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CHAPTER 23INFANTILE SPASMS(WEST’S SYNDROME)PAOLO CURATOLO, MDInfantile spasms are a catastrophic form of epilepsy typicall...
Infantile Spasms (West’s Syndrome) / 135Spikes seem focal in one part of the cortex, but they rapidly       Repeated norma...
136 / The Office Visit: Seizures and EpilepsyTABLE 23-1. Differential Diagnosis of Infantile Spasms               and to es...
Infantile Spasms (West’s Syndrome) / 137with reduced rapid eye movement sleep, are consistent                  VGB leads t...
138 / The Office Visit: Seizures and Epilepsywith intractable infantile spasms. The location of these              The long...
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  1. 1. CHAPTER 23INFANTILE SPASMS(WEST’S SYNDROME)PAOLO CURATOLO, MDInfantile spasms are a catastrophic form of epilepsy typically occurring in infancy. Because of the multiple etiologies associatedwith this condition, also known as West’s syndrome, its evolution and treatment are complex. Favorable seizure and cognitiveoutcomes are reported only in children whose spasms are controlled and in whom hypsarrhythmia disappears.Infantile spasms are a catastrophic form of epileptic seizure a fraction of a second to 1 to 2 seconds. Infantile spasmsthat typically occur in infancy and are characterized by sud- occur in clusters of individual jerks, with up to 60den bilateral contractions of the muscles of the neck, trunk, seconds between spasms. Clusters typically occur uponand extremities. Infantile spasms were first described in awakening. Infantile spasms may be flexor or extensor1841, when Dr W.J. West published a letter in the Lancet but are most commonly mixed, although they are influ-describing his own son’s condition and providing the first enced by position. If the trunk remains vertical, spasmsobservation of the characteristic clusters of brief, tonic- will be mostly flexing, whereas if a patient is in a hori-flexor spasms associated with developmental delay. In 1952, zontal position, spasms will be mostly extending.Gibbs and Gibbs first described the electroencephalogram The diagnosis of spasms is easy to make when they are(EEG) pattern commonly observed in infants with infan- typical. Sometimes motor components can be minimal.tile spasms and named this pattern hypsarrhythmia. Polygraphic and video recordings reveal that parents miss The estimated incidence of this condition, also known as a large number of spasms. Unusual variants have also beenWest’s syndrome (WS), varies between 2 and 4 per 10,000 live described. These consist of subtle head nodding, shoulderborn, 60% being boys, and has not changed during the past shrugging, abdominal contractions, eye opening, eye30 years. Although the onset of WS has been reported from rolling, grimacing, and yawning. Asymmetric spasms arethe newborn period to the age of 4 years, the highest inci- strongly associated with a symptomatic etiology anddence rate is observed in infants between 4 and 7 months of should raise suspicion of an underlying cerebral In 2% of patients, onset may be delayed to after the age Spasms are usually not recognized, or not reported byof 1 year. The syndrome combines three main features: parents, at their first appearance. As a consequence, diag-(1) sudden axial muscle contraction occurring in clusters, nosis is often delayed. Primary care physicians also may(2) diffuse paroxysmal activity on the EEG, and (3) devel- misdiagnose spasms as colic, and consistently treat themopmental delay or deterioration. In this chapter, we review as such, or as startle responses or even normal infantthe clinical and EEG features of the syndrome and discuss behavior. Repetitive, stereotyped characterization of anycurrent treatment options as well as the long-term outcome. movements in infancy should arouse the suspicion of infantile spasms and lead to an immediate EEG recording. Diagnosis EEG Manifestations The term hypsarrhythmia describes a very disorganized Ictal Manifestations interictal EEG pattern that is virtually pathognomonic ofThe spasms are sudden, bilateral contractions of the WS. This pattern is characterized by high-voltage, randommuscles of the neck, trunk, and extremities, lasting from slow waves, sharp waves, and spikes in all cortical regions.Current Management in Child Neurology, Third Edition© 2005 Bernard L. Maria, All Rights Reserved Infantile Spasms (West’s Syndrome)BC Decker Inc Pages 134–138
