Pediatric Epilepsy Diagnosis and Therapy - part 4 pot

16 • SEVERE ENCEPHALOPATHIC EPILEPSY IN INFANTS: INFANTILE SPASMS (WEST SYNDROME) 253 Fp1-A1 Fp2-A2 C3-A1 C4-A2 O1-A1 O2-A2 T5-A1 T6-A2 Fp1-C3 Fp2-C4 C3-O1 C4-O2 C3-T3 C4-T4 T3-Fp1 T4-Fp2 FIGURE 16-3 Hypsarrhythmia. Digital recording from a 6-month-old male. repetitive and highly organized pattern that could be confused with a discharge of the petit mal or petit mal variant type. The abnormality is almost continuous, and in most cases it shows as clearly in the waking as in the sleeping record. This prototypic pattern is usually seen in the early stages of the disorder and most often in younger infants (younger than 1 year of age). The pattern has been reported in 7% to 75% of patients with infantile spasms (10, 12, 37–41). In addition, variations or modi- fications of this pattern may be seen in many patients. In 1984, we identified five variations of the originally described pattern after reviewing the 24-hour EEG-video monitoring studies in 67 infants with infantile spasms (29). These variations include hypsarrhythmia with a consistent focus of abnormal discharge, hypsarrhyth- mia with increased interhemispheric synchronization, hypsarrhythmia comprising primarily high-voltage, slow-wave activity with very little spike or sharp wave activity, asymmetrical or unilateral hypsarrhythmia, and hypsarrhythmia with episodes of generalized, regional, or localized voltage attenuation, which, in its maximal expression, is referred to as the “suppression-burst vari- ant.” These variations were subsequently confirmed by Alva-Moncayo et al (37) in 100 cases. In addition to demonstrating these basic varia- tions, 24-hour EEG-video monitoring studies have shown that hypsarrhythmia is a highly dynamic pat- tern, with transient alterations in the pattern occurring throughout the day. The hypsarrhythmic activity tends to be most pronounced and to persist to the latest age in slow-wave (non-rapid-eye movement [NREM]) sleep. During NREM sleep there is a tendency for group- ing of the multifocal spike and sharp wave discharges resulting in a quasi-periodic appearance of the back- ground activity (29, 42, 43). Also during NREM sleep, attenuation episodes frequently occur. The hypsarryth- mic pattern is least evident or completely absent dur- ing REM sleep, when the background activity may III • AGE-RELATED SYNDROMES 254 F p1-A1 F p2-A2 C3-A1 C4-A2 O1-A1 O2-A2 T5-A1 T6-A2 F p1-C3 F p2-C4 C3-O1 C4-O2 C3-T3 C4-T4 T3-Fp1 T4-Fp2 FIGURE 16-4 Digital recording from a 6-month old male showing ictal EEG change associated with infantile spasms. Note the period of voltage attenuation associated with superimposed fast activity. appear normal (42). Transient disappearance or reduc- tion of the hypsarrhythmic activity is usually seen on arousal from sleep; this normalization may last from a few seconds to many minutes. In addition, there is usually a reduction or disappearance of the hypsar- rhythmic pattern during a cluster of spasms, with the pattern returning immediately following cessation of the spasms (15). Although hypsarrythmia or one of its variants is most commonly seen in patients with infantile spasms, several other interictal patterns may occur (1, 26). These include diffuse slowing of the background activity, focal slowing, focal or multifocal spikes and sharp waves, generalized slow-spike-and-slow-wave activity, focal depression, paroxysmal slow or fast bursts, or continuous spindling. These patterns may occur in isolation or in various combinations. In a small number of infants, the background activity may appear normal. Ictal Patterns A variety of ictal EEG patterns have been identified (15). These include generalized slow-wave transients, sharp-and- slow-wave transients, and attenuation episodes, occur- ring alone or with superimposed faster frequencies. These patterns occur singly or in various combinations. However, the most common ictal EEG change is a gener- alized slow-wave transient, followed by an abrupt attenu- ation of background activity in all regions (Fig 16-4). The duration of the ictal EEG event may range from less than 1 second to more than 1 minute, with the longer episodes being associated with arrest phenomena. Also, episodes of generalized voltage attenuation may occur in 16 • SEVERE ENCEPHALOPATHIC EPILEPSY IN INFANTS: INFANTILE SPASMS (WEST SYNDROME) 255 the absence of clinical spasms. These observations have been confirmed by many authors (16, 33, 44–55). There is no close correlation between the character of the ictal EEG event and the type of spasm, with the exception that an asymmetric ictal pattern usually correlates with focal or lateralized brain lesions (47, 56). PATHOPHYSIOLOGY The pathophysiological mechanism underlying infan- tile spasms is not known, and a