Epilepsy
Kevin Chapman
Daniel G. Glaze
Epilepsy is the symptomatic expression of an underlying brain disease or disordered brain function, not a disease in the usual sense. The incidence of epilepsy has been reported to range from 0.8% to 1.1%. Epilepsy is the most common neurologic disorder seen in children, and approximately 50% of all cases of epilepsy start in childhood. Epilepsy is defined as a randomly recurring stereotyped symptom complex resulting from an unprovoked episodic disturbance of central nervous system (CNS) function, associated with an excessive, self-limited, neuronal discharge. Variation in clinical manifestations results from variation in the portion of the brain involved.
Epilepsy can have many causes; in general, any event having the potential to produce insult to the brain can result in epilepsy. In many children, the cause is static or nonprogressive encephalopathy secondary to historical antecedents such as hypoxia, hemorrhage, CNS infection, head trauma, and developmental defects of the brain. Cerebral insult as a consequence of labor and delivery complications is a much less common cause than previously thought. Although specific entities such as tuberous sclerosis, neurofibromatosis, brain tumors, some degenerative diseases, and certain inborn errors of metabolism can present initially with recurrent seizures, these diagnoses are suggested by other signs and symptoms revealed by the history and physical examination. For certain seizure disorders, historical evidence of a genetic predisposition may be present. Several gene mutations affecting membrane channels have been identified as the cause of an increasing number of epileptic syndromes. Mutations in the sodium channel genes have been linked to the syndrome of generalized epilepsy with febrile seizures plus, severe myoclonic epilepsy of infancy, and benign neonatal infantile seizure. gamma-Aminobutyric acid (GABA) receptor mutations have been associated with autosomal dominant juvenile myoclonic epilepsy. Most of these gene tests currently are available for research purposes only, but they highlight the increasing recognition that genetic factors have an integral role in the evaluation of epilepsy. Seizures can occur in certain autosomal recessive disorders (e.g., phenylketonuria), X-linked disorders (e.g., fragile X syndrome), chromosomal abnormalities (e.g., Angelman syndrome, Down syndrome), and mitochondrial disorders (e.g., mitochondrial myopathies). In approximately one-half of all children with recurrent seizures, the diagnostic workup does not disclose a specific cause.
Isolated seizures can occur as a consequence of hypoglycemia or other acute metabolic derangements. Such seizures do not constitute epilepsy because specific therapy for the primary disorder obviates the necessity of maintenance therapy with antiepileptic drugs (AEDs). The risk of experiencing unprovoked seizures by age 5 years in children with developmental disability is 3%, which is approximately fourfold greater than that of the general population. Selected subgroups with major impairments account for most of this increased risk. The risk is only 1%, similar to the general population, in those without cerebral palsy or mental retardation.
CLASSIFICATION AND DESCRIPTION OF SEIZURE TYPES
Diagnostic accuracy and treatment options have improved greatly since the 1980s as a consequence of advances made in many areas. These areas include the adoption of a universally
accepted descriptive classification system, the increased availability of serum drug monitoring, the development of new AEDs, advances in video-electroencephalographic (EEG) monitoring and neuroimaging techniques, and improved knowledge of drug interactions. Nonetheless, a carefully detailed history and physical examination remain of prime importance to diagnosis.
accepted descriptive classification system, the increased availability of serum drug monitoring, the development of new AEDs, advances in video-electroencephalographic (EEG) monitoring and neuroimaging techniques, and improved knowledge of drug interactions. Nonetheless, a carefully detailed history and physical examination remain of prime importance to diagnosis.
Epilepsy is a clinical, not a laboratory, diagnosis, and errors in diagnosis, seizure classification, and subsequent treatment are most often the consequence of an inadequate history and physical examination. Numerous relatively benign, episodic spells often are misdiagnosed and even treated as seizures. They include breath-holding spells, benign paroxysmal vertigo, syncope, tics, and even masturbation. The physician rarely has the opportunity actually to witness a clinical seizure and usually must rely on a description provided by the parents. A seizure often is a frightening experience for parents, and their ability to recall details, time relationships, and the sequence of events understandably can be limited. Frequently, the parents may not have witnessed the event and can report only what they were told by a teacher or other witness. Often, obtaining a description by telephone from the actual witness is worthwhile. When the available clinical description is vague and unconvincing, an appropriate approach may be to delay definitive diagnosis and treatment and to instruct parents about what to look for should attacks recur. Asking the parents to videotape an event may provide useful information for the clinician.