  2. 2. Infantile Spasms (West’s Syndrome) / 135Spikes seem focal in one part of the cortex, but they rapidly Repeated normal EEGs, including prolonged sleepmigrate and are sometimes generalized, giving the EEG recordings, rules out the diagnosis of infantile spasms.the typically described “chaotic” appearance. This activity Differential diagnosis of infantile spasms should take intois continuous when the infant is awake and fragmented account both nonepileptic and epileptic seizures or syn-during sleep. dromes with onset during the first year of life that can mimic When infantile spasms occur, high-amplitude slow infantile spasms (Table 23-1). Benign myoclonus of earlywaves followed by abrupt attenuation of the background infancy may closely mimic infantile spasms, but the EEG isactivity appear (Figure 23-1). Spasms need to be distin- normal. Epileptic syndromes closely related to WS includeguished from tonic seizures, in which the contraction is early myoclonic encephalopathy, early infantile epilepticlonger—lasting several seconds—and combined with low- encephalopathy, and early onset Lennox-Gastaut syndrome.amplitude fast activity, and from myoclonic jerks, which All these conditions underlie serious brain pathology.are shorter—lasting a fraction of a second—and combinedwith a generalized spike-wave discharge. Developmental Manifestations Although hypsarrhythmia is pathognomonic for WS, Psychomotor and behavioral regression may occur at theother EEG patterns can occur in about one-third of onset of the spasms, but developmental delay may havepatients, most commonly represented by multifocal inde- preceded them by several months. For some infants withpendent spike discharges. The term “modified hypsar- spasms, psychomotor retardation is present from birth. Inrhythmia” is used if there is some preservation of back- these patients, both early onset paroxysmal events and con-ground rhythm, significant asymmetry, or synchronous tinuous nonconvulsive paroxysmal activity may accountburst of generalized spike-wave activity. Some brain mal- for the generation of developmental delay. Major cerebralformations, such as hemimegalencephaly, lissencephaly, malformations, such as hemimegalencephaly, Aicardi’stuberous sclerosis, and Aicardi’s syndrome, show charac- syndrome, and lissencephaly, exhibit psychomotor delayteristic EEG patterns. Focal features, including asymmet- before the onset of the epilepsy, which begins very early inric spasms and focal spikes or slow waves, indicate the life, and may consist of partial seizures before the occur-presence of a hemispheric brain lesion, such as schizen- rence of spasms. Other patients, particularly those withcephaly, porencephaly, polymicrogyria, or focal cortical tuberous sclerosis, usually exhibit normal developmentdysplasia. In patients with focal lesions, the age of onset of until the first weeks of the disorder. Cognitive deteriorationthe epilepsy has been shown to be related to the topo- in tuberous sclerosis develops slowly, owing to majorgraphy, with occipital lesions producing spasms earlier epileptogenic activity in multiple areas of the cortex and tothan frontal ones. secondary generalization during sleep.FIGURE 23-1. Ictal electroencephalogram(EEG) showing typical spasms in a 4-month-old child, with high-amplitude diffuse slowwaves on the EEG.Current Management in Child Neurology, Third Edition© 2005 Bernard L. Maria, All Rights Reserved Infantile Spasms (West’s Syndrome)BC Decker Inc Pages 134–138
  3. 3. 136 / The Office Visit: Seizures and EpilepsyTABLE 23-1. Differential Diagnosis of Infantile Spasms and to establish whether there is a need for genetic coun-Nonepileptic syndrome mimicking infantile spasms seling. A comprehensive history, especially with regard to Abdominal pain (colic) hereditary disorders and prenatal and perinatal events, as Benign neonatal sleep myoclonus well as a careful clinical examination to check for signs of Hyperexplexia tuberous sclerosis or dysmorphic features should always be Sandifer’s syndrome undertaken. Magnetic resonance imaging (MRI) may Early breath-holding spells and syncopal attacks Benign infantile dystonia reveal abnormalities in at least two-thirds of patients. If the Increased Moro reflex and attacks of opisthotonus etiology is still unclear, a cerebrospinal fluid evaluation Self-gratification or masturbation-like episodes and/or a screening of serum and urine for inborn error of Benign paroxysmal tonic upward gaze