suitable animal model exhibiting the major clinical and electroencephalo- graphic features of this disorder has yet to be developed. At present, it is not even known whether the disorder occurs in any species other than humans. For those interested in a thorough discussion of the proposed pathophysiological mechanisms underlying this disor- der, it is suggested that the reader review our recently published study on this topic (1). Here, we will provide only a brief overview of some of the hypotheses that have been proposed. Considerable evidence implicates the brainstem as the area in which epileptic spasms and the hypsarrhyth- mic EEG pattern originate (42, 57–61). We previously described a pathophysiological model of infantile spasms, based on our long-term polygraphic-video monitoring experience (42, 62), which suggested that dysfunction of certain monoaminergic or cholinergic regions of the brainstem involved in the control of sleep cycling may be responsible for the generation of the spasms and the EEG changes seen in this disorder (62). According to this model, the clinical spasms would result from pha- sic interference of descending brainstem pathways that control spinal reflex activity, whereas the hypsarrhythmic EEG pattern, and perhaps the cognitive dysfunction seen in these patients, would result from activity occurring in ascending pathways projecting from these brainstem regions to the cerebral cortex. Various other investigators have also suggested that dysfunction of monoaminer- gic neurotransmitter systems may be responsible for the generation of epileptic spasms (63–68). It has also been reported that corticosteroids (65) and ACTH (69) sup- press central serotonergic activity, a finding consistent with this brainstem hypothesis. However, this model did not exclude the possibility that these critical brainstem region(s) might be affected by distant sites, because the brainstem sleep system receives input from many other areas (62). Several years later, Chugani and coworkers (60, 70) expanded our hypothesis. Primarily on the basis of PET scan studies, these authors suggested that the brainstem dysfunction causing infantile spasms was pro- duced by an abnormal functional interaction between the brainstem (raphe nuclei) and a focal or diffuse cortical abnormality. According to this hypothesis, the cortical abnormality exerts a noxious influence over the brain- stem from where the discharges spread caudally and rostrally to produce spasms and the hypsarrhythmic EEG pattern. The association of partial seizures with infantile spasms (described previously) was further evidence used to support the hypothesis that a primary cortical gen- erator interacts with subcortical structures, resulting in infantile spasms. This model provides for the observation that a subset of infantile spasms patients with localized lesions in the cortex may have cessation of seizures and improved EEGs after resection of focal cortical lesions (70–73). A similar model proposing that spasms arise from subcortical structures was provided by Dulac et al (74). This group hypothesized that the epileptic spasms result from a functional deafferentation of subcortical structures such as the basal ganglia caused by abnormal cortical activity, but the hypsarrhythmic EEG pattern directly reflects the cortical dysfunction. A cortical-subcortical interaction was also pos- tulated by Avanzini et al (75) and Lado and Moshe (76). Another major hypothesis is that infantile spasms is the result of a defect in the immunological system (62, 77, 78). Supportive evidence for this hypothesis includes the presence of antibodies to extracts of normal brain tissue in the sera of patients with infantile spasms (79, 80), the presence of increased numbers of activated B cells and T cells in the peripheral blood of patients with infantile spasms (81), and abnormal leukocyte antigen studies in patients with infantile spasms compared with control subjects (82–84). Although these findings indi- cate abnormal immune function in patients with infantile spasms, there is no direct evidence that an immunologic defect causes this disorder. Another hypothesis is that corticotropin-releasing hormone (CRH) may play a mechanistic role in infan- tile spasms (85–87). According to this model, stress or injury during early infancy results in the release of excess amounts of CRH, which in the presence of an abun- dance of CRH receptors, produces epileptogenic altera- tions in the brainstem pathways that result in spasms. The therapeutic benefit of corticosteroids and ACTH in this disorder would be secondary to the suppression of CRH synthesis by these hormones. However, although injection of CRH into the brains of infant rodents does produce seizures, the ictal behaviors and EEG features are not