Chapter 63 - Infantile spasms

https://doi.org/10.1016/B978-0-444-52891-9.00063-4Get rights and content

Abstract

Infantile spasms are a unique disorder of infancy and early childhood. The average age at onset of infantile spasms is 6 months and the average incidence of the disorder is approximately 0.31 per 1000 live births. Approximately one-quarter of patients will spontaneously stop having spasms within 1 year of onset. There are three main types of epileptic spasms: flexor, extensor, and mixed flexor–extensor. Spasms frequently occur in clusters and commonly occur upon arousal from sleep. The motor spasms are frequently confused with other normal and abnormal infant behaviors. Typically, the interictal EEG reveals hypsarrhythmia or one of its variants. A variety of ictal EEG patterns may be seen, the most common of which is a generalized slow-wave transient followed by an attenuation of the background activity in all regions. The primary treatment objective is to improve the EEG and stop the spasms as soon as possible and to avoid prolonged treatment durations with any form of therapy. Currently, there is no conclusive evidence that medical or surgical treatment of infantile spasms significantly alters long-term outcome. Although the pathophysiological mechanism underlying infantile spasms is unknown, several animal models of infantile spasms have been developed in recent years

Introduction

Infantile spasms (West syndrome) is a unique disorder of infancy and early childhood and was first described by an English physician, William West, in 1841 in his own son (West, 1841). Over the last half century, many synonyms have been used to describe the disorder including massive spasms, flexion spasms, salaam spasms, jack-knife seizures, nodding convulsions, blitzkrampfe, and lightning fits (Frost and Hrachovy, 2003). In 1952, Gibbs and Gibbs first described the interictal EEG pattern, hypsarrhythmia (Gibbs and Gibbs, 1952), which was noted to occur in a majority of patients with infantile spasms and in 1958, Sorel and Dusaucy-Bauloye reported cessation of spasms and EEG improvement in infantile spasms in patients treated with ACTH (Sorel and Dusaucy-Bauloye, 1958). In this article, we will briefly describe the electroencephalographic and clinical features of the disorder and discuss the unresolved issues of treatment and pathophysiology.

Section snippets

Epidemiology

The reported age at onset of infantile spasms varies from the first week of life to more than 3 years, with the average onset being at 6 months of age. Most cases (94%) begin within the first year of life (Frost and Hrachovy, 2003, Eisermann et al., 2006).

The average incidence of infantile spasms is approximately 0.31 per 1000 live births although a wide range has been reported (0.05–0.60 per 1000 live births). The prevalence of infantile spasms ranges from 0.14 to 0.52 per 1000 children with

Natural course

Infantile spasms is a time limited condition. In early work by Jeavons and coworkers (1973), it was found that 28% of patients were spasm free before 1 year of age, 49% before age 2, 65% before age 3, and 74% before age 4. However, some of these patients had been treated with steroids. We studied the spontaneous remission rate retrospectively in a group of patients not treated with hormonal therapy and found that 25% of patients stopped having spasms within 1 year of onset. Few patients

Interictal

The most common interictal EEG pattern associated with infantile spasms is hypsarrhythmia (Gibbs and Gibbs, 1952, Lacy and Penry, 1976, Hrachovy et al., 1984, Frost and Hrachovy, 2003). This pattern consists of high voltage, generally asynchronous, slow activity mixed with multifocal spikes and sharp waves. The pattern is usually most pronounced during non-REM sleep and markedly reduced or absent during REM sleep (Hrachovy et al., 1981, Hrachovy et al., 1984). This prototypic pattern is

Diagnostic approach and patient classification

The presence of infantile spasms is usually suggested when a description of spasm like events which occur in clusters on arousal from sleep is obtained. Careful general and neurological examinations must be performed. An ophthalmic evaluation and examination of the skin with a Wood's lamp is helpful to rule out such conditions as tuberous sclerosis. Initially, a routine EEG, recorded with the patient awake and asleep, should then be obtained in all patients to help establish the diagnosis. If

Pathophysiology and animal models

The pathophysiological mechanism underlying infantile spasms remains elusive. In a recent review of this topic, we provided a thorough discussion of various proposed mechanisms (Frost and Hrachovy, 2005). The following is a brief review of some of these hypotheses.

The regions of the brain that generate the epileptic spasms associated with this disorder have been debated for decades. Initial studies suggested that dysfunction of certain regions in the brainstem was responsible for generating the

Treatment

Because of the flawed design of most previous studies evaluating the effectiveness of various agents in the treatment of this disorder, several divergent opinions have evolved over the decades as to the best treatment of infantile spasms (Hrachovy et al., 1983, Hrachovy et al., 1994b, Baram et al., 1996; Vigevano and Cilio, 1997; Frost and Hrachovy, 2003, Hancock and Osborne, 2003, Lux et al., 2004, Lux et al., 2005, Mackay et al., 2004, Hamano et al., 2006, Oguni et al., 2006, Desguerre et

Long-term outcome

Currently, there is no definitive evidence that medical or surgical treatment of infantile spasms alters the developmental/mental outcome of these patients because the designs of most studies concerned with long-term outcome do not permit definitive conclusions to be reached. We analyzed the long-term outcome in studies with at least 25 patients per study and an average duration of follow-up of 31 months (Frost and Hrachovy, 2003), and concluded that only 16% of patients in these studies had

References (60)

  • S. Ohtahara et al.

    The early-infantile epileptic encephalopathy with suppression-burst: developmental aspects

    Brain Dev

    (1987)
  • M.H. Scantlebury et al.