The classification system for epileptic seizures currently in use is based on both clinical and EEG features (Box 401.1). It divides seizures into two major categories, generalized and partial. Generalized seizures are those in which the clinical features indicate the involvement of both cerebral hemispheres from the start. Consciousness usually is impaired, and, when motor involvement is present, it is bilateral and relatively symmetric from the beginning. Conversely, partial seizures are characterized by clinical features suggesting that only a limited functional area of one cerebral hemisphere is involved. These seizures begin focally, although they may become generalized. Partial seizures are divided further into those with elementary or simple symptoms and those with complex symptoms. In children, elementary partial seizures most commonly are focal motor or focal sensory phenomena, and consciousness is preserved unless secondary generalization occurs. Complex partial seizures usually have their origin in temporal or frontal lobe structures, and the clinical features encompass a spectrum of complex phenomena, including behavioral automatisms, alterations of perception, hallucinations, changes in affect and memory, and ideational distortions.
BOX 401.1 Classification of Epileptic Seizures
Generalized Seizures
Tonic-clonic
Clonic
Tonic
Atonic
Myoclonic
Absence
Partial Seizures
Elementary symptomatology
With motor symptoms
With sensory symptoms
Complex symptomatology
With impairment of consciousness only
With cognitive symptoms
With affective symptoms
With psychosensory symptoms
Compound forms
Secondarily generalized
Footnote
Reprinted from
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489.
Generalized Seizures
Generalized tonic-clonic seizures are characterized clinically by an abrupt arrest of activity and an immediate loss of consciousness. The tonic phase, consisting of sustained, generalized contraction of flexor or extensor muscles, usually lasts only a few seconds. The clonic phase that follows is characterized by symmetric, rhythmic, clonic activity consisting of alternating contraction and relaxation of major appendicular or axial muscle groups. The clonic phase lasts longer than the tonic phase, but often it terminates spontaneously in less than 5 minutes. Respiration may be irregular and stridulous, and sphincter incontinence may or may not be present. The clonic phase usually is followed by a variable period of confusion and lethargy, which may persist from minutes to hours, and sleep is common.
Clonic seizures are identical to the clonic phase of tonic-clonic seizures. Generalized tonic seizures are characterized by sustained contraction of flexor or extensor muscle groups, thus giving the child a stiff or rigid appearance. A coarse tremor may be superimposed, but it should not be confused with the rhythmic, alternating muscle contraction and relaxation of clonic activity. A distinction often can be made by asking the parents to supplement their verbal description with a demonstration of what they observed. Both clonic and tonic seizures are followed by postictal signs and symptoms similar to those seen with generalized tonic-clonic seizures.
Myoclonic seizures are characterized by brief, random contractions of a muscle or group of muscles occurring unilaterally or bilaterally, either singly or in clusters. Consciousness usually is preserved. Myoclonic seizures are seen most often with progressive or degenerative types of encephalopathy accompanied by intellectual deficits, as well as other overt abnormalities, on neurologic examination. Atonic or “drop” attacks are a subclass of myoclonic seizures and are characterized by a precipitous loss of postural tone. The child abruptly becomes limp and drops to the floor. With nonambulatory infants, precipitous loss of tone resulting in head nodding or slumping forward may occur. The duration of myoclonic seizures is only a few seconds, and immediate resumption of normal activity with no postictal lethargy or confusion occurs.
Absence seizures are characterized clinically by brief episodes of altered awareness during which transient arrest of activity occurs and the child appears to stare blankly. The duration of these episodes seldom is longer than 5 to 10 seconds, but they can recur many times a day. They rarely are seen in children younger than 3 years old, and most have their onset before 10 years of age. The child commonly is not aware that a seizure has occurred and frequently is assumed to be daydreaming. A child who is daydreaming, however, is aware of doing so and usually responds when his or her name is called or he or she is touched. In contrast, a child with absence seizures usually denies awareness of any lapse and does not respond to verbal
or physical stimuli. Subtle motor activity such as rhythmic eye blinking, drooping of the head, or slight movements of the arms may accompany the staring episodes. The seizure is terminated by the immediate return of environmental awareness, and the child may resume an activity at the point at which it was interrupted. A generalized, symmetric three/second spike-and-wave pattern, which may be induced with hyperventilation, is the EEG hallmark of absence seizures.