typical of those seen in the human condition (88). In addition, CRH levels are not elevated in the cerebro- spinal fluid (CSF) of patients with infantile spasms (86). Furthermore, treatment of patients with infantile spasms with a competitive antagonist of CRH did not alter spasm frequency or significantly change the EEG pattern (89). Several additional pathophysiological mechanisms underlying this disorder have also been proposed. It has been suggested that infantile spasm results from a failure or delay of normal developmental processes (90). This theory is based largely on the assumption that ACTH and III • AGE-RELATED SYNDROMES 256 corticosteroids accelerate certain normal developmental processes in immature animals (91–95). Also, several biochemical and metabolic distur- bances have been reported in patients with infantile spasms. These include dysfunction of metabolic pathways for neuropeptides, pyridoxine, and amino acids, such as aspirate, glutamate, and gamma-aminobutyric acid (1). Finally, there are 13 genetically based conditions associated with infantile spasms (1), some of which involve the same region of the X chromosome. For example, Aicardi syndrome has been associated with X chromosome abnormalities near Xp22 (96). Patients with incontinentia pigmenti type I have abnormalities in the same region, with evidence of X/autosomal trans- location at Xp11 (97). Patients with X-linked infantile spasms have mutations involving the ARX gene located on the X chromosome at Xp22 (98–102) and the CDKL5 (STK9) gene (103–109). Pyruvate dehydrogenase com- plex deficiency, a metabolic defect associated with infan- tile spasms, has been localized to Xp22.1–Xp22.2, a region similar to that associated with X-linked infantile spasms (110). These findings suggest that defects in the involved region of the X chromosome and products of the involved gene (or genes) may play a role in the patho- physiology of this disorder (1, 101, 111). Recently, we proposed a new model concerning the pathophysiology of this disorder based on devel- opmental desynchronization (112). According to this model, infantile spasms results from a particular tem- poral desynchronization of two or more developmental processes, resulting in a specific disturbance of brain function. As shown in Figure 16-5, the developmental desynchronization could be produced by (1) a mutation or inherited abnormality affecting the primary genes governing ontogenesis, (2) a mutation or inherited abnormality affecting the genes specifying transcrip- tion factors (or other genetic modulators), or (3) an injurious external environmental factor affecting the maturational processes of brain tissues, neurochemi- cal systems, or both. Each mechanism (or combina- tion of mechanisms) could be manifested at different locations and at different points of development. As a Birth PostnatalPretnatal Months +12 -6 +6 Regulatory genes specifying transcription factors and other modulators of primary gene expression Environmental factors influencing development (e.g., injury, toxicity, agents interfering with gene expression) Developmental processes (specified and controlled by primary genes) This developmental process is out of synchronization with the others at 6 months of age. FIGURE 16-5 Developmental desynchronization model of infantile spasms pathogenesis showing schematically the interaction of developmen- tal processes controlled by primary genes (e.g., neurogenesis, myelination, synaptogenesis, apoptosis, neurotransmitter systems) (horizontal lines) with regulatory gene effects (vertical lines from bottom) and environmental factors (vertical lines from top). Vertical dashed lines indicate hypothetical maximal extent of desynchronization consistent with normal function at 6 months. Reprinted from J.D. Frost, Jr. and R.A. Hrachovy, Pathogenesis of infantile spasms: A model based on developmental desynchronization, J. Clin Neurophysiol. 22:25–36, Figure 1, page 28; copyright 2005, with kind permission from Wolters Kluwer/Lippincott Williams & Wilkins. 16 • SEVERE ENCEPHALOPATHIC EPILEPSY IN INFANTS: INFANTILE SPASMS (WEST SYNDROME) 257 result, at least one developmental process would lag behind other processes, resulting in a loss of integra- tion of brain function. This model would allow for the observation that multiple, seemingly unrelated, conditions and insults occurring at different points of development (prenatal, perinatal, or postnatal) could result in the same functional deficit. Also, this hypo- thetical model would be consistent with the response of patients with infantile spasms to a diverse group of therapeutic agents with different modes of action. All agents would not be effective in all patients because of the different fundamental impairments responsible for the common functional