    A model of symptomatic infantile spasms syndrome

    Neurobiol Dis

    (2010)
  • W.J. West

    On a peculiar form of infantile convulsions

    Lancet

    (1841)
  • J. Aicardi

    Infantile spasms and related syndromes

  • T.Z. Baram

    Pathophysiology of massive infantile spasms: perspective on the putative role of the brain adrenal axis

    Ann Neurol

    (1993)
  • T. Baram et al.

    High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study

    Pediatrics

    (1996)
  • H.T. Chugani et al.

    Positron emission tomography with 18F-2-fluorodeoxyglucose in infantile spasms

    Ann Neurol

    (1984)
  • H.T. Chugani et al.

    Infantile spasms: I

    PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol

    (1990)
  • H.T. Chugani et al.

    Infantile spasms: II

    Lenticular nuclei and brain stem activation on positron emission tomography. Ann Neurol

    (1992)
  • H.T. Chugani et al.

    Surgery for intractable infantile spasms: neuroimaging perspectives

    Epilepsia

    (1993)
  • I. Desguerre et al.

    The management of infantile spasms

    Arch Dis Child

    (2008)
  • O. Dulac et al.

    Infantile spasms: a pathophysiological hypothesis

    Semin Pediatr Neurol

    (1994)
  • M.M. Eisermann et al.

    Cryptogenic late-onset epileptic spasms: an overlooked syndrome of early childhood?

    Epilepsia

    (2006)
  • J.D. Frost et al.

    Infantile Spasms

    (2003)
  • J.D. Frost et al.

    Pathogenesis of infantile spasms: A model based on developmental desynchronization

    J Clin Neurophysiol

    (2005)
  • F.A. Gibbs et al.

    Atlas of Electroencephalography

    (1952)
  • R. Guerrini et al.

    Expansion of the first PolyA tract ARX causes infantile spasms and status dystonicus

    Neurol

    (2007)
  • E. Hancock et al.

    Treatment of infantile spasms

    Cochrane Database Syst Rev

    (2003)
  • E.C. Hancock et al.

    Treatment of infantile spasms

    Cochrane Database Syst Rev

    (2008)
  • R.A. Hrachovy et al.

    Infantile spasms: a disorder of the developing nervous system

  • Cited by (35)

    • Infantile spasms: Knowledge, attitude, and practice of pediatricians in Turkey

      2022, Epilepsy and Behavior
      Citation Excerpt :

      In general, the participants were aware of the clinical spasm types which frequently occur immediately upon arousal or just before sleep. Only in the most severe ictal phenotypes can the spasms also be noticed during sleep [1,7]. Nearly half of the respondents knew that seizures are mostly observed while waking up or falling asleep, whereas 30.5% believed they occur during sleep.

    • Early 17β-estradiol treatment reduces seizures but not abnormal behaviour in mice with expanded polyalanine tracts in the Aristaless related homeobox gene (ARX)

      2021, Neurobiology of Disease
      Citation Excerpt :

      Children with infantile spasms associated with severe intellectual disabilities respond poorly to anti-convulsant medication. Adrenocorticotrophic hormone (ACTH) therapy known to stimulate production and release of corticosteroids is a frontline treatment for these disorders but often has low efficacy, high relapse rates and severe side effects that alongside early-onset seizures, are thought to further exacerbate the behavioural and cognitive deficits in affected children (Hrachovy and Frost, 2013). A preclinical trial in the Arx PA1 mouse (Price et al., 2009) model found that short-term 17β-estradiol (E2) given daily in the first postnatal week alleviated the severe seizure phenotype in adult male mice (Price et al., 2009; Olivetti et al., 2014).

    • Extensive phenotyping of two ARX polyalanine expansion mutation mouse models that span clinical spectrum of intellectual disability and epilepsy

      2017, Neurobiology of Disease
      Citation Excerpt :

      Prescribed anticonvulsant drug treatments for infantile spasms are often associated with high relapse rates, ongoing seizures and long-lasting side effects, often limiting the child's cognitive development during key, early milestone periods, leading to varying degrees of ID in adolescence and adult life (Partikian and Mitchell, 2007; Hrachovy and Frost, 2013; Poeta et al., 2013). While the synthetic glucocorticoid prednisone and adrenocorticotropic hormone (ACTH) remains the primary treatment option (Pellock et al., 2010; Hrachovy and Frost, 2013), more recent work into the neuroprotective role of androgens during brain development has shown that early treatment with 17β-estradiol ameliorated the seizure phenotype in male mice modelling a common ARX mutation (Olivetti et al., 2014), suggesting that the early postnatal brain is still amenable to change, at least in mice. While Olivetti et al. (2014) hypothesized 17β-estradiol as a prospective treatment for ISSX, at least due to disturbed interneuron development, phenotypic analysis of this treatment across the clinical spectrum of ARX mutations is necessary to fully establish the resulting neuro-restorative effects.

    • Atonic elements combined or uncombined with epileptic spasms in infantile spasms

      2017, Clinical Neurophysiology
      Citation Excerpt :

      In our study, most patients showed hypsarrhythmia variants during the interictal period, suggesting a possible preponderance of atypical hypsarrhythmia in cases with atonic elements. A variety of ictal EEG patterns was reported to be seen in infantile spasm patients, consisting of generalized slow-wave transients, episodes of voltage attenuation, and bursts of fast activity, which could occur alone or in various combinations (Hrachovy and Frost, 2013). During the episodes of epileptic spasms in our patients, all the above patterns were seen.

    View all citing articles on Scopus
    View full text