metabolism, including amino acids, can be justified. A Shuddering attacks number of cases formerly classified as cryptogenic can now Benign myoclonus of early infancy be included in the symptomatic group owing to the useEpileptic syndromes mimicking infantile spasms of more advanced imaging techniques, including high- Early myoclonic encephalopathy definition MRI and positron emission tomography (PET). Early infantile epileptic encephalopathy Benign myoclonic epilepsy of infancy In our experience, 70% of infantile spasm cases are symp- Cryptogenic or symptomatic myoclonic-atonic-astatic epilepsies tomatic, 25% are cryptogenic, and 5% are idiopathic. Early-onset Lennox-Gastaut syndrome In idiopathic cases, psychomotor development is normal Partial seizures mimicking asymmetric infantile spasms at the onset of spasms, and there is no evidence of devel- opmental arrest or regression. Approximately 40% of chil- dren with idiopathic spasms are neurologically normal. Cognitive disorders associated with infantile spasms are Familial occurrence of infantile spasms is rare. In recentheterogeneous. They can consist of different combinations years, linkage to the X chromosome has been reported in twoof speech delay, visuomotor dyspraxia, autistic features, families with WS. The region of interest (Xp21.3–Xp22.1)and mental retardation. Localized brain lesions can produce includes candidate genes involved in syndromic and non-selective neuropsychologic disorders, depending on their syndromic mental retardation as well as radixin, a proteintopography. In this regard, tuberous sclerosis is a promis- involved in neuroaxonal processing. Familial idiopathicing model because the course of cognitive disorder depends spasms have also been reported, but no linkage has beenmainly on the clinical course of the epilepsy, which is related the localization of the major cortical tubers. Pathophysiology Etiology The pathophysiologic mechanisms of WS remain poorlyMany prenatal, perinatal, and postnatal abnormalities of understood. Heterogeneous pathophysiologic mecha-the brain have been identified as presumed etiologic fac- nisms, including dysfunction of the brainstem, abnormaltors for WS. The findings in a recent large population- cortical-subcortical interaction, disturbances of corticalbased cohort reported by Riikonen are given in Table 23- synaptogenesis, and abnormal brain-adrenal axis may be2. Brain malformations and tuberous sclerosis may responsible for the genesis of infantile spasms.account for up to 35% of patients. However, cerebral mal- WS could be produced by the brainstem, with pro-formations can explain up to 45% of neuropathologic jections going both to the cortex and to the spinal cordcases. Perinatal causes, including hypoxic-ischemic to generate hypsarrhythmia and the spasms, respec-encephalopathy, porencephaly, multicystic encephaloma- tively. Modifications observed in the sleep-wake cycle,lacia, and ulegyria account for about 10% of cases. Peri-and postnatal brain lesions tend to produce later-onsetWS compared with prenatal lesions. When the cause of TABLE 23-2. Etiological Factors in a Population-Basedthe spasms is identifiable (symptomatic spasms), the infant Studyis usually neurologically or developmentally abnormal Symptomatic Causes Percentwhen the spasms begin. Microcephaly is more common in Brain malformations and tuberous sclerosis 35this group. Nonsymptomatic infantile spasms can be split Undetermined pre-/perinatal factors 19into two groups: (1) cryptogenic cases are usually associ- Perinatal insults 9ated with “hidden” lesions; (2) idiopathic cases are char- Symptomatic neonatal hypoglycemia 8acterized by absence of any brain lesion. Familial or metabolic causes 9 Careful search for etiologic factors should be under- Early infections 2 Cryptogenic 18taken in every case to determine an accurate prognosisCurrent Management in Child Neurology, Third Edition© 2005 Bernard L. Maria, All Rights Reserved Infantile Spasms (West’s Syndrome)BC Decker Inc Pages 134–138