deficit resulting in spasms. Also, the phenomenon of spontaneous remission could result from internal control mechanisms detecting the developmental desynchronization that caused spasms and responding to it by the activation or modulation of other gene regulatory systems. DIAGNOSTIC EVALUATION AND TREATMENT Diagnostic Evaluation The diagnosis of infantile spasms is suggested on the basis of a good clinical history. Thorough general physical and neurological examinations must be per- formed. This should include a careful ophthalmic evalu- ation and close examination of the skin using a Wood’s lamp to rule out such conditions as tuberous sclerosis. A routine EEG, recorded with the infant awake and asleep, is then obtained, which helps confirm the diag- nosis. If the routine EEG does not reveal hypsarrhyth- mia and if the typical ictal EEG patterns (described previously) or spasms are not recorded, a prolonged video-EEG monitoring study should be performed to establish the presence of the disorder. Neuroimaging studies, preferably MRI, should be obtained to search for structural brain abnormalities. If ACTH or corti- costeroids are to be started, the neuroimaging studies should be obtained before institution of such therapy, because these agents produce enlargement of CSF spaces that cannot be easily distinguished from preexisting cerebral atrophy. Routine laboratory studies including complete blood count with differential, renal panel with electrolytes and glucose, liver panel, serum calcium, magnesium, and phosphorus, and urinalysis should be obtained in all cases before institution of therapy. If an associated etiology is not identified on the basis of the previous information, a metabolic workup including serum lactate and pyruvate, plasma ammonia, urine organic acids, serum and urine amino acids, and serum biotinidase should be obtained. Chromosomal analysis should be performed. The CSF should be evaluated for cell count, glucose, protein, viral and bacterial culture, lactate and pyruvate, and amino acids. Associated Etiological and Clinical Factors In approximately 40% of patients, no associated etio- logical factor can be clearly identified. In the other 60%, various prenatal, perinatal, and postnatal factors have been implicated. In our recent review of the more than 400 published reports concerning etiology (1) more than 200 associated conditions were identified. These include such prenatal conditions as cerebral dysgenesis (e.g., lis- sencephaly), intrauterine infection, hypoxia-ischemia, prematurity, and genetic disorders (e.g., tuberous scle- rosis), perinatal conditions such as traumatic delivery and hypoxia-ischemia, and postnatal conditions such as inborn errors of metabolism (e.g., nonketotic hypergly- cinemia), head injury, central nervous system (CNS) infec- tion, hypoxia-ischemia, and intracranial hemorrhage. Approximately 80% of patients with infantile spasms show some degree of mental and developmental retardation, and approximately the same percentage of patients have neurologic deficits (1). Diffuse and focal abnormalities on MRI and CT scans may be seen in (70–80%) of cases. In addition, MRI may also reveal evidence of delayed myelination (113–115). PET reportedly detects focal or diffuse hypometabolic changes in up to 97% of patients with infantile spasms (116). However, these changes do not necessarily persist over time, suggesting that cortical hypometabolism in some patients with infantile spasms does not represent a structural lesion, but only a functional change (115, 117, 118). Immunization During the last several decades, there has been a major dis- agreement as to whether immunization is an etiological fac- tor for infantile spasms. This is an important issue, not only from a medical standpoint but also from a legal point of view, as evidenced by the large number of lawsuits against manufacturers of vaccines. Of the various vaccines that have been reported to be associated with infantile spasms, the one most frequently implicated is the diphtheria- pertussis-tetanus (DPT) vaccine. The pertussis agent has generated the most concern, and a number of publications have reported its apparent relationship to the development of infantile spasms (119–125). The major problem in deter- mining whether there is a causal relationship between DPT immunization and infantile spasms is that the vaccine is given at the same age as the usual onset of infantile spasms. Therefore, if a large population were studied, an association between infantile spasms and DPT immunization would be expected on the basis of coincidence alone. Few studies have approached this problem in a manner amenable to statistical analysis; however, those that have done so have demonstrated that the apparent association between DPT immunization