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Infantile Spasms: Outcome in Clinical Studies

  • Raili Riikonen
    Correspondence
    Communications should be addressed to: Dr. Riikonen; Children’s Hospital; University of Eastern Finland and Kuopio University Hospital; P.O. Box 1627; FI-70211, Kuopio, Finland.
    Affiliations
    Children’s Hospital, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
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      Abstract

      Children with infantile spasms are likely to have a poor outcome. Outcome measures for infantile spasms include primary response to treatment, relapse of spasms, neurological development, death, and progression to another type of epilepsy (Consensus Statements of the WEST Delphi Group 2004). This review is based mainly on prospective studies and emphasizes data about the current first-line drugs, adrenocorticotropic hormone, vigabatrin, and prednisolone, taking into account the proportion of patients with known and unknown etiology, which has a very strong effect on seizure outcome. In most studies, hormonal treatment (adrenocorticotropic hormone or prednisolone) is the optimal monotherapy, except for patients with tuberous sclerosis complex, in whom vigabatrin appears superior. Combination therapy (hormones plus vigabatrin) may well be more effective than either agent alone. The underlying etiology is the most important prognostic factor. In studies with a long follow-up (up to 50 years), a favorable cognitive outcome has been observed in approximately one quarter of patients and complete seizure freedom in one-third. Autism is relatively frequent, and premature mortality is high throughout life. Modifiable prognostic factors include early recognition of the spasms with prompt treatment, short duration of hypsarrhythmia, prompt treatment of relapses of spasms and multifocal epileptic discharges, and early treatment of adverse effects. It is hoped that eventually advanced genetics and molecular data will allow an understanding of the pathogenetic mechanisms of many specific etiologies to allow disease-specific treatment such as is emerging for tuberous sclerosis.

      Keywords

      Introduction

      An important goal for the treatment of children with infantile spasms is good cognitive outcome, but unfortunately, most of them have significant neurodevelopmental deficits. Good cognitive outcome seems to be dependent on prompt cessation of spasms and resolution of hypsarrhythmia. A number of well-designed clinical trials have compared current treatment options, although most studies have evaluated only short-term outcome. There are only a few prospective studies—most have short follow-ups and long-term outcome studies are scarce.
      Outcome measures for infantile spasms have been outlined by the West Delphi Group using a Delphi methodology with 46 invited clinicians from 15 countries.
      • Lux A.
      • Osborne J.
      A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of West Delphi Group.
      Consensus was reached for the importance of the following outcomes: primary clinical response, primary electroclinical response, relapse-free primary response (clinical and electroclinical), continuing subtle spasms without clinical spasms, distribution of time to relapse, proportion of relapse-free remission over time, development at age two years, death and other serious events, presence of seizures and progression to other seizure types, and nonserious adverse events. Most of these outcome measures apply both to study design and clinical practice. The group failed to reach a consensus on the definition of hypsarrhythmia.
      • Lux A.
      • Osborne J.
      A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of West Delphi Group.

      Outcome

      This review emphasizes several key issues about infantile spasms—the relationship between etiology and outcome, the results of short-term treatment, adverse effects of treatment, long-term outcome, and the changes that could be made to therapeutic protocols to improve the outcome.

      Does the etiology influence the outcome?

      Etiology appears to be the most important predictor of outcome. In the past, etiology of infantile spasms was charcterized as symptomatic and cryptogenic, terms that have been used inconsistently in the literature by various authors. A small number of patients was said to have an idiopathic etiology. The updated classification refers simply to known (symptomatic) and unknown (cryptogenic) etiologies.
      • Berg A.
      • Berkovic S.
      • Brodie M.
      • et al.
      Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology 2005-2009.
      ,
      • Scheffer I.
      • Berkovic S.
      • Capovilla G.
      • et al.
      ILAE classification of epilepsies: position paper of the ILEA commission for classification and terminology.
      In symptomatic spasms, there is often a pre-existing encephalopathy, abnormal neurological signs, and/or significant abnormalities on brain imaging. Individuals with no known cause ("cryptogenic") for their infantile spasms typically have normal prior development, symmetric spasms, and no atypical features (such as asymmetric, asynchronous, focal, subtle spasms, or spasms associated with partial seizures). They also tend to exhibit typical findings on electroencephalography (EEG).
      • Gaily E.
      • Shewmon D.
      • Chugani H.
      • Curran J.
      Asymmetric and asynchronous infantile spasms.
      Some patients have no known cause for their infantile spasms ("cryptogenic") even after undergoing a thorough evaluation, including state-of-the-art brain imaging and any relevant metabolic and genetic studies.
      Idiopathic spasms are attributed to a known or presumed genetic predisposition and have a favorable outcome.
      • Vigevano F.
      • Fusco L.
      • Cusmai R.
      • Clays D.
      • Ricci S.
      • Milani L.
      The idiopathic form of West syndrome.
      Idiopathic spasms cannot be confirmed with certainty at the time of diagnosis, and the terms idiopathic and cryptogenic spasms are often synonymous in the older literature.
      • Mackay M.T.
      • Weiss S.K.
      • Adams-Webber T.
      • et al.
      Practice parameter: medical treatment of infantile spasms.
      Over time, the evaluation of spasms has become more sophisticated, with genetic and metabolic studies and more comprehensive magnetic resonance imaging (MRI) investigations. Consequently, some children with a previously unknown etiology would now be classified as having symptomatic spasms. The most recent classification of the etiology of infantile spasms groups the causes as structural-metabolic, genetic, infectious-immune, and unknown groups.
      • Berg A.
      • Berkovic S.
      • Brodie M.
      • et al.
      Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology 2005-2009.
      ,
      • Scheffer I.
      • Berkovic S.
      • Capovilla G.
      • et al.
      ILAE classification of epilepsies: position paper of the ILEA commission for classification and terminology.
      Thus symptomatic and cryptogenic are not very satisfactory descriptive terms. However, the literature that defines most of what we know about infantile spasms uses the old classification and consistently has found that "cryptogenic" group has the best response to treatment and best long-term outcome. In this review these older, established terms are often used
      • Lux A.
      • Osborne J.
      The influence of etiology upon ictal semiology, treatment decisions and long-term outcomes in infantile spasms and West syndrome.
      because they cannot be easily translated into the newer classification. Where possible the newer classification will be applied.
      MRI appears to be the most important tool to categorize patients as having cryptogenic (unknown cause) or symptomatic etiology (known cause), and brain structural abnormalities markedly influence the prognosis. MRI may be repeated between age 18 months and two years, because subtle focal cortical dysplasia may be undetectable at onset of infantile spasms but become visible as myelination progresses. According to Wirrell et al., cost-effective evaluation for those without an obvious cause after initial clinical evaluation and MRI includes an array comparative genomic hybridization followed by an epilepsy gene panel if the microarray is not definitive, serum lactate, serum amino acids, and urine organic acids.
      • Wirrell E.
      • Shellhaas R.
      • Joshi C.
      • et al.
      Pediatric Research Consortium
      How should children with West syndrome be efficiently and accurately investigated? Results from the National Infantile Spasms Consortium.
      In this multicentered study (the National Infantile Spasms Consortium) 251 patients were investigated. An obvious cause was found after initial examinations (clinical assessment and/or MRI) in 138 (58%). For those without an identified cause after the initial examination, genetic testing showed a causal abnormality in 23.5% and a variant of unknown significance in 14.8%. Only three children underwent whole-exome sequencing, all with normal results.
      • Wirrell E.
      • Shellhaas R.
      • Joshi C.
      • et al.
      Pediatric Research Consortium
      How should children with West syndrome be efficiently and accurately investigated? Results from the National Infantile Spasms Consortium.
      In the multicenter, Epilepsy/Genome Project database, 100 of 126 patients with infantile spasms of unknown etiology underwent whole-exome sequencing. Pathogenetic de novo variants were identified in 15 individuals (15%). If no cause is identified, whole-exome sequencing should be strongly considered.
      Infantile spasms of unknown cause: who can have a good outcome?.
      At the first clinical evaluation the doctor may be able to offer the prognosis to parents, if it looks favorable. If the etiology remains unknown and development was normal before spasm onset, the patient will become free of spasms and have normal or nearly normal psychomotor development in about 80% cases.
      • Granström M.-L.
      • Gaily E.
      • Liukkonen E.
      Treatment of infantile spasms: results of a population-based study with vigabatrin as the first drug for spasms.
      • Cohen-Sadan S.
      • Kramer U.
      • Ben-Zeev B.
      • et al.
      Multicenter long- term follow-up of children with idiopathic West syndrome: ACTH versus vigabatrin.
      • Kivity S.
      • Lerman P.
      • Ariel B.
      • Danziger Y.
      • Mimouni M.
      • Shinnar S.
      Long-term cognitive outcomes of a cohort of children with cryptogenic infantile spasms treated with high-dose adrenocorticotropic hormone.
      • Gaily E.
      • Lommi R.
      • Lapatto R.
      • Lehesjoki A.-E.
      Incidence and outcome of epilepsy syndromes with onset in the first year of life: a retrospective population-based study.
      Some symptomatic cases may also have a favorable prognosis; spasms may also cease in 50% patients, and the development will be roughly normal in about 20% cases.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      • Granström M.-L.
      Prognosis of infantile spasms.
      • Lagae L.
      • Velhest H.
      • Ceulemans B.
      • et al.
      Treatment and longterm outcome in West syndrome: the clinical reality. A multicentre follow-up study.
      Patients with symptomatic etiology may have a favorable seizure outcome if the etiology is neonatal hypoglycemia (N = 9 of 147),
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      Down syndrome (N = 17 of 43),
      • Nabbout R.
      • Melki I.
      • Gerbaka B.
      • Dulac O.
      • Akatcherian C.
      Infantile spasms in Down syndrome: good response to a short course of vigabatrin.
      ,
      • Caraballo R.
      • Cersosimo H.
      • Arroyo H.
      • Fejerman N.
      Symptomatic West’s syndrome: specific etiological link to unexpected response to treatment.
      stroke or infarct (N = 12 of 377),
      • Osborne J.
      • Edwards S.
      • Alber F.
      • et al.
      The underlying etiology of infantile spasms (West syndrome): information from the International Collaborative infantile Spasms Study (ICISS).
      periventricular leukomalacia (PVL) (N = 8 of 32),
      • Cusmai R.
      • Ricci J.
      • Pinard P.
      • Plouin P.
      • Dulac O.
      West syndrome due to perinatal insults.
      and neurofibromatosis (N = 4 of 5).
      • Caraballo R.
      • Cersosimo H.
      • Arroyo H.
      • Fejerman N.
      Symptomatic West’s syndrome: specific etiological link to unexpected response to treatment.
      The outcome is almost always poor in children with severe brain malformations,
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      postinfectious etiology,
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      and tuberous sclerosis complex (TSC) (N = 53 of 53).
      • Riikonen R.
      • Simell O.
      Tuberous sclerosis and infantile spasms.
      ,
      • Capal J.
      • Bernardino-Cuesta B.
      • Horn P.
      • et al.
      Influence of seizures on early development in tuberous sclerosis complex.
      Individuals with primarily genetic causes, such as SCN2A, are more likely to have poor developmental outcomes.
      • Yuskaitis C.
      • Ruzhnikov M.
      • Howell K.
      • et al.
      Infantile spasms of unknown cause; Who can have a good outcome?.
      ,
      • Sundaram K.
      • Chugani H.
      • Tiwari V.
      • Huq A.
      SCN2A mutation is associated with infantile spasms and bilateral glucose hypometabolism.