  4. 4. Infantile Spasms (West’s Syndrome) / 137with reduced rapid eye movement sleep, are consistent VGB leads to the control of infantile spasms in up to 65%with this hypothesis. The presence of frequent focal cor- of patients. Children with tuberous sclerosis have a 95%tical lesions, detected by both structural and functional response rate. The efficacy of VGB can be assessed in less thanneuroimaging, has recently raised the hypothesis that a 10 days, but usually a few days’ treatment with a dose of 50cortical lesion could trigger some subcortical structure, to 100 mg/kg/d stops infantile spasms. In contrast, steroids,and then the basal ganglia and the cortex, resulting in benzodiazepines, or sodium valproate can take weeks to showspasms and hypsarrhythmia. Another pathophysiologic efficacy. The cessation of spasms is associated with a markedmechanism is inferred from the peculiar characteristics improvement in cognitive and behavioral development.of the brain cortex in the first year of life. During this Unfortunately, in recent years, several reports have focusedperiod, in which there are excessive excitatory synapses, on the appearance of visual field disorders in patients treatedany triggering factor could initiate epileptic discharges with VGB. The use of VGB is associated with delayed appear-with subsequent involvement of wide areas of the cor- ance of concentric narrowing of the visual fields in up to 40tex. Finally, the occurrence of partial seizures during to 50% of cases. This narrowing can be severe and irre-the cluster of infantile spasms in some children with a versible, and continuation of the drug can be associated withsymptomatic etiology suggests these two types of progressive visual-field loss. Despite this adverse effect, VGBseizure may be generated independently at different lev- remains, in most countries, the drug of first choice for symp-els of the brain. Because of an age-dependent peculiar tomatic infantile spasms associated with tuberous sclerosis.cortical-subcortical interaction, infantile spasms may Currently, the minimum duration and doses of VGB treat-be produced in these cases at a subcortical level, trig- ment that can produce side effects are unknown. The feasi-gered by focal cortical discharges. bility of low dosages and short treatment periods (2 to 3 months) is now under investigation. Medical Treatment Recent results of a pilot study of topiramate show that 45% of patients are seizure-free on high doses. Studies inSeizure control is necessary to improve the natural history Japan and the United States have shown that two-thirds ofof WS. Therefore, identifying the most appropriate ther- patients become spasm-free when treated with zonisamideapy is an urgent matter, so seizures can be controlled after other therapies have failed. Improvement of seizurequickly, while a child still has the maximum potential for control has been observed with benzodiazepines and val-improved development. proic acid in high doses. However, none of these drugs has The best treatment for infantile spasms remains uncer- shown responses comparable with those of VGB or corti-tain. There are few drugs with proven efficacy: hormonal costeroid therapy; no controlled studies have been per-therapy (in the form of adrenocorticotropic hormone formed and their effects on EEG abnormalities are limited.[ACTH] or prednisone), vigabatrin (VGB), topiramate, and At our institution, we recommend a 10-day course ofzonisamide. The ideal dose and duration of ACTH or pred- VGB as initial therapy. ACTH should be the first drug ofnisone have not been established. An initial dose of 20 to choice if VGB is not available. When VGB or ACTH fails to30 IU/d for 2 to 6 weeks is just as effective as an initial dose control spasms, then topiramate can be prescribed. Clinicalof 150 IU/d tapered over 10 weeks. A 2-week course of oral experience suggests that titration has to be slow and pro-prednisone, 2 mg/kg/d, has similar efficacy. The response to gressive. A small proportion of cases of infantile spasmshormonal therapy is never graded; control of spasms is may represent atypical pyridoxine-dependent seizures.either complete or nonexistent. Even when the response is High doses of pyridoxine (30 to 40 mg/kg/d) are reportedfavorable, one-third of patients relapse. A second course of to be effective in 40% of patients with cryptogenic spasmtreatment is effective in 75% of cases in which the first but only in 10% of symptomatic cases.course was successful. Failure to respond and relapse occur To conclude, it is important to underline that manymore often in symptomatic cases. ACTH, particularly in risks and adverse effects are associated with the medica-high doses, has been shown to be more effective than tions used in the treatment of infantile spasms. As a gen-steroids in 70 to 80% of children with WS. The enhanced eral rule, when selecting a drug regimen for a