and infantile spasms is coincidental and that no causal relationship exists (126–129). III • AGE-RELATED SYNDROMES 258 Patient Classification In the past, the classification of infantile spasm patients was variable and inconsistent (1, 26). Currently, patients are best classified on the basis of medical history, develop- mental history, neurologic examination, and neuroimag- ing studies (MRI, CT, and perhaps PET). Based on these criteria, patients can be divided into two main groups: cryptogenic or symptomatic. Those with no abnormality on neurologic examination, no known associated etio- logical factor, normal development before onset of the spasms, and normal neuroimaging studies are categorized as cryptogenic. Currently, approximately 20% of patients with infantile spasms are classified as cryptogenic (1), with the remaining 80% classified as symptomatic. This classification scheme can be helpful in the management of these patients because patients in the cryptogenic category have the best prognosis for spasm control and long-term developmental outcome (see following discussion). Differential Diagnosis The diagnosis of infantile spasms is often delayed for weeks or months because parents, and even physicians, do not recognize the motor phenomena as seizures. Colic, Moro reflexes, and startle responses are diagnoses fre- quently made by pediatricians. Parents also may confuse infantile spasms with hypnagogic jerks occurring during sleep, head banging, transient flexor-extensor posturing of trunk and extremities of nonepileptic origin, and other types of myoclonic activity. Infants with benign myoclonic epilepsy in infancy (BMEI) may have repetitive jerks, but the seizures are much briefer than spasms, and the EEG during the seizures reveals 3-Hz spike-and-wave or polyspike-and-wave activity. The background EEG activity is usually normal. These myo- clonic seizures are treated with standard anticonvulsants, and the long-term prognosis in these patients is favor- able. Another type of myoclonic movement that has been reported to be confused with infantile spasms is so-called benign myoclonus of early infancy (130). Infants with this disorder reportedly have tonic and myoclonic movements involving either the axial or limb musculature, which, like infantile spasms, may occur in clusters. The age at onset of this disorder (3 to 8.5 months) coincides with the age at onset of infantile spasms. In none of the reported cases did these movements persist beyond the age of 2 years. Unlike patients with infantile spasm, infants with benign myoc- lonus of early infancy have normal development, normal neurologic examinations, and normal EEGs. The motor movements are not accompanied by EEG changes, thus sug- gesting a nonepileptiform basis for the events. Patients with severe myoclonic epilepsy in infancy (SMEI), a disorder that may be confused with infantile spasms, usually have a family history of seizures and the disorder often begins following a prolonged febrile seizure. Unilateral clonic seizures, generalized tonic-clonic seizures, and myoclonic seizures, but not epileptic spasms, typically occur in these patients. The EEG reveals generalized spike-and-wave or polyspike-and-wave activity (131–133). The seizures are typically refractory to anticonvulsants and mental retarda- tion and neurological deficits are common. Epilepsy with myoclonic-astatic seizures (EMAS) may also be confused with infantile spasms. However, these patients experience brief myoclonic seizures, not epileptic spasms. The EEG typically shows spike-and-wave or polyspike-and-wave activity (134). Most patients are developmentally normal before onset of this disorder, which tends to be at a later age (7 months to 10 years) than infantile spasms. Related Syndromes Three different epilepsy syndromes—early myoclonic encephalopathy (EME), early infantile myoclonic epilepsy (EIEE) and Lennox-Gastaut syndrome—may be difficult to differentiate from infantile spasms. They may share a common pathophysiological basis, with each disorder being expressed at a different age. A comparison of the important ictal and interictal features of these disorders, as well as the other myoclonic epilepsies described previ- ously, is provided in Table 16-1. Ohtahara (135) proposed that the syndrome of infantile spasms, suppression-burst activity in the EEG, and developmental retardation, when seen in the first few months of life, represents a disorder different from that seen in older infants, and he termed this disorder early infantile epileptic encephalopathy (EIEE). This disorder, which has been reported by many authors (133, 136–143), has a high mortality rate. The major reported difference between EIEE and infantile spasms is that the suppression-burst pattern seen with EIEE is continuous during