      What is the effect of treatment of infantile spasms on short-term outcome

      Most studies report the results of short-term treatment, usually after two to three weeks of treatment. The proportion of patients with known versus unknown etiology should be noted in every study, because the response to therapy is consistently better in the unknown etiology group.
      • Cohen-Sadan S.
      • Kramer U.
      • Ben-Zeev B.
      • et al.
      Multicenter long- term follow-up of children with idiopathic West syndrome: ACTH versus vigabatrin.
      ,
      • Kivity S.
      • Lerman P.
      • Ariel B.
      • Danziger Y.
      • Mimouni M.
      • Shinnar S.
      Long-term cognitive outcomes of a cohort of children with cryptogenic infantile spasms treated with high-dose adrenocorticotropic hormone.
      The methodology of reported studies has been very variable including the choice of drugs and their formulations, lead time from spasm onset to therapy, and dose and duration of therapies.
      Prospective studies of children treated with hormonal and vigabatrin (VGB) therapies are shown in TABLE 1., TABLE 2.. Based on these studies, hormonal therapy with adrenocorticotropic hormone (ACTH), tetracosactide, or prednisolone or VGB treatment are currently the preferred first-line treatments for infantile spasms. The proportion of patients with resolution of their spasms varies in prospective studies. For ACTH, response rates vary from 36.7% to 87% (mean 61%, 10 studies); for prednisolone, from 11% to 70% (mean 46%, four studies), and for VGB, from 11% to 58% (mean 36%, eight studies) (TABLE 1., TABLE 2.).
      TABLE 1.Short-Term Outcome of Patients With Infantile Spasms Treated With Steroids or ACTH in Prospective Studies
      Class of EvidenceNo. of PatientsCIS (% of Patients)ACTH DoseDuration at Full Dose (Weeks)Total Treatment Duration (Weeks)Spasms Stopped (%)EEG ResolutionTime Point to Evaluate the ResponseReferences
      III10539110 IU/m238493910 moLombroso
      • Lombroso C.T.
      A prospective study of infantile spasms: clinical and therapeutic correlations.
      I26ND150 IU/m2312542323 moHrachovy et al.
      • Hrachovy R.
      • Frost J.
      • Glaze D.
      High-dose, long-duration versus low-dose, short-duration corticotrophin therapy for infantile spasms.
      2420 IU/m2312582121 mo
      I1525150 IU/m224878716 moBaram et al.
      • Baram T.
      • Michell W.
      • Tourney A.
      • Snead 3rd O.
      • Hanson R.
      • Horton E.
      High-dose corticotrophin therapy for infantile spasms. A prospective, randomized, blinded study.
      1240Prednisolone 2 mg/kg/d24333316.9 mo
      III194810 IU3-5; 55-674789-44 moVigevano and Cilio
      • Vigevano P.
      • Cilio M.
      Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study.
      III2548Tetracosactide 0.5 mg every second day2ND76702 wkLux et al.; UKISS
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      The United Kingdom infantile spasm study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomized controlled trial.
      3043Prednisolone 40 mg/d210707010 wk
      III971420-40 IU/d35-664773 wkRiikonen
      • Riikonen R.
      A long-term follow-up study of 214 children with the syndrome of infantile spasms.
      5413120 IU/d3554743 wk
      I9725ACTH2455N.D.3 moKnupp et al.
      • Knupp K.
      • Coryel J.
      • Nickels K.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      5413Prednisolone2423
      149ND40-60 IU/d2536,7184 wkWanigashinghe et al.
      • Wanigashinghe J.
      • Arambepola C.
      • Sri Ranganathan S.
      • Sumanasena S.
      Randomized, single-blind, parallel clinical trial on efficacy of oral prednisolone versus intramuscular corticotropin: a 12-month assessment of spasm control in West syndrome.
      48NDPrednisolone2558,3444 wk
      118645Hormonal therapy with VGB, combination therapy42 d3 mo726642 dO’Callaghan et al.; ICISS study
      • O’Callaghan F.J.K.
      • Edwards S.W.
      • Alber E.D.
      • et al.
      Safety and effectiveness of hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomized, multicentre, open-label trial.
      1191