patient,potency of ACTH compared with steroids is consistent with physicians must weigh the risk for morbidity or mortalitydirect, steroid-independent actions of ACTH within the versus the benefit of increasing developmental potential ifcentral nervous system. Adverse events, including hyper- the seizures are controlled quickly.tension, hypokalemia, irritability, and poor sleep are closelyrelated to dosage, duration of therapy, and patient’s suscep- Surgical Treatmenttibility to ACTH. Adverse events are minimized if the dosageis quickly tapered; however, few patients with symptomatic The discovery of focal or multifocal cortical lesions has ledinfantile spasms require long courses of therapy. to a surgical approach for the treatment of some patientsCurrent Management in Child Neurology, Third Edition© 2005 Bernard L. Maria, All Rights Reserved Infantile Spasms (West’s Syndrome)BC Decker Inc Pages 134–138
  5. 5. 138 / The Office Visit: Seizures and Epilepsywith intractable infantile spasms. The location of these The long-term outcome is strongly influenced by thelesions should be concordant with localization of focal structural abnormalities underlying the syndrome. Theictal and/or interictal EEG abnormalities before proceed- outcome is worse in children with severe brain malforma-ing with cortical resection. Interictal glucose metabolism tions and tuberous sclerosis. Risk factors for a poor prog-PET scans show unifocal cortical hypometabolism in nosis include the presence of neurologic abnormalitiesabout 20% of children with intractable cryptogenic infan- before the onset of spasms, developmental regression, focaltile spasms. When a single lesion is present on the MRI or EEG findings, failure of medication to promptly correctPET, and there is good correlation with EEG localization, developmental arrest or regression, recurrence of spasmssurgical removal of the hypometabolic area, which usually and hypsarrhythmia after an effective response to drug,proves to contain dysplastic tissue, often provides seizure onset before 4 months of age, presence of an underlyingcontrol. To achieve the best seizure outcome, it is impor- structural lesion, and abnormal neuroimaging findings.tant to resect the entire nociferous area, rather than just the Despite recent improvement in clinical and etiologicseizure focus. However, the long-term effects of large sur- diagnosis of infantile spasms, many crucial problemsgical resection on neurologic functions have not been fully remain unresolved. Physicians should take a broad look atevaluated, and it is not clear to what extent cognitive devel- all the therapeutic options available to achieve seizure con-opment is affected by such radical treatment. trol and reverse the poor prognosis associated with WS. Prognosis Suggested Readings Curatolo P, Seri S, Verdecchia M, et al. Infantile spasms in tuber-Most children with infantile spasms have a poor progno- ous sclerosis complex. Brain Dev 2001;23:502–7.sis because of intractable epilepsies, severe developmentaldelay, and/or significant cognitive impairment. Epileptic Dulac O. What is West syndrome? Brain Dev 2001;23:447–52.seizures persist in approximately 50% of patients. The nat- Shields WD. West’s syndrome. J Child Neurol 2002;17(Suppl 1):ural history of epilepsy is characterized by the development S76–9.of Lennox-Gastaut syndrome and temporal lobe partialepilepsy. However, the occurrence of Lennox-Gastaut syn- Practitioner and Patient Resourcesdrome after WS has considerably decreased in the pastdecade owing to new therapeutic options. Epilepsy Foundation Only 5 to 10% of children with infantile spasms have 4351 Garden City Drive, Suite 406 Landover, MD 20785-2267normal development. The vast majority of children are Phone: (301) 459-3700 or (800) EFA-1000left with cognitive or motor delay, and often with behav- E-mail: postmaster@efa.orgior disorders. Psychiatric disorders, such as autism and http://www.epilepsyfoundation.orghyperactive behavior, can occur in about 20% of children, The Epilepsy Foundation will ensure that people with seizures arebut they are significantly more frequent in children with able to participate in all life experiences and will prevent, control, andtuberous sclerosis (about 40%). cure epilepsy through research, education, advocacy and services.Current Management in Child Neurology, Third Edition© 2005 Bernard L. Maria, All Rights Reserved Infantile Spasms (West’s Syndrome)BC Decker Inc Pages 134–138