wakefulness and sleep, whereas infantile spasms are associated with hypsarrhyth- mia. However, as discussed previously, a suppression-burst variant of hypsarrhythmia may be seen in patients with infantile spasms. Without knowing the age and clinical his- tory of the patient, it is not possible to differentiate between these two suppression-burst patterns. Another reported dif- ference between EIEE and infantile spasms is that in infantile spasms the spasms occur almost entirely while the patient is awake, whereas the spasms associated with EIEE reportedly occur both during wakefulness and sleep (138, 142). A similar syndrome, early myoclonic encephalopathy (EME), has an onset within the first few weeks of life (132, 133, 144). This syndrome differs from EIEE and infantile spasms chiefly by the main type of clinical seizure observed. EME patients reportedly have fragmentary myoclonus, whereas patients with infantile spasms and EIEE have epi- leptic spasms. However, EME patients reportedly begin to experience epileptic spasms as they grow older. Also, the EEG in EME shows a suppression-burst pattern, but it is 16 • SEVERE ENCEPHALOPATHIC EPILEPSY IN INFANTS: INFANTILE SPASMS (WEST SYNDROME) 259 TABLE 16-1 Comparison of Childhood Epileptic Syndromes: Typical or Most Common Features EARLY BENIGN SEVERE EPILEPSY INFANTILE EARLY LENNOX- MYOCLONIC MYOCLONIC WITH EPILEPTIC MYOCLONIC INFANTILE GASTAUT EPILEPSY EPILEPSY IN MYOCLONIC ENCEPHALOPATHY ENCEPHALOPATHY SPASMS SYNDROME IN INFANCY INFANCY ASTATIC SEIZURES Age of onset 0–3 m 0–3 m 3–8 m 1–8 y 1–2 y 3 m–7 y 7 m–10 y Ictal events Epileptic (tonic) spasms ϩϩϩ ϩ ϩϩϩ ϩ Ϫ Ϫ Ϫ Tonic seizures Ϫ Ϫ ϩ ϩϩϩ Ϫ ϩ ϩ Clonic seizures Ϫ Ϫ ϩ ϩ Ϫ ϩϩϩ ϩ Tonic-clonic seizures ϪϪϩϩϩϩϩϩ Myoclonic seizures Ϫ ϩϩϩ ϩ ϩ ϩϩϩ ϩϩ ϩϩϩ Atonic seizures Ϫ Ϫ Ϫ ϩϩϩ Ϫ Ϫ _ Absence seizures Ϫ Ϫ Ϫ ϩϩϩ Ϫ ϩ ϩ Partial seizures ϩϩ ϩϩ ϩϩ ϩϩ Ϫ ϩϩ _ Interictal EEG pattern Hypsarrhythmia Ϫ Ϫ ϩϩϩ Ϫ Ϫ Ϫ Ϫ Suppression-burst ϩϩϩ ϩϩϩ ϩ Ϫ Ϫ Ϫ Ϫ Slow spike-wave Ϫ Ϫ Ϫ ϩϩϩ Ϫ Ϫ Ϫ Other abnormality Ϫ Ϫ ϩ ϩ ϩ ϩϩϩ ϩϩϩ Normal Ϫ Ϫ Ϫ Ϫ ϩϩϩ Ϫ Ϫ ϩϩϩ very common; ϩϩ common; ϩ occasional; Ϫ rare or never. Reprinted from Frost JD Jr, Hrachovy RA, Infantile Spasms, Table 7.2, page 91, copyright © 2003 Kluwer Academic Publishers, with kind permission from Springer Science and Business Media. III • AGE-RELATED SYNDROMES 260 reportedly less persistent than the suppression-burst pattern seen in EIEE. The various etiologies associated with these three disorders overlap, although EME has been reported to be associated primarily with metabolic disorders, whereas EIEE is more likely to be associated with structural brain abnormalities (133, 137, 142, 144–146). It is usually not difficult to differentiate Lennox- Gastaut syndrome from infantile spasms in the infant younger than 1 year of age. However, in older patients, the myoclonic, brief tonic and atonic seizures seen in the patient with Lennox-Gastaut syndrome may be confused with infantile spasms, particularly on the basis of clinical description alone. The fact that these syndromes transition from one to the other also complicates the issue. For example, an average of 71% of patients with EIEE transition to infantile spasms. Some of these patients then transition to Lennox-Gastaut syndrome. Some cases of EME report- edly transition to EIEE, and some cases of EIEE may evolve directly to Lennox-Gastaut (1, 136, 138, 147). In addition, an average of 17% of patients with infantile spasms will evolve to Lennox-Gastaut syndrome. If these disorders do share a common pathophysiological mecha- nism, with the stage of brain maturation being the only factor affecting the appearance of each disorder, it is dif- ficult to explain why the following evolution is not seen in all or most patients: EME q EIEE q infantile spasms q Lennox-Gastaut syndrome. From this brief discussion, it is clear that much additional work is needed to clarify the relationship of these disorders. Differentiation of infantile spasms from nonepileptic events, other types of myoclonic activity, and the three syn- dromes just described frequently requires that video-EEG monitoring studies be performed to capture the question- able episodes and thus provide a definitive diagnosis. TREATMENT No aspect of this disorder has created as much confu- sion and controversy as the area of therapy. During the past four decades, numerous studies on the treatment of infantile spasms have been published; however, the results of these studies are so diverse that no consensus exists, and no true “standard of care” has been established. In this section, we briefly review the prevailing attitudes and opinions on the treatment of this disorder and make recommendations for the most appropriate therapy based on the best available data. Medical Therapy Since 1958, when