      ACTH N = 60

      Prednisolone N = 130
      46ACTH 0.5 mg every second day, prednisolone 40-60 mg/d, hormonal therapy42 d1 mo575542 dO′Callaghan et al.; ICISS study
      • O’Callaghan F.J.K.
      • Edwards S.W.
      • Alber E.D.
      • et al.
      Safety and effectiveness of hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomized, multicentre, open-label trial.
      III6648Prednisolone after VGBVGB 3 mo prednisolone 42 d672ND7 moKo et al.
      • Ko A.
      • Youn S.E.
      • Chung H.J.
      • et al.
      Vigabatrin and high-dose prednisolone therapy for patients with West syndrome.
      Abbreviations:
      ACTH = Adrenocorticotropic hormone
      CIS = Cryptogenic infantile spasms
      EEG = Electroencephalography
      IU= International units
      ND = No data
      VGB = Vigabatrin
      TABLE 2.Short-Term Outcome of Patients With Infantile Spasms Treated With Vigabatrin in Seven Prospective Studies
      Class of EvidenceNo of PatientsCIS (% of Patients)Vigabatrin mg/kg/dDuration at Full DoseSpasms Stopped (%)EEG Resolution %Time Point to Response EvaluationReferences
      I203050-1505 d352312 dAppleton et al.
      • Appleton R.
      • Peters A.
      • Mumford J.
      • Shaw D.
      Randomized, placebo- controlled study of vigabatrin as first-line treatment of infantile spasms.
      III752818-3612 wk11ND14 dElterman et al.
      • Elterman R.D.
      • Shields W.D.
      • Bittman R.M.
      Vigabatrin for the treatment of infantile spasms: final report of a randomized trial.
      6733100-15012 wk23ND14 d
      III2339150ND483620 dVigevano and Cilio
      • Vigevano P.
      • Cilio M.
      Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study.
      III5238100-15014 wk545014 dLux et al.
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      The United Kingdom infantile spasm study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomized controlled trial.
      I472100-150Variable36ND3 moKnupp et al.
      • Knupp K.
      • Coryel J.
      • Nickels K.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      III1802550-15017 d585614 dDjuric et al.
      • Djuric M.
      • Kravljanac R.
      • Tadic B.
      • Mrljes-Popovic N.
      • Appleton R.
      Long-term outcome in children with infantile spasms treated with vigabatrin: a cohort of 180 patients.
      III422350-1507-20 d262620 dGranström et al.
      • Granström M.-L.
      • Gaily E.
      • Liukkonen E.
      Treatment of infantile spasms: results of a population-based study with vigabatrin as the first drug for spasms.
      Abbreviations:
      CIS = Cryptogenic infantile spasms
      EEG = Electroencephalography
      ND = No data
      There are two large prospective studies from the United States and United Kingdom.

      US study

      Knupp et al.
      • Knupp K.
      • Coryel J.
      • Nickels K.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      reported the results of the multicenter, prospective National Infantile Spasms Cohort study. A total of 230 consecutive children with infantile spasms had their treatment selected by the attending physician, and cases included both those with unknown and known etiology. The overall response rate was lower than reported in studies focusing on low-risk patients. The clinical and electrographic treatment response was evaluated three months after the onset of treatment. A good response occurred in 53 of 97 (55%) of those who received ACTH, 21 of 54 (39%) of those who received prednisolone, and 17 of 47 (36%) who received VGB. Surprisingly, neither the etiology nor the pretreatment developmental status substantially modified the treatment response.

      UK study

      The large, multicenter, randomized, United Kingdom Infantile Spasm Study (UKISS) compared hormonal (prednisolone or tetracosactide) therapy and VGB in the short-term treatment (14 days) of infantile spasms in 107 children. The response rates at 14 days were 40 of 55 (73%) for infants assigned to hormonal treatments (prednisolone 21 of 30 [70%], tetracosactide 19 of 25 [76%]) and 28 of 52 (54%) for infants assigned to VGB. Cessation of spasms was statistically more likely in infants receiving hormonal treatment than in those given VGB. TSC was excluded.
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      The United Kingdom infantile spasm study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomized controlled trial.
      However, with further follow-up to 14 months, there was no difference in spasm control between treatments.
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes at age 14 months: a multicentre randomised trial.
      Better initial control of spasms by hormonal treatment in those with no identified underlying etiology was considered to lead to improved developmental outcome.
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes at age 14 months: a multicentre randomised trial.

      The International Collaborative Infantile Spasms Study

      O’Callaghan et al. presented a multicenter, open-label, randomized trial, the International Collaborative Infantile Spasms Study (ICISS), carried out in 102 hospitals in five countries. This study with 377 patients is the largest randomized trial of treatment of infantile spasms and found that a combination of hormonal (tetracosactide or high-dose prednisolone) and VGB was more effective at stopping the spasms between days 14 and 42 than hormonal (ACTH or prednisolone) therapy alone. The spasm resolution response rate was 133 of 186 (72%) patients on hormonal therapy combined with VGB, versus 108 of 191 (57%) patients on hormonal therapy alone.
      • O’Callaghan F.J.K.
      • Edwards S.W.
      • Alber E.D.
      • et al.
      Safety and effectiveness of hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomized, multicentre, open-label trial.
      Details of specific diseases and their response to treatment were given in a further ICISS report by Osborne et al. One hundred fifty-seven (42%) had no identified etiology and 219 (58%) had a proven etiology, of whom 128 responded, 58 of 108 (54%) were allocated hormonal treatment, and 70 of 111 (63%) were allocated combination treatment. Stroke and infarct had a better average response to treatment than other underlying etiologies.
      • Osborne J.
      • Edwards S.
      • Alber F.
      • et al.
      The underlying etiology of infantile spasms (West syndrome): information from the International Collaborative infantile Spasms Study (ICISS).
      TSC was excluded from the study.
      A few other, small, less rigorous studies
      • Granström M.-L.
      • Gaily E.
      • Liukkonen E.
      Treatment of infantile spasms: results of a population-based study with vigabatrin as the first drug for spasms.
      ,
      • Knupp K.
      • Coryel J.
      • Nickels K.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      ,
      • Ko A.
      • Youn S.E.
      • Chung H.J.
      • et al.
      Vigabatrin and high-dose prednisolone therapy for patients with West syndrome.
      have suggested that polytherapy may be more effective than monotherapy; however, these studies used different medications with different mechanisms of action and are not considered definitive. It seems clear that when the first treatment has failed, an alternative should be given. Increasing evidence suggests that combination of steroid and VGB, either successively or simultaneously, is more effective than one drug alone.
      Nonetheless, it may be important to emphasize that simultaneous administration of the two drugs exposes the patients to the adverse effects of both drugs.

      ACTH

      ACTH has been in use for treatment for infantile spasms since 1952 and remains the first-line drug for treatment, as shown in the current therapeutic algorithm (Table 3).
      TABLE 3.Seizure-Free Patients at Three to Four Months After Hormonal or Vigabatrin Treatments
      Number of PatientsDrugSeizure-free Patients (%)References
      200ACTH44Matsumoto et al.
      • Matsumoto A.
      • Watanabe K.
      • Negoro T.
      • et al.
      Long-term prognosis after infantile spasms: a statistical study of prognostic factors in 200 cases.
      147ACTH42Riikonen
      • Riikonen R.
      A long-term follow-up study of 214 children with the syndrome of infantile spasms.
      ,
      • Riikonen R.
      Long-term outcome of patients with infantile West syndrome.
      19

      23
      ACTH

      VGB
      42

      43
      Vigevano and Cilio
      • Vigevano P.
      • Cilio M.
      Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study.
      28VGB43Wohlrab et al.
      • Wohlrab G.
      • Bolthauser E.
      • Schmitt B.
      Vigabatrin as a first-line drug in West syndrome: clinical and electroencephalographic outcome.
      20VGB42Appleton et al.
      • Appleton R.
      • Peters A.
      • Mumford J.
      • Shaw D.
      Randomized, placebo- controlled study of vigabatrin as first-line treatment of infantile spasms.
      97ACTH55Knupp et al.
      • Knupp K.
      • Coryel J.
      • Nickels K.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      54Prednisolone39Knupp et al.
      • Knupp K.
      • Coryel J.
      • Nickels K.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      Abbreviations:
      ACTH = Adrenocorticotropic hormone
      EEG = Electroencephalography
      VGB = Vigabatrin
      In 2004 and 2012, the American Academy of Neurology and Child Neurology Society reported guidelines for the treatment of infantile spasms.
      • Mackay M.T.
      • Weiss S.K.
      • Adams-Webber T.
      • et al.
      Practice parameter: medical treatment of infantile spasms.
      ,
      • Go C.
      • Mackay M.
      • Weiss S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      The aim was to determine the overall strength of evidence and formulate recommendations. Relevant studies during the period 2002 to 2011 were separated from a collection of studies published before 2002. These systematic reviews identified 1935 possibly relevant publications, but based on methodology, only 68 were selected for detailed review and only 26 contributed to the final analysis. In 2015, the International League Against Epilepsy Commission on Pediatrics also provided a summary of recommendations for management of infantile seizures.
      • Wilmshurst J.
      • Gaillard W.
      • Vinayan K.
      • et al.
      Summary of recommendations for management of infantile seizures: task force report for the ILEA commission of pediatrics.
      All three of these summary statements were published before the ICISS combination study.

