystagmus. Status epilepticus thus evolves in a manner analogous to a lethal cardiac dysrhythmia, proceeding from clinically overt convulsive convu lsive movements toward
an eventual electromechanical dissociative state where the epileptic seizure continues as a subclinical electrographic discharge evident only during EEG monitoring. Management of status epilepticus begins with securing the airway, respiration, and circulation and placement of two large-bore intravenous catheters for drug administration and fluid resuscitation. Obtaining a stat glucose is appropriate before rapid administration of thiamine, followed by intravenous dextrose (to avoid Wernicke encephalopathy in malnourished patients). If intravenous access is not readily available, rectal diazepam (Diastat) or intramuscular fosphenytoin (Cerebyx) can be used. Rectal diazepam is also useful in the out-of-hospital treatment of prolonged seizures or seizure clusters in adolescents and adults, potentially obviating escalation into status epilepticus and preventing an emergency department visit. Initial pharmacotherapy of status epilepticus begins with intravenous lorazepam (Ativan) given at 2mg/minute to a goal of 0.1mg/kg (or 8mg total) with cautious respiratory monitoring, then loading with phenytoin (Dilantin) at 20mg/kg, given no faster than 50mg/minute to avoid hypotension, with ECG and hemodynamic monitoring. Phenytoin should be given through a dedicated peripheral intravenous line because of potential for cardiotoxicity and to avoid precipitation by other drugs. Intravenous phenytoin, a highly insoluble alkaline solution, may lead substantialissoft-tissue toxicity (including feared purple-glove phenomenon). Antoalternative fosphenytoin, which may be the much administered at up to 150mg/min, and is not associated with tissue injury if extravasation occurs. The success of treatment of status epilepticus can be measured clinically, but if the patient remains unresponsive after the convulsive movements stop, an urgent EEG may be needed to exclude nonconvulsive status epilepticus. Refractory status epilepticus can be treated with midazolam (Versed),[1] pentobarbital (Nembutal), sodium pentothal (Thiopental), or phenobarbital.[1] Case series reports suggest that intravenous valproate, lacosamide, and levetiracetam may also be effective. An advantage of short-acting agents such as midazolam is the rapidity with which pharmacologically induced coma can be reversed to examine the patient, whereas valproate, lacosamide, and levetiracetam offer the advantage of avoiding hemodynamic or respiratory complications. Although propofol (Diprivan)[1] was also a favored therapy for the adjunctive treatment of refractory status epilepticus, recent reports have led to declining use for this application given that fatal propofol infusion syndrome (characterized by irreversible metabolic acidosis, bradycardia, bradycardia, myocardial and/or renal failure, rhabdomyolysis, and cardiopulmonary arrest) may be an underrecognized complication. An expanding therapeutic armamentarium for acute seizures and status epilepticus is expected, given that several non-oral treatments are currently being developed, including an intravenous form of carbamazepine, as well as intravenous, intramuscular, and intranasal forms of novel investigational AEDs.