Sorel and Dusaucy-Bauloye (4) reported that treatment of patients with infantile spasms using ACTH resulted in cessation or amelioration of spasms and disappearance of the hypsarrhythmic EEG pattern, many reports have appeared on the treatment of this disorder with ACTH and corticosteroids and more traditional anti- convulsants (1, 148, 149). To date, most of these studies have been plagued with methodological shortcomings that hamper interpretation and comparison of results. Some of the problems encountered are the following: 1. The natural history of the disorder is not completely understood—particularly the phenomenon of sponta- neous remission. As noted previously, we reported in a retrospective study (25) that spontaneous remission could begin within 1 month of onset of the disorder, and within 12 months of onset, one quarter of patients had disappearance of the hypsarrhythmic pattern and cessation of spasms. More recently, Appleton et al. (150) performed a comparative trial of vigabatrin and placebo and reported that 2 of 20 patients (10%) responded to placebo. In addition, there are several case reports documenting the spontaneous remission of infantile spasms (1, 151–153). 2. There have been marked variations in dosages of medications used and durations of treatment. 3. Usually, an objective method of determining treat- ment response (video-EEG monitoring) has not been used. Instead, most studies have relied on parental observation to determine spasm frequency, which, as we have shown in previous studies, is unreliable. As shown in Figure 16-6, parents often underestimate spasm frequency to such an extent that they might FIGURE 16-6 Spasm frequency after institution of ACTH or prednisone therapy: comparison of parents’ estimates with results of 24-hour polygraphic-video monitoring. The coefficient of determination (r 2 ) between the parents’ and video monitoring counts was 0.26. The 24-hour monitoring studies were per- formed 2 to 4 weeks after institution of ACTH or prednisone therapy. Patients who failed to respond to ACTH were treated with prednisone and vice versa. Sixteen patients eventually responded to hormonal therapy. 0 0 10 20 tnuoc'stneraP 30 40 50 100 200 Monitoring count 300 261 16 • SEVERE ENCEPHALOPATHIC EPILEPSY IN INFANTS: INFANTILE SPASMS (WEST SYNDROME) report that no spasms occurred in a child who, in fact, is experiencing many spasms per day. In 8 of 24 patients, parents reported complete cessation of spasms during ACTH or prednisone therapy; how- ever, in 3 of these patients, the presence of spasms was documented by long-term polygraphic-video monitoring. Conversely, parents may report that spasms did occur in a child who, in reality, does not have spasms. These discrepancies are prob- ably related to the fact that spasms often occur in clusters shortly after arousal from sleep; they occur relatively equally during the nighttime and daytime; they are relatively brief in duration and may be subtle in appearance, and they are easily confused with other types of infant behavior (see previous discussion). 4. In most studies, response to therapy has been defined in a graded fashion. However, there is no reliable evidence that spasms respond to any form of ther- apy in such a manner. Our long-term monitoring of patients with infantile spasms treated with ACTH and prednisone indicates that the response to therapy is an all-or-none phenomenon—complete control or no control (154–157). This point is emphasized in the Guidelines to Antileptic Drug Trials in Children (Commission, 1994 [158]). 5. Almost all reported studies were inadequately pow- ered because of small study populations and so do not provide meaningful statistical data. 6. Few well-controlled, prospective studies have been performed. Most studies have been case reports or ret- rospective studies that are uncontrolled and unblinded (1, 26, 148, 149). In our initial analysis of the vari- ous therapeutic agents used to treat this disorder, we categorized 214 treatment studies into six different groups (1) (Table 16-2). The most rigorously designed studies are listed in the first column of the table. The remaining studies meeting progressively less stringent criteria are listed in the remaining columns. Only six studies (150, 156, 157, 159–161) were prospective, using blinded and randomized protocols. Further- more, only eight studies (154–157, 159, 162, 163) used serial 24-hour video-EEG monitoring to deter- mine response to therapy objectively. Of the 15 agents shown in the table, 8 have never been evaluated using prospective, blinded, and randomized protocols, or with 24-hour EEG/video monitoring. In addition, Table 16-2 lists the response rates to the various agents used to treat these patients. The dosages and durations of treatment, side