      Dose and duration of therapy

      Doses of ACTH vary in different countries: Japan, 0.1 mg/day,
      • Fukuyama Y.
      The Japanese scheme of ACTH therapy in West syndrome.
      and more recently, 0.0125 mg/kg/day
      • Hamano S.
      • Nagai T.
      • Matsuura R.
      • et al.
      Treatment of infantile spasms by pediatric neurologists in Japan.
      ; Finland, 0.5 mg on alternate days
      • Riikonen R.
      A European perspective—comments on infantile spasms: a U.S. consensus report.
      ,
      • Riikonen R.
      Epilepsy: update to guidelines on treatment of infantile spasms.
      ; United Kingdom, 0.5 mg on alternate days
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      The United Kingdom infantile spasm study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomized controlled trial.
      ; and the United States, 60 to 80 IU/day (=0.6 to 0.8 mg/day).
      • Stafstrom C.
      • Arnason B.
      • Baram T.
      • et al.
      Treatment of infantile spasms: emerging insights from clinical and basic science perspectives.
      Considerably higher doses per kilogram are used for infants in the United States than in Japan. The reason for this difference is unknown.
      In the analysis by the American Academy of Neurology and Child Neurology Society, it was concluded that there are insufficient data to recommend an optimal dose of ACTH or duration of treatment for infantile spasms.
      • Mackay M.T.
      • Weiss S.K.
      • Adams-Webber T.
      • et al.
      Practice parameter: medical treatment of infantile spasms.
      In 2012, the evidence-based guidelines update
      • Go C.
      • Mackay M.
      • Weiss S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      suggested that low-dose ACTH is probably as effective as high-dose ACTH for short-term treatment of infantile spasms (Class I and II evidence). Therefore, the following recommendation was given: low-dose ACTH should be considered as an alternative to high-dose ACTH for treatment of infantile spasms (Level B moderate research-based evidence).
      Still, in 2012 high-dose ACTH continued to be the most commonly used first-line drug for infantile spasms in the United States.
      • Mytinger J.R.
      • Joshi S.
      Pediatric Epilepsy Research ConsortiumSection on Infantile Spasms
      The current evaluation and treatment of infantile spasms among members of the Child Neurology Society.
      Large doses were recommended by Snead et al.,
      • Snead 3rd, O.
      • Benton J.
      • Hosey L.
      • et al.
      Treatment of infantile spasms with high-dose ACTH, efficacy and plasma levels of ACTH and cortisol.
      Baram et al.,
      • Baram T.
      • Michell W.
      • Tourney A.
      • Snead 3rd O.
      • Hanson R.
      • Horton E.
      High-dose corticotrophin therapy for infantile spasms. A prospective, randomized, blinded study.
      and Stafström et al.
      • Stafstrom C.
      • Arnason B.
      • Baram T.
      • et al.
      Treatment of infantile spasms: emerging insights from clinical and basic science perspectives.
      It has been strongly suggested that effective treatment should result in both cessation of the spasms and resolution of hypsarrhythmia in the EEG and is thought to be an “all or none response.”
      • Pellock J.
      • Hrachovy R.
      • Shinnar S.
      • et al.
      Infantile spasms: a U.S. consensus report.
      Timely EEG to observe the effect of the treatment and prompt treatment modification, if needed, are important.
      • Pellock J.
      • Hrachovy R.
      • Shinnar S.
      • et al.
      Infantile spasms: a U.S. consensus report.
      Only short courses of hormonal therapy (two weeks followed by a taper) are recommended by many authors
      • Stafstrom C.
      • Arnason B.
      • Baram T.
      • et al.
      Treatment of infantile spasms: emerging insights from clinical and basic science perspectives.
      ,
      • Pellock J.
      • Hrachovy R.
      • Shinnar S.
      • et al.
      Infantile spasms: a U.S. consensus report.
      because a short course, in many patients, results in a permanent response.
      • Heiskala H.
      • Riikonen R.
      • Santavuori P.
      • et al.
      West syndrome: individualized ACTH therapy.
      Unfortunately, there are no studies comparing the effects of “natural” (porcine or bovine) ACTH, the corticotropin used in the United States, and synthetic ACTH (tetracosactide) used in other parts of the world.

      Oral steroids

      In the UKISS trial by Lux et al.
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      The United Kingdom infantile spasm study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomized controlled trial.
      oral steroids (prednisolone 40 to 60 mg/day) had a similar response as ACTH (0.5 mg on alternative days). In contrast, in another randomized prospective study from Sri Lanka
      • Wanigashinghe J.
      • Arambepola C.
      • SriRanganathan S.
      • Sumanaseno S.
      • Attanapola G.
      Randomized, single-blind, parallel clinical trial on efficacy of oral prednisolone versus intramuscular corticotropin on immediate and continued spasm control in West syndrome.
      ACTH was statistically inferior to oral steroids at five weeks (response 18 of 49 = 40% and 28 of 48 = 58%, respectively). An electroclinical response was obtained more slowly with ACTH than with prednisolone when measured at 28 days. In the Sri Lankan study the response rate (cessation of spasms) with ACTH was exceptionally low compared with the UKISS (19 of 25 patients, 76%).
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      The United Kingdom infantile spasm study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomized controlled trial.
      The reason for this difference is unknown but may be related to a longer lead time to treatment in the Sri Lankan study or the different ACTH formulas used (Acton Prolongatum, Himachal Pradesh, India, and Synacthen Depot, respectively). In four prospective studies (Table 1) the mean response rate to prednisolone was 46%.
      A recent systematic review concluded that it is possible to offer only a Level C recommendation to support the efficacy of oral corticosteroids for the acute clinical control of epileptic spasms and EEG resolution based on Class III evidence.
      • Raga S.
      • Wilmhurst J.
      Epileptic spasms: evidence for oral corticosteroids and implications for low and middle income countries.
      The use of prednisolone in high doses is preferred by some authors, particularly in economically less developed countries because of its low cost. More studies, however, are needed comparing ACTH and prednisolone in prospective randomized trials. The long-term developmental outcome of patients treated by prednisolone needs to be evaluated.

      Vigabatrin

      The results of seven prospective studies of VGB in infantile spasms are shown in Table 2. In the study of 179 infants by Elterman et al.
      • Elterman R.
      • Shields W.
      • Mansfield K.
      • Nagakagawa J.
      The US Infantile Spasms Vigabatrin Group
      Randomized trial of vigabatrin in patients with infantile spasms.
      patients were randomized to low- or high-dose VGB, and the seizure outcome was confirmed by video-EEG. The response rate with VGB at day 14 was 23% but 60% at three months. The time to response was shorter in those receiving high-dose versus low-dose VGB.
      • Elterman R.D.
      • Shields W.D.
      • Bittman R.M.
      Vigabatrin for the treatment of infantile spasms: final report of a randomized trial.
      The response to VGB seems to come later and in fewer infants than with ACTH, a finding also noted in a Finnish study.
      • Granström M.-L.
      • Gaily E.
      • Liukkonen E.
      Treatment of infantile spasms: results of a population-based study with vigabatrin as the first drug for spasms.
      In this Finnish prospective, crossover study by Granström et al., VGB (50 to 100 mg/kg/day) was effective in 26% of 42 patients with a variety of etiologies. Total cessation of the spasms and resolution of hypsarrhythmia was monitored by video-EEG. VGB was given as the first-line drug. ACTH was then offered in combination with VGB. The total response rate was 60%.
      • Granström M.-L.
      • Gaily E.
      • Liukkonen E.
      Treatment of infantile spasms: results of a population-based study with vigabatrin as the first drug for spasms.
      As shown in the UKISS study, the combination of hormonal and VGB treatment may give better results.
      • Granström M.-L.
      • Gaily E.
      • Liukkonen E.
      Treatment of infantile spasms: results of a population-based study with vigabatrin as the first drug for spasms.
      ,
      • O’Callaghan F.J.K.
      • Edwards S.W.
      • Alber E.D.
      • et al.
      Safety and effectiveness of hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomized, multicentre, open-label trial.
      ,
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes at age 14 months: a multicentre randomised trial.
      ,
      • Knupp K.
      • Coryell J.
      • Nickels K.
      • Ryan N.
      • Leister E.
      Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort.
      Lux et al.
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      The United Kingdom infantile spasm study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomized controlled trial.
      and Bitton et al.
      • Bitton J.
      • Sauerwein H.
      • Weiss S.
      • et al.
      A randomized controlled trial of flunarizine as add-on therapy and effect on cognitive outcome in children with infantile spasms.
      reported higher response rates to VGB, 52% and 62%, respectively (infants with TSC were excluded in both studies). VGB nonresponders may respond to steroids, and vice versa. More than one-third of children with infantile spasms respond to a second medication.
      • Knupp K.
      • Coryell J.
      • Nickels K.
      • Ryan N.
      • Leister E.
      Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort.
      VGB treatment may alter the semiology of spasms so that they become more minor or subtle and are accompanied by multifocal spikes on EEG.
      • Gaily E.
      • Liukkonen E.
      • Paetau R.
      • Rekola M.
      • Granström M.-L.
      Infantile spasms: diagnosis and assessment of treatment response by video-EEG.
      When multifocal spikes or hypsarrhythmia persist, there are always spasms on video-EEG,
      • Gaily E.
      • Liukkonen E.
      • Paetau R.
      • Rekola M.
      • Granström M.-L.
      Infantile spasms: diagnosis and assessment of treatment response by video-EEG.
      and recovery is likely to be incomplete with a poor prognosis. “Little seizures have big consequences.”
      • Shields W.D.
      Infantile spasms: little seizures, BIG consequences epilepsy.