or physical stimuli. Subtle motor activity such as rhythmic eye blinking, drooping of the head, or slight movements of the arms may accompany the staring episodes. The seizure is terminated by the immediate return of environmental awareness, and the child may resume an activity at the point at which it was interrupted. A generalized, symmetric three/second spike-and-wave pattern, which may be induced with hyperventilation, is the EEG hallmark of absence seizures.
Partial Seizures
Partial seizures are classified based on the loss or preservation of consciousness. During complex partial seizures, awareness is lost, compared with simple partial seizures, in which the patient remembers the event. The initial semiologic features of a partial seizure are especially important. Tonic deviation of the head and eyes to one side, or some other localized motor or sensory feature preceding a secondarily generalized tonic-clonic seizure, may be a clue to focal cortical origin of the attack. In children, elementary partial seizures usually are focal motor or sensory. The initial feature may be focal twitching involving the distal portion of an extremity, which may remain localized or spread to become a hemiconvulsion. Similarly, focal sensory seizures may be initiated by the appearance of a sensation of numbness or tingling in an extremity, which may remain confined to that area or spread to involve the entire side of the body. Consciousness often is preserved but is lost if secondary generalization occurs.
Various types of auras may precede and herald the onset of a complex partial seizure. These subjective cognitive symptoms may be characterized clinically by an abrupt alteration in mental state that involves disruption of time relationships and memory. Older children sometimes describe feelings of unreality, remoteness, detachment, or depersonalization. Forced thinking, a deluge of thoughts, or perseveration of a thought also have been described. Déjà vu or jamais vu, the impression of an inappropriate familiarity or unfamiliarity with a place or situation, occasionally may be reported. Attacks characterized by affective symptoms may be described as inexplicable feelings of fear or dread or other emotional experiences that intrude abruptly on the patient’s prevailing affective state. Attacks characterized by somatosensory disturbances are notable for distortions of perception or hallucinations. Some children report transient distortions of perception concerning the size of objects (micropsia or macropsia), and others describe hallucinations involving taste or smell, as well as formed visual hallucinations.
Complex partial seizures have a variety of clinical expressions and are subclassified on this basis. One form that causes impairment of consciousness only is characterized by transient, blank staring or confusion. These episodes can be mistaken for absence seizures, but the attacks usually last 30 seconds or longer, whereas absence episodes commonly last less than 10 seconds. An EEG can be helpful in distinguishing between the two forms because a three/second generalized spike-and-wave pattern is the hallmark of absence seizures, whereas focal discharge from temporal or frontal areas is seen in complex partial seizures.
Probably the most familiar complex partial seizure is the psychomotor attack that is characterized by semipurposeful motor automatisms. The stereotyped automatisms may be persistent, and the child exhibits continuing repetition of the activity in which he or she was engaged before the onset of the seizure. For example, if the child were walking, he or she may continue to walk, but without purposeful direction. If the child was writing, he or she may continue to move the pencil across the page without producing decipherable script. The simplest types of automatisms are masticatory, sucking, and lip-pursing movements. Patting, scratching, or picking at clothing also may be seen. More complex behaviors such as fumbling with clothing as if to undress or turning about as if searching for something are less common. Finally, compound forms that incorporate various elements of the several varieties just described may be seen. In an individual child, the form taken usually is stereotyped from one attack to another.
Epileptic Syndromes
The international classification of epileptic seizures is confined to a description of individual seizure types. Increasing numbers of distinct epileptic syndromes are recognized, and the terminology used in daily communication consists of descriptions of syndromes. The Commission on Classification and Terminology of the International League Against Epilepsy has proposed a classification system for the epileptic syndromes. This system initially divides all epileptic syndromes according to whether the epilepsy is partial, generalized, or uncertain and then subdivides these categories according to the presence or absence of presumed cause. The epilepsy is considered to be secondary (or symptomatic) if obvious disease is demonstrable, if the patient has a history of or demonstrates neurologic or mental impairment, or if the causes are presumed on the basis of studies of previous patients with the same seizure type and location. A modified classification of the epileptic syndromes is shown in Box 401.2.