effects, formulations, proposed mechanisms of action, and response character- istics of each of these agents may be found in our review of the topic (1). Between 2003 and 2006, more than 30 additional studies reporting the effectiveness of various treatment modalities have been published. Review of these studies reveals that almost all of these studies suf- fer from the same methodological shortcomings described previously, with the exception of two randomized, con- trolled studies (164, 165). Because of these methodological problems, several opinions have been published regarding the treatment of infantile spasms. After their review of the subject, Hancock and Osborne (148) concluded that no single treatment could be proven to be more efficacious than any other in terms of long-term psychomotor devel- opment or subsequent epilepsy rates. Vigabatrin may be more efficacious than placebo, and ACTH may be more efficacious than low doses of prednisone in stopping spasms. Vigabatrin may be more efficacious than hydrocortisone in stopping spasms in the group of patients with tuberous sclerosis. However, they found no treatment to be more efficacious than any other with regard to reduction in number of spasms, relapse rates, or resolution of hypsarrhythmia. Mackay et al (149) published a best practice parameter for the treat- ment of infantile spasms for the American Academy of Neurology and the Child Neurology Society. This group concluded that ACTH is probably effective in the short-term treatment of infantile spasms, but the evidence was insufficient to recommend the optimal dosage or duration of treatment. Vigabatrin is pos- sibly effective in the short-term treatment of infantile spasms and possibly effective in children with tuber- ous sclerosis. However, there was insufficient evidence to recommend any other treatment for this disorder. Also, there was insufficient evidence to conclude that successful treatment of infantile spasms improves long- term prognosis. On the basis of our analysis of the available data, we believe that it is reasonable to conclude that: 1. All agents listed in Table 16-2 have shown some efficacy in the treatment of infantile spasms. 2. As concerns treatment of this disorder with corti- costeroids and ACTH, most investigators believe ACTH to be more effective. 3. There is no convincing evidence that higher doses of ACTH are more effective than lower doses of the drug. 4. Vigabatrin appears to be particularly effective in stopping the spasms in patients with tuberous scle- rosis. 5. Response to any form of therapy usually occurs relatively quickly (within 1–2 weeks). 6. About 25% to 33% of patients will relapse after initial response to an agent. 7. There are no factors (e.g., treatment lag or patient classification) that can definitely be used to predict response to therapy. III • AGE-RELATED SYNDROMES 262 TABLE 16-2 Summary of 214 Therapeutic Trials (1958–2002) TYPE OF TRIAL 24H MON. a SUBJ. b P ROS. c PROS. c 24H MON. a SUBJ. b RAND. d RAND. d PROS. c PROS. c THERAPY BLINDED BLINDED OPEN e OPEN e RETRO. f CASE REPORTS g N H % i N H % i N H % i N H % i N H % i N H % i ACTH 3 42–58 1 74 11 20–94 27 7–93 25 0–100 ACTH (High dose) 2 50–87 1 93 4 54–100 6 50–100 Corticosteroid 2 29–33 1 25 3 33– 67 9 14–77 9 0–100 Vigabatrin 1 35 1 48 13 23–100 7 47–100 8 0–100 Nitrazepam 1 2 25 5 20–82 3 0–30 Valproate 1 2 22–50 4 18–43 5 0–50 Pyridoxine (vitamin B 6 ) 5 3–29 3 0–27 4 0–100 Surgery 1 61 16 0–100 Clonazepam 2 12 2 25–26 5 0–40 Immunoglobulin 2 26–82 4 33–43 TRH 2 47–54 1 31 1 Zonisamide 3 20–36 2 38 2 33 Topiramate 1 45 2 33–50 1 15 2 20–57 Lamotrigine 4 15–29 1 100 Felbamate 1 2 75 a 24h Mon. ϭ 24-hour video-EEG monitoring. b Subj. ϭ Subjective observation by parent/caregiver and/or short-term video-EEG monitoring (Ͻ 24 hours). c Pros. ϭ Prospective design. d Rand. ϭ Randomized study. e Open ϭ Open-label design. f Retro. ϭ Retrospective design. g Case reports ϭ Case reports or trials with fewer than 11 subjects. h N ϭ Number of trials in category. i % ϭ Range of reported initial response to therapy is expressed as the percentage of patients exhibiting complete cessation of spasms. Reprinted from Frost JD Jr, Hrachovy RA, Infantile Spasms, Table 11.1, page 168, copyright © 2003 Kluwer Academic Publishers, with kind permission from Springer Science and Business Media. 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ENCEPHALOPATHIC EPILEPSY IN INFANTS: INFANTILE SPASMS (WEST SYNDROME) 253 Fp1-A1 Fp2-A2 C3-A1 C4-A2 O1-A1 O2-A2 T5-A1 T6-A2 Fp1-C3 Fp2-C4 C3-O1 C4-O2 C3-T3 C4-T4 T3-Fp1 T4-Fp2 FIGURE 1 6-3 Hypsarrhythmia spasms, and the EEG during the seizures reveals 3-Hz spike -and- wave or polyspike -and- wave activity. The background EEG activity is usually normal. These myo- clonic seizures are treated with standard