      Tuberous sclerosis complex and infantile spasms

      TSC represents an important cause of infantile spasms, up to 10% cases. There are several peer-reviewed publications that report convincing evidence of the effectiveness of VGB in treating children with infantile spasms, especially those with TSC. The consensus is that VGB is the drug of choice to treat infantile spasms in children with TSC.
      • Hancock E.
      • Osborne J.
      Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review.
      ,
      • Curatolo P.
      • Nabbout R.
      • Lagae L.
      • et al.
      Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations.
      TSC results from mutations in the TSC1 and TSC2 genes. These are tumor suppressor genes that influence the mammalian target of rapamycin (mTOR) signaling pathway. Mutations of these genes cause hyperactivation of the mTOR system and result in cell growth and hamartomatous tumors in multiple organs. VGB blocks the breakdown of γ-aminobutyric acid (GABA) transaminase, which is responsible for the metabolism of GABA, a major inhibitory neurotransmitter. VGB has also been shown to inhibit activation of the mTOR pathway and seizures in a mouse model of TSC complex
      • Zhang B.
      • McDaniel S.
      • Rensing N.
      • Wong M.
      Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex.
      ; however, in the future, mTOR inhibitors (e.g., rapamycin) may challenge the role of VGB as the preferred drug for infantile spasms.
      • Raffo E.
      • Coppola A.
      • Ono T.
      • Briggs S.W.
      • Galanopoulou A.S.
      A pulse rapamycin therapy for infantile spasms and associated cognitive decline.
      The first small prospective study
      • Chiron C.
      • Dumas C.
      • Jambaque I.
      • Mumford J.
      • Dulac O.
      Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis.
      of children with infantile spasms and TSC found VGB to be more effective than hydrocortisone in stopping the spasms. In a large, single-blind multicenter three-year study by Elterman et al. published in 2001, there was a significantly higher response rate to VGB for children who had TSC (13 of 15) than for children with other etiologies (19 of 117).
      • Elterman R.
      • Shields W.
      • Mansfield K.
      • Nagakagawa J.
      The US Infantile Spasms Vigabatrin Group
      Randomized trial of vigabatrin in patients with infantile spasms.
      A Finnish study noted that the response rate to ACTH in patients with TSC was also high (73%) (16 of 22 infants),
      • Riikonen R.
      • Simell O.
      Tuberous sclerosis and infantile spasms.
      but because of the need for prolonged therapy, VGB is likely a better choice.

      Other therapies for infantile spasms

      Some patients with medically refractory spasms have causative, localized brain lesions; resective surgery yields improvement in both seizure control and cognitive development.
      • Chugani H.
      • Ilyas M.
      • Kumar A.
      • et al.
      Surgical treatment for refractory epileptic spasms: the Detroit series.
      Ketogenic diet is also a reasonable treatment alternative for infantile spasms, especially for children refractory to antiepileptic drugs. Ketogenic diet may be better tolerated than steroids.
      • Kossoff E.
      • Hedderick E.
      • Turner Z.
      • Freeman J.
      A case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms.
      ,
      • Dressler A.
      • Benninger F.
      • Trimmel-Schwahofer P.
      • et al.
      Efficacy and tolerability of the ketogenic diet versus high-dose adrenocorticotropic hormone for infantile spasms: a single-center parallel-cohort randomized trial.

      Relapses of infantile spasms after initial treatment

      The proportion of patients who are seizure-free three to four months following ACTH or VGB are very similar, 44%, on average (Table 4). Unfortunately, relapses of spasms occur relatively frequently after an initial response to all current therapies. The overall relapse rate after ACTH treatment has been estimated to be 15% to 34%, 15% to 24% in Class I to III studies, 33% in the Class II study, and 19% to 24% in Class III studies.
      • Mackay M.T.
      • Weiss S.K.
      • Adams-Webber T.
      • et al.
      Practice parameter: medical treatment of infantile spasms.
      TABLE 4.Where Does ACTH Sit in the Therapeutic Algorithm?
      Hormonal treatment is the best single treatment of the spasms (Cochrane Review
      • Hancock E.
      • Osborne J.
      • Edwards S.
      Treatment of infantile spasms.
      )

      ACTH might be more effective than prednisolone (Go et al.
      • Go C.
      • Mackay M.
      • Weiss S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      )

      ACTH might be more effective than vigabatrin in other etiologic categories except tuberous sclerosis (Cochrane review
      • Hancock E.
      • Osborne J.
      • Edwards S.
      Treatment of infantile spasms.
      )

      Hormonal therapy (ACTH or prednisolone) as the first-line drug might be connected with better cognitive outcome in the group of infantile spasms with unidentified etiology (Darke et al.
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • et al.
      Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multicentre randomised trial.
      ; Go et al.
      • Go C.
      • Mackay M.
      • Weiss S.
      • et al.
      Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      )

      Both drugs, either ACTH or vigabatrin, may be the second-line drug for children who do not respond to the first-line drug in 2-3 weeks (Knupp et al.
      • Knupp K.
      • Coryell J.
      • Nickels K.
      • Ryan N.
      • Leister E.
      Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort.
      )

      Combination treatment (vigabatrin and hormones) may have a better short-term response rate (ICISS) than ACTH alone
      • O’Callaghan F.J.K.
      • Edwards S.W.
      • Alber E.D.
      • et al.
      Safety and effectiveness of hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomized, multicentre, open-label trial.
      Abbreviations:
      ACTH = Adrenocorticotropic hormone
      ICISS = International Collaborative Infantile Spasms Study
      After initial therapy, these relapses occur after a few days up to 18 months, with a mean of 4.6 months.
      • Riikonen R.
      A long-term follow-up study of 214 children with the syndrome of infantile spasms.
      In the ICISS, 57 of 298 (19%) relapses occurred by day 42. Of these, 33 occurred after combination therapy (VGB + hormones), and 24 occurred after hormonal therapy.
      • Ko A.
      • Youn S.E.
      • Chung H.J.
      • et al.
      Vigabatrin and high-dose prednisolone therapy for patients with West syndrome.
      Relapses occurred after all treatments but were more common with oral steroids than with ACTH or VGB in the study by Knupp et al.
      • Knupp K.
      • Coryel J.
      • Nickels K.
      • et al.
      Response to treatment in a prospective national infantile spasms cohort.
      Relapse rates after small or large doses of ACTH were similar in the Finnish study.
      • Riikonen R.
      A long-term follow-up study of 214 children with the syndrome of infantile spasms.
      In the Sri Lankan study, the risk of relapse following ACTH or prednisolone therapy was similar.
      • Wanigashinghe J.
      • Arambepola C.
      • Sri Ranganathan S.
      • Sumanasena S.
      Randomized, single-blind, parallel clinical trial on efficacy of oral prednisolone versus intramuscular corticotropin: a 12-month assessment of spasm control in West syndrome.
      Nabbout et al.
      • Nabbot R.
      • Chiron C.
      • Mumford I.
      • Dumas C.
      • Dulac O.
      Viagabatrin in partial seizures in children.
      reported that children with TSC not only had the best response rate but also the highest relapse rate after VGB therapy. The prediction of relapses is often inaccurate, but EEG spike discharges during “remission” may have value in identifying patients whose spasms will reappear or in whom other seizure types emerge.
      • Yamada K.
      • Toribe Y.
      • Kimizu T.
      • et al.
      Predictive value of EEG findings at control of epileptic spasms for seizure relapse in patients with West syndrome.
      Unfortunately, no pharmacologic treatment exists to prevent relapses. Other drugs, such as topiramate and zonisamide have been unsuccessful.
      • Rajaraman R.
      • Lay J.
      • Alayari A.
      • Anderson K.
      • Sankar R.
      • Hussain S.
      Prevention of infantile spasms relapse: zonisamide and topiramate provide no benefit.

      Side effects of therapy

      The common side effects of both drugs (steroids and VGB) are irritability, sleep disturbances, and drowsiness. Both also have severe side effects. The risk-benefit ratio should always be considered.