Several epileptic syndromes are unique to childhood and contain certain features that distinguish them from the more typical primary or secondary types of epilepsy. Infantile spasms or infantile massive spasms are peculiar to infancy and early childhood, with a peak incidence of onset occurring in children between 2 and 7 months of age. They have been described as occurring in three clinical forms. Flexor spasms consist of sudden flexion of the neck, trunk, and extremities, which may be so violent that the torso will jackknife at the waist. Extensor spasms consist of abrupt extension of the neck and trunk with adduction or abduction of the extremities. The predominant form is a mixed flexor-extensor spasm most commonly consisting of flexion of the neck, trunk, and arms with extension of the legs and, less commonly, flexion of the legs and extension of the arms. Infantile spasms tend to occur in clusters, with each cluster consisting of 2 to 125 individual spasms. Each individual spasm lasts only for a few seconds, although a cluster may extend over several minutes. Spasms rarely occur during actual sleep but frequently occur on arousal. In most instances, the EEG shows the distinctive pattern of hypsarrhythmia.
Infantile spasms must be distinguished from benign myoclonus of early infancy and benign neonatal sleep myoclonus, which are characterized by normal EEG results, normal development, and occurrence during sleep. Massive spasms frequently are misinterpreted as startle responses or attacks of colic. A careful history usually elicits the absence of a preceding startle stimulus or the information that the episodes are too precipitous in onset and offset and too short in duration to fit the usual clinical picture of colic. Although crying may follow an infantile spasm, it is not the inconsolable crying that is encountered in infants with cramping abdominal pain.
Infantile spasms have occurred in association with numerous and seemingly unrelated pathologic states, and no one specific factor or circumscribed group of factors has been identified as a common etiologic abnormality. Etiologic associations provide the basis for division of these spasms into two broad groups. In the idiopathic or cryptogenic group, no demonstrable cause is present, the child’s development usually has been normal until the onset of spasms, and the results of magnetic resonance imaging (MRI) scans of the brain are normal. In the symptomatic group, a specific etiologic factor can be identified,
developmental or neurologic abnormalities have preceded the onset of spasms, and the results of MRI scans of the brain often are abnormal. The cryptogenic group represents no more than 10% to 15% of the total, and it has a better prognosis than the symptomatic group.
developmental or neurologic abnormalities have preceded the onset of spasms, and the results of MRI scans of the brain often are abnormal. The cryptogenic group represents no more than 10% to 15% of the total, and it has a better prognosis than the symptomatic group.
BOX 401.2 Modified Classification of Epileptic Syndromes
Localization-related (focal, local, partial) epilepsies and syndrome
Idiopathic with age-related onset
Benign childhood epilepsy with centrotemporal spikes
Childhood epilepsy with occipital paroxysms
Primary reading epilepsy
Symptomatic, all other partial epilepsies consequent to a known or suspected disorder of the central nervous system
Generalized epilepsies and syndromes
Idiopathic with age-related onset
Benign neonatal familial convulsions
Benign neonatal convulsions
Benign myoclonic epilepsy in infancy
Childhood absence epilepsy
Juvenile absence epilepsy
Juvenile myoclonic epilepsy
Cryptogenic or symptomatic
West syndrome (infantile spasms)
Lennox-Gastaut syndrome
Symptomatic
Nonspecific origin
Early myoclonic encephalopathy
Specific syndromes such as those associated with inborn—errors of metabolism, malformations
Epilepsies and syndromes undetermined, whether focal or generalized
With both generalized and focal seizures
Neonatal seizures
Severe myoclonic epilepsy in infancy
Acquired epileptic aphasia (Landau-Kleffner syndrome)
Without unequivocal generalized or focal features
Special syndromes
Situation-related seizures
Febrile convulsions
Isolated seizures
Seizures occurring only when there is an acute metabolic or toxic event
Footnote
Reprinted from
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389.
Causes associated with the symptomatic group of infantile spasms include cerebral dysgenesis, intrauterine infections, and genetic disorders. Two syndromes of cerebral dysgenesis that have been associated with infantile spasms are the Miller-Dieker syndrome (lissencephaly with or without a deletion in the LIS-1 gene on chromosome 17) and the Aicardi syndrome (girls with agenesis of the corpus callosum, distinctive chorioretinopathy, and mental retardation).