      ACTH

      Contraindications for ACTH treatment include acute infections, a history of clinically apparent infection with herpes or cytomegalovirus, and severe heart failure. The main side effects of ACTH are hypertension, suppression of the immune system with infections, electrolyte imbalances, gastrointestinal problems, hypertrophic cardiomyopathy, and adrenal hypofunction after therapy.
      • Perheentupa J.
      • Riikonen R.
      • Dunkel L.
      • Simell O.
      Adrenocortical hypo responsiveness after treatment with ACTH of infantile spasms.
      • Riikonen R.
      • Donner M.
      ACTH therapy in infantile spasms: side effects.
      • Riikonen R.
      Steroids or vigabatrin in the treatment of infantile spasms.
      Infections were significantly more common (in 21 of 54, 39%) with large doses (120 IU/day) than with smaller doses (40 IU/day) (22 of 97, 23%) in the Finnish cohort of 162 patients.
      • Riikonen R.
      • Donner M.
      ACTH therapy in infantile spasms: side effects.
      • Riikonen R.
      Steroids or vigabatrin in the treatment of infantile spasms.
      • Riikonen R.
      ACTH therapy of West syndrome: Finnish views.
      Five had proven bacterial sepsis during treatment with ACTH, with three deaths. Adverse effects were more frequent with synthetic derivates than with natural corticotropins
      • Riikonen R.
      Steroids or vigabatrin in the treatment of infantile spasms.
      ,
      • Riikonen R.
      ACTH therapy of West syndrome: Finnish views.
      probably due to the prolonged effect of the synthetic derivates. In a recent study from the Netherlands, patients were treated with high-dose tetracosactrin (0.8 mg/day = 80 IU/day) for four weeks and then tapered off over four weeks for a total treatment of eight weeks. Mortality was high; 37 of 162 patients died by age three years, although late deaths were unlikely related to hormonal treatment.
      • Krijgh E.
      • Catsman C.
      • Neuteboom R.
      Early seizure freedom is a prognostic factor for survival in patients with West syndrome.
      ACTH-induced severe side effects are avoidable by careful vigilance, use of low ACTH doses with individualized therapy according to the response, and slow tapering of ACTH followed, if needed, by substitution of cortisol with careful monitoring of the hypothalamic-pituitary-adrenal (HPA) axis. Severe side effects from ACTH were not seen in the later years of an ACTH spasms study from Finland.
      • Heiskala H.
      • Riikonen R.
      • Santavuori P.
      • et al.
      West syndrome: individualized ACTH therapy.
      It would seem safest to give ACTH at the minimal effective dose for the minimal effective time.
      • Riikonen R.
      ACTH therapy of West syndrome: Finnish views.
      ,
      • Ito M.
      • Aiba H.
      • Hashimoto K.
      • et al.
      Low-dose ACTH therapy for West syndrome: initial effects and long-term outcome.

      Prednisolone

      A retrospective study of 87 children treated with high-dose oral corticosteroids for infantile spasms reported that 52% had side effects. There were four with severe side effects and one case of death.
      • Gonzales-Giraldo E.
      • Stafström C.
      • Stanfield A.
      • Kossoff E.
      Treating infantile spasms with high-dose oral corticosteroids: a retrospective review of 87 children.
      In the UKISS
      • Lux A.
      • Edwards S.
      • Hancock E.
      • et al.
      United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes at age 14 months: a multicentre randomised trial.
      one child died of Staphylococcus aureus septicemia on day 15 of treatment with prednisolone. Of course, high-dose prednisolone for long periods of time can lead to suppression of the HPA axis.

      Adrenal insufficiency

      Withdrawal of ACTH or prednisolone at the end of treatment can expose HPA dysfunction with the risk of adrenal insufficiency. Higher doses and longer use are associated with the highest risk.
      • Broersen L.H.
      • Pereira A.M.
      • Jørgensen J.O.
      • Dekkers O.M.
      Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis.
      ACTH preparations with more prolonged action such as tetracosactrin probably cause more pronounced post-treatment suppression and involution of adrenal cortex than corticotropin.
      Signs of mild adrenal insufficiency in infants are nonspecific (nausea, fatigue, poor feeding) and not clinically evident without stress (e.g., a febrile illness).
      • Mytinger J.
      • Bowden S.
      Adrenal function testing following hormone therapy for infantile spasms: case series and review of literature.
      Even minor degrees of adrenal insufficiency can be fatal in a stressed child. Given the seriousness of adrenal crisis, the Finnish protocol
      • Perheentupa J.
      • Riikonen R.
      • Dunkel L.
      • Simell O.
      Adrenocortical hypo responsiveness after treatment with ACTH of infantile spasms.
      calls for direct testing for hypocortisolism in patients with prolonged ACTH and cortisone treatment with the provision of appropriate cortisol substitution until full recovery is confirmed.
      There have been only four small infantile spasm studies with a total of 35 patients who underwent post-treatment assessment of adrenal function.
      • Mytinger J.
      • Bowden S.
      Adrenal function testing following hormone therapy for infantile spasms: case series and review of literature.
      In one study, two-thirds of the patients had abnormal stimulation tests up to 2 weeks after stopping corticotropin.
      • Perheentupa J.
      • Riikonen R.
      • Dunkel L.
      • Simell O.
      Adrenocortical hypo responsiveness after treatment with ACTH of infantile spasms.
      Mytinger and Bowden
      • Mytinger J.
      • Bowden S.
      Adrenal function testing following hormone therapy for infantile spasms: case series and review of literature.
      found a relatively low incidence of abnormal adrenal function (two of 14 patients) tested two to 18 weeks after the last day of hormone therapy. The authors recommend that clinicians should be vigilant in monitoring for signs of adrenal insufficiency for at least three months after withdrawal of hormone therapy. Prophylactic hydrocortisone was not routinely recommended, except if there were concerns about adrenal insufficiency, especially in stress situations. The nonspecific and subtle nature of the signs of adrenal insufficiency make this recommendation somewhat questionable, unless there is a direct assessment of adrenal function.
      The incidence of abnormal HPA function and time to full recovery after ACTH and prednisolone therapy should be more carefully studied.

      Vigabatrin side effects

      VGB-specific adverse effects include peripheral visual field defects (VFDs), the most feared adverse effect, and structural changes in the brain MRI scan. The VFDs seem to be irreversible. Sustained retinal damage, assessed by electroretinogram (ERG), can be detected at two to three months of VGB treatment.
      • Willimore L.
      • Abelson M.
      • Ben-Menachem E.
      • et al.
      Vigabatrin: 2008: update.
      In the United States, VGB is available only under a special restricted, distribution program (the Support, Help and Resources for Epilepsy (SHARE) program (http://www.lundbeckshare.com; FDA, 2009)). “While taking VGB, patients should have periodic ophthalmologic evaluations beginning at the baseline evaluation at initiation of therapy as well as three to six months after cessation of treatment.” This is a very challenging task for infants because ERG or measurements of the loss of retinal nerve fiber layer using optical coherence tomography may require general anesthesia and specialized ophthalmologists to interpret the results. At present, there are no reliable methods to judge whether VFDs emerge during VGB therapy in infancy.
      Visual field defects occur in 30% to 40% adults treated with VGB sometimes severe enough to hamper driving a motor vehicle. VFDs are an additional complication for disabled children, who may already have impaired vision for other reasons. A recent study showed that after six and 12 months of VGB treatment 5.5% and 13.3% children, respectively, developed VGB retinal defects as measured by ERG.
      • Westall C.
      • Wright T.
      • Cortese F.
      • Kumarappah A.
      • Snead 3rd O.
      • Buncic J.
      Vigabatrin toxicity in children with infantile spasms: an observational cohort study.
      The cohort included 146 participants with infantile spasms treated with VGB, and more than 500 assessments were collected at multiple visits. There is, however, uncertainty about how ERG deficits correlate with VFDs.
      • Moskowitz A.
      • Hansen R.
      • Eklund S.
      • Fulton A.B.
      Electroretinographic (ERG) responses in pediatric patients using vigabatrin.
      Gaily et al.
      • Gaily E.
      • Jonsson H.
      • Lappi M.
      Visual field defects at school-age in children treated with vigabatrin in infancy.
      studied 15 children, aged six to seven years, who were started on VGB treatment during the first year of life. The risk of VFDs was considered low. A larger, more recent multicenter study on VFDs in 35 school-aged children treated with VGB during infancy for infantile spasms
      • Riikonen R.
      • Rener-Primec Z.
      • Carmant L.
      • et al.
      Does vigabatrin treatment for infantile spasms cause visual field defects: an international, multicentre study.
      showed that VGB causes VFDs in children at rates comparable to adults (34%). The rate increased from 9% to 63% as the duration of treatment increased. Three of 10 children (30%) who received VGB for 12 to 24 months had VFDs. Patients with TSC who underwent longer VGB treatment were the most likely to have VFDs. It appears that retinal toxicity starts to increase after six months of therapy.
      • Westall C.
      • Wright T.
      • Cortese F.
      • Kumarappah A.
      • Snead 3rd O.
      • Buncic J.
      Vigabatrin toxicity in children with infantile spasms: an observational cohort study.
      An important goal of future studies should be identification of both patients who are less susceptible to VGB-induced retinal toxicity and those who are at especially high risk.
      Several theories have been proposed to explain the cause of VGB-associated VFDs. These include toxic reactions, idiosyncratic reactions, polypharmacy, pharmacogenetic differences, elevated levels of retinal ornithine, taurine deficiency, GABA accumulation in the retina, dysfunction in GABA-innervated horizontal and amacrine cells in the inner plexiform layer of the retina, and the infantile spasms themselves.
      • Riikonen R.
      • Rener-Primec Z.
      • Carmant L.
      • et al.
      Does vigabatrin treatment for infantile spasms cause visual field defects: an international, multicentre study.
      Unexpected movement disorders were relatively frequent (14 of 186 patients) in the ICISS when large doses of VGB were combined with hormonal therapy.
      • O’Callaghan F.J.K.
      • Edwards S.W.
      • Alber E.D.
      • et al.
      Safety and effectiveness of hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomized, multicentre, open-label trial.
      ,
      • O’Callaghan F.J.K.
      • Edwards S.W.
      • Alber F.D.
      • et al.
      Vigabatrin with hormonal treatment versus hormonal treatment alone (ICISS) for infantile spasms: 18-month outcomes of an open-label, randomised controlled trial.
      The relationship of these movement disorders to VGB remains unclear because they were not related to the MRI changes that are associated with VGB therapy.
      Many studies have reported that VGB may produce transient MRI abnormalities consistent with intramyelinic edema.
      • Pearl P.
      • Vezina L.
      • Sareto R.
      Cerebral MRI abnormalities associated by vigabatrin therapy.
      • Dracopoulos A.
      • Widjaja E.
      • Raybaud C.
      • et al.
      Vigabatrin-associated reversible MRI signal changes in patients with infantile spasms.
      • Wheless J.W.
      • Carmant L.
      • Bebin M.
      • et al.
      Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy.
      MRI abnormalities may appear in a third of patients as early as after three months of treatment and seem to be restricted to infancy. The MRI abnormalities resolve following withdrawal of VGB in almost all patients. MRI abnormalities occur in the thalami, basal ganglia, brainstem tegmentum, and cerebellar dentate nuclei. The abnormalities may rarely be accompanied by dystonia, but the majority of affected children are asymptomatic. For infants receiving VGB who develop a new neurological abnormality such as dystonic movements, an MRI is likely appropriate.
      Intramyelinic edema has not been detected in adult VGB-treated patients with neuropathological examinations at autopsy or with surgical brain samples. However, a recently reported 27-month-old boy with infantile spasms died of sudden unexpected death in epilepsy. At autopsy, his brain showed white matter spongiosis, identical to lesions previously demonstrated in animal models of VGB therapy.
      • Pearl P.L.
      • Poduri A.
      • Prabhu S.P.
      • et al.
      White matter spongiosis with vigabatrin therapy for infantile spasms.

      Long-term outcome

      Table 5 shows studies of patients with infantile spasms and long follow-up.
      TABLE 5.Long-Term Outcome of Patients With Infantile Spasms
      Number of PatientsFollow-up Time, yearsTherapyDuration of TherapyNormal PercentMortality PercentAuthor
      1503-13ACTH 40-60 IU/d, prednisolone 2 mg/kg/d, dexamethasone 0.3 mg/kg/d3 wk-3 mo1622Jeavons et al.
      • Jeavons P.
      • Bower M.
      • Dimitracoudi M.
      Long-term prognosis of 150 cases of West syndrome.
      100>5ACTH 20-40 IU/d, prednisolone 2 mg/kg/d, dexamethasone 0.3 mg/kg/d3-5 wk-3 mo21
      Mildly impaired included IQ > 70-75.
      19O’Donohoe et al.
      • O’Donohoe N.
      A 15-year follow-up of 100 children with infantile spasms.
      200>5N.D.N.D.2319Matsumoto et al.
      • Matsumoto A.
      • Watanabe K.
      • Negoro T.
      • et al.
      Long-term prognosis after infantile spasms: a statistical study of prognostic factors in 200 cases.
      21420-35 mean 25.6ACTH 20-40 IU/d, ACTH 120 IU/d5-6 wk25
      Mildly impaired included IQ > 70-75.
      31Riikonen
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      ,
      • Riikonen R.
      A long-term follow-up study of 214 children with the syndrome of infantile spasms.
      138>2ACTH 0.2-1.28 IU/kg1-5 wk6
      Relatively short follow-up, young age of the patients.
      2Ito et al.
      • Ito M.
      • Kumagai T.
      • Yamazaki Y.
      • et al.
      Long-term prognosis of patients with West syndrome in Japan.
      1802.4-18.9 mean 10.6450-150 mg/kg2-6 mo33
      Mildly impaired included IQ > 70-75.
      5.5Djuric et al.
      • Djuric M.
      • Kravljanac R.
      • Tadic B.
      • Mrljes-Popovic N.
      • Appleton R.
      Long-term outcome in children with infantile spasms treated with vigabatrin: a cohort of 180 patients.
      20724-54 mean 39.5ACTH 20-40 IU/d, ACTH 120 IU/d5-6 wk25
      Mildly impaired included IQ > 70-75.
      49Sillanpää et al.
      • Sillanpää M.
      • Riikonen R.
      • Saarinen M.
      • Schmidt D.
      Long-term mortality of patients with West syndrome.
      Abbreviations:
      ACTH = Adrenocorticotropic hormone
      IQ = Intelligence quotient
      IU = International units
      N.D. = No data
      Mildly impaired included IQ > 70-75.
      Relatively short follow-up, young age of the patients.

      The Finnish study (Riikonen)

      The only population-based study with long-term follow-up is from Finland. This study began in the 1960s and was prospective and longitudinal. Overall, 214 children with infantile spams were followed for 20 to 35 years or until death,
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      and follow-up data were obtained from 100% patients. As outlined below, the study documented intellectual outcome, academic achievement, social success, psychiatric disorders, and later epilepsy.
      All patients had epileptic spasms and either hypsarrhythmia or “modified hypsarrhythmia.” The spasms were classified as “cryptogenic” (cause unknown) in 29 patients and “symptomatic” (cause known or neurological abnormality) in 185 patients. The diagnosis was made at a mean age of six months. Large doses of ACTH (80 to 120 IU [0.8 to 0.12 mg/day]) were given to 54 patients and lower doses (20 to 40 IU [0.02 to 0.04 mg]) to 97 patients. The response rates were 64% (60 of 97 patients) and 54%, (29 of 54 patients), respectively. The duration of the treatment was relatively short, five to six weeks. All adults with favorable outcome had a short lead time to treatment.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      Patients who responded to ACTH had a better cognitive outcome than the other groups
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      ; this applied to both the cryptogenic group (70%) and, interestingly, the symptomatic group (23%). Long-term cognitive outcome was better with the low-dose (20 to 40 IU/day) regimen than the high-dose (80 to 120 IU/day) regimen.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      Intellectual outcome of the 147 surviving patients was classified either by conventional psychological tests or based on educational status
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      in the following way: normal school (intelligence quotient [IQ] greater than 85), 25 patients; school for the educationally handicapped (slightly impaired, IQ 68 to 85), 11 patients; training school (mild learning disability, IQ 40 to 60), 36 patients; and the rest uneducable (IQ less than 40), 75 patients. Thirty six (24%) had a favorable outcome with IQ greater than 68. The developmental state was evaluated for 114 children aged six years by conventional psychological tests (Cattel, Vineland, Bender, Terman-Merrill, Bayley, and Wechsler Intelligence Scale for Children). Seven of the 25 children with normal intelligence had some difficulty with fine motor tasks in writing, reading, and mathematics. Similar specific deficits were described by Gaily et al.
      • Gaily E.
      • Appelqvist K.
      • Kantola-Sorsa E.
      • et al.
      Cognitive deficits after cryptogenic infantile spasms.
      and Lagae et al.
      • Lagae L.
      • Velhest H.
      • Ceulemans B.
      • et al.
      Treatment and longterm outcome in West syndrome: the clinical reality. A multicentre follow-up study.
      in individuals without a known cause of infantile spasms.