The relationship of pertussis immunization to the onset of infantile spasms has generated interest and concern for many years. The Child Neurology Society and the American Academy of Neurology have reviewed this subject, reached similar conclusions, and issued position papers based on the scientific data available. These organizations concluded that no specific clinical or neuropathologic syndrome is associated with diphtheria-tetanus-pertussis (DTP) vaccine and no means exist by which a diagnosis of brain damage resulting from DTP immunization can be established in an individual case. Well-designed, controlled epidemiologic studies have failed to prove an association between DTP immunization and infantile spasms. Children receive their initial DTP immunizations at an age when infantile spasms have their onset. The administration of pertussis vaccine is associated with a short-term increase in the risk of seizures (mostly febrile seizures), and complete recovery is expected. Children whose neurologic problems begin soon after immunization warrant a full diagnostic workup.
The Lennox-Gastaut syndrome is one type of symptomatic or cryptogenic generalized epilepsy, that is age-dependent. The Lennox-Gastaut syndrome is characterized by the onset in early childhood of mixed seizures (including tonic, tonic-clonic, atonic, akinetic or myoclonic, and absence), refractoriness to common AEDs, an abnormal EEG pattern (generalized, slow-spike and slow-wave activity), and a high incidence of developmental and mental retardation. This syndrome frequently is preceded by infantile spasms. Etiologic factors are similar to those outlined with infantile spasms. In 30% of the cases, the Lennox-Gastaut syndrome appears in children who have no antecedents, previous epilepsy, or clinical or neurologic evidence of brain damage and who have had previously normal development.
Benign focal epilepsy of childhood (also called benign epilepsy of childhood with rolandic or centrotemporal spikes) is a form of partial epilepsy that is characterized by an onset between the ages of 4 and 10 years. The seizures typically occur during sleep, although daytime seizures also may be seen. The seizures most frequently begin with clonic twitching of one side of the face. Involvement of the tongue or an upper extremity, and secondary generalization may occur. If the child is awake, he or she may experience paresthesias involving the mouth and throat. The child usually appears well immediately after the seizure. The occurrence of seizures during sleep may cause uncertainty regarding whether the child has had a nightmare or a seizure. The children are otherwise well and have a history of normal development. Neuroimaging studies in these children have been unremarkable. The EEG is characterized by independent spike discharges occurring focally in one or both central (rolandic) regions. Focal spike activity is enhanced during sleep and may occur only at this time. EEG background activity is otherwise normal. Both the seizures and the spike focus typically have a short natural history and usually are resolved by puberty or soon afterward. This natural history, in addition to normal development of the child and normal results of neuroimaging studies, suggests the terminology of benign focal epilepsy. The EEG trait (the central spike with a normal background) may be inherited as an autosomal dominant gene with a particular age penetrance. The inheritance pattern of the seizures is familial, but it appears to be multifactorial. Similar varieties of benign focal epilepsy have been identified in association with temporal, parietal, and occipital spike foci.
Childhood epilepsy with occipital paroxysms is associated with an EEG pattern that is characterized by unilateral or bilateral occipital spike or sharp waves and seizures that are hemiclonic or consist of automatisms and that typically are preceded by visual symptoms (amaurosis, phosphenes, illusions, or hallucinations). In 25% of the cases, the seizures are followed immediately by migraine-like headaches.
ANCILLARY LABORATORY STUDIES
In approaching the laboratory evaluation, the physician must recall that epilepsy is primarily a clinical diagnosis. Some laboratory studies are necessary to establish a baseline for future comparison, and others can help with formulating medical treatment and prognosis. Indications for laboratory studies should be based on information extracted from the history and physical examination. If specific disease entities such as hypocalcemia, hypoglycemia, or other metabolic, toxic, or degenerative disorders are valid considerations, additional studies relevant to the particular entity are, of course, appropriate.
Electroencephalography
An EEG has value only when it is interpreted in the context of the child’s age, history, and physical findings. The quality of information gained from an EEG is related directly to the standards of the laboratory and the training and experience of the personnel. A routine EEG always should be recorded during wakefulness and sleep and, in older children, during hyperventilation and photic stimulation. Because normal organizational and frequency characteristics change rapidly with advancing age and cerebral maturation, it is of particular importance that the interpretation of EEGs in infants and young children be done by an electroencephalographer who has had specific training and experience with this age group. EEGs in many laboratories are interpreted by neurologists with little or no experience with infants and young children. Additional information about the use of EEGs in epilepsy is presented in Box 401.3.
Normal EEG results should not necessarily dissuade a physician from making a diagnosis of epilepsy in the presence of a convincing clinical description. The initial EEG often does not contain epileptiform discharges. Investigators have found that the initial EEG in 25% to 58% of affected children may be normal or borderline without epileptiform abnormalities. Similarly, abnormal EEG results do not necessarily confirm a clinical suspicion of epilepsy. The type and location of an abnormality are expected to correlate with the clinical data. When the available clinical and EEG data do not provide a basis for confident classification regarding seizure type, or in cases in which pseudoseizures are suspected, video-EEG monitoring may be justified. Medically refractory patients may undergo video-EEG monitoring to assess their candidacy for epilepsy surgery. Patients with daily episodes may need only short-term monitoring, whereas those with infrequent seizures may need longer monitoring with tapering or discontinuation of medication to encourage seizures.
BOX 401.3 Electroencephalography in Epilepsy
The duration of a routine electroencephalogram (EEG) in most laboratories is approximately 1 hour. This 1-hour sample is taken to be representative of the patient’s cerebral electrical activity during any average 24-hour period. An obvious potential exists for sampling to take place at a time when no epileptiform activity is present. A sleep-deprived EEG or a routine EEG obtained at a subsequent date may demonstrate abnormalities that were not evident in the initial sample. The yield of useful information is enhanced when the EEG can be scheduled in particular relation to a clinical seizure. The EEG should be recorded as soon as possible after any seizures that occur in neonates and infants up to 6 months of age. If an EEG is recorded in children with febrile seizures who are 6 to 36 months of age, the test should be delayed until 5 to 10 days after the seizure because the child’s postictal brain wave activity may be transiently and diffusely slow for several days, and its significance could be misinterpreted. For patients with nonfebrile seizures, the EEG should be recorded as soon as possible after the event.
Neuroimaging
Routine skull radiography seldom is indicated or helpful except when overt bony disease is detected by physical examination. Neuroimaging studies may be indicated in cases of partial seizures or if the history and physical examination suggest structural lesions, degenerative diseases, or a congenital structural abnormality. High-resolution ultrasound is a useful technique in the investigation of premature infants and term neonates with seizures. MRI has virtually replaced computed tomography in the evaluation of patients with epilepsy. MRI allows for the clear imaging of intraparenchymal structures, without bony artifacts and exposure to ionizing radiation; it allows acquisition of multiplanar anatomic data and the ability to reconfigure the data for enhanced visualization; and it visualizes important substrates of epilepsy such as malformations of cortical development, abnormal neuronal and glial proliferation, abnormal neuronal migration, tumors, vascular malformations, encephalomalacia, and mesial temporal sclerosis. The development of the fast fluid-attenuated inversion-recovery imaging (FLAIR) technique provides superior detection of small cortical-based epileptogenic lesions and improved ability to identify gliosis. MRI should be customized to answer the appropriate clinical question, and discussion regarding the region of interest with the neuroradiologist may improve detection of smaller lesions.
Hematologic and Hepatic Tests
Because most of the AEDs in use have the potential to produce hematologic or hepatic side effects, a baseline complete blood count, platelet count, and liver enzyme analysis should be obtained, dependent on the known toxic effects of the drug to be used.
MEDICAL TREATMENT
Successful treatment of a child with epilepsy demands more than just preventing recurrent seizures. The sensitive physician must adopt both an educational and an advocacy position, thus ensuring acceptance of the child’s epilepsy by the family, teachers, classmates, and the community. Misconceptions about epilepsy still abound and often have an adverse effect on a child’s self-esteem and psychosocial development. Time invested in providing a clear explanation, in lay language, of the nature of epilepsy, the objectives of treatment, and the simple fundamentals of pharmacokinetics can allay apprehensions, dispel misconceptions, and promote compliance with the prescribed drug regimen.
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