      Academic achievements, marital status, children, driving license, and military service

      At the end of follow-up, 25% were employed at jobs ranging from professional to manual labor. Occupations of the patients with normal (25) or slightly impaired intelligence (11) were the following: professionals (7): physician (1), engineer (1), professional in forestry at the university level (1), elementary school teacher (1), special teacher for educationally impaired children (1), illustrator (1), and university student (mathematics) (1). Other occupations were manual worker (1), office worker (1) retail/sales (8), housewife (1), retired (3), and other (6), altogether 36 different occupations. All except two had a full-time job, and all had the usual level of income.
      Ten were married or living with an adult partner. Five had children, and all nine children were healthy. Eleven had a driving license. Eight of the 13 men had completed compulsory military service.

      Psychiatric outcome

      In the complete Finnish cohort (n = 214), autism was diagnosed in 33 (13%) patients, and hyperkinetic behavior, in 29 (14%).Two patients had a psychosis.
      • Riikonen R.
      • Amnell G.
      Psychiatric disorders in children with earlier infantile spasms.
      Altogether a quarter had psychiatric disorders. Temporal focal abnormalities in the EEG were found in 70% patients with autism,
      • Riikonen R.
      • Amnell G.
      Psychiatric disorders in children with earlier infantile spasms.
      a similar finding to the results of positron emission tomographic (PET) studies by Chugani et al.
      • Chugani H.
      • Da Silva E.
      • Chugani D.
      Infantile Spasms: III. Prognostic implications of bitemporal hypometabolism on positron emission tomography.
      These PET studies showed that of 110 children with infantile spasms, 18 showed bitemporal hypometabolism, of whom 10 had diagnostic features of autism.

      Later epilepsy and EEG

      Infantile spasms usually disappear at age three to four years. The transition from infantile spasms to Lennox-Gastaut syndrome occurred in 18%.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      At 20 to 35 years after the onset of infantile spasms, a third of the 147 surviving patients were seizure-free (in remission for at least two years), another third had daily to monthly seizures, and the remaining third had seizures less frequently.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      ,
      • Riikonen R.
      Long-term outcome of patients with infantile West syndrome.
      Most often seizures were focal, often with secondary generalization.
      The EEG at last examination was normal or only slightly abnormal in a fifth of the cases.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      In patients with normal intelligence EEG was normal in 60%, but it was normal only in 13% of the others.

      Mortality

      At the end of 20 to 35 years of follow-up of the 214 patients with infantile spasms, a third (67 patients) had died.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      One-third of the 67 deaths (23 patients) occurred before age three years. The most common immediate cause was infection, and eight patients (12% of all deaths) died during ACTH treatment (all demonstrated adrenal enlargement and hypertrophic cardiomyopathy).
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      ,
      • Riikonen R.
      Long-term outcome of patients with infantile West syndrome.
      ,
      • Riikonen R.
      Steroids or vigabatrin in the treatment of infantile spasms.
      Five of these eight deaths occurred when the patients were receiving daily synthetic ACTH or very large ACTH doses.
      • Riikonen R.
      Long-term outcome of patients with infantile West syndrome.
      Neuropathological examinations performed in 38 (57%) cases showed a wide range of lesions including brain malformations in 26 (66%) autopsied patients.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      ,
      • Chugani H.
      • Da Silva E.
      • Chugani D.
      Infantile Spasms: III. Prognostic implications of bitemporal hypometabolism on positron emission tomography.
      With even longer follow-up of the same patients, nearly one half had died by age 50 years with a mean age of death of 19 years.
      • Sillanpää M.
      • Riikonen R.
      • Saarinen M.
      • Schmidt D.
      Long-term mortality of patients with West syndrome.
      One-fourth had died by age 17.2 years. The mean annual mortality was 15.3 per 1000 patients-years.
      • Sillanpää M.
      • Riikonen R.
      • Saarinen M.
      • Schmidt D.
      Long-term mortality of patients with West syndrome.
      Autopsy reports were available in 73% of 102 patients and indicated that in the vast majority, pneumonia was the immediate cause of death, presumably related to the underlying neurological disorder. Ten percent deaths were classified as sudden unexpected death in epilepsy, and 7% were thought to be the direct result of a seizure.
      • Sillanpää M.
      • Riikonen R.
      • Saarinen M.
      • Schmidt D.
      Long-term mortality of patients with West syndrome.
      Patients with a known etiology compared with those with an unknown etiology had a five-fold higher risk of death.
      • Sillanpää M.
      • Riikonen R.
      • Saarinen M.
      • Schmidt D.
      Long-term mortality of patients with West syndrome.

      Other long-term studies

      UKISS and ICISS

      In the UKISS, patients were followed for four years. In patients with no identified etiology, intelligence at the end of follow-up was significantly higher when the initial treatment was hormonal therapy than with VGB.
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • et al.
      Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multicentre randomised trial.
      In the ICISS, combination therapy (VGB plus hormones) had a more rapid response in a higher proportion of patients than hormonal therapy alone. Disappointingly, combination therapy did not result in improved developmental or epilepsy outcomes at 18 months compared with hormonal therapy alone.
      • O’Callaghan F.J.K.
      • Edwards S.W.
      • Alber F.D.
      • et al.
      Vigabatrin with hormonal treatment versus hormonal treatment alone (ICISS) for infantile spasms: 18-month outcomes of an open-label, randomised controlled trial.
      Further studies of combination treatment will be welcome.

      Vigabatrin

      Djuric et al.
      • Djuric M.
      • Kravljanac R.
      • Tadic B.
      • Mrljes-Popovic N.
      • Appleton R.
      Long-term outcome in children with infantile spasms treated with vigabatrin: a cohort of 180 patients.
      reported their experience with 180 children treated with VGB and followed for an average of 10 years. At the end of follow-up 33% had normal intelligence (IQ greater than 70) and 58% were seizure-free. These results compare favorably with the Finnish study of 147 ACTH-treated patients wherein 36% were seizure-free and 24% had a favorable cognitive outcome: IQ greater than 85 in 25 patients and IQ 68 to 85 in 11 patients and seizure freedom in 36%.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      ,
      • Riikonen R.
      A long-term follow-up study of 214 children with the syndrome of infantile spasms.

      Autistic spectrum disorder

      Patients with infantile spasms are at increased risk of autistic spectrum disorders. A meta-analysis showed that about 20% children with infantile spasms have autistic spectrum disorder compared with about 6% of overall childhood-onset epilepsy.
      • Strasser L.
      • Downes M.
      • Kung J.
      • Cross J.H.
      • De Haan M.
      Prevalence and risk factors for autism spectrum disorder in epilepsy: a systematic review and meta-analysis.
      Patients with infantile spasms who have TSC seem to be at a particularly high risk of autism. Autistic behavior was observed in 37 of 69 (57%) children with TSC and infantile spasms in the study by Hunt and Dennis
      • Hunt A.
      • Dennis J.
      Psychiatric disorder among children with tuberous sclerosis.
      as opposed to 13% in a Finnish study of children who had infantile spasms from all causes.
      • Riikonen R.
      • Amnell G.
      Psychiatric disorders in children with earlier infantile spasms.

      Epilepsy and EEG

      Development of Lennox-Gastaut syndrome after infantile spasms occurred in 23% of 105 patients in the prospective follow-up study by Lombroso.
      • Lombroso C.T.
      A prospective study of infantile spasms: clinical and therapeutic correlations.
      Based on a review of 15 studies that evaluated the long-term prognosis of infantile spasms, an average of 17% (range 0 to 54%) eventually developed Lennox-Gastaut syndrome.
      • Frost J.
      • Hrachovy R.
      Infantile spasms, management and prognosis.
      Investigators have failed to find any correlation between various EEG features associated with infantile spasms and long-term outcome, except for asymmetrical EEG patterns due to underlying structural abnormalities of the brain, which were associated with an unfavorable outcome. Gaily et al.
      • Gaily E.
      • Liukkonen E.
      • Paetau R.
      • Rekola M.
      • Granström M.-L.
      Infantile spasms: diagnosis and assessment of treatment response by video-EEG.
      reported that persistence of multifocal spikes was always associated with continuing spasms after VGB therapy. The transition from motor spasms to subtle spasms has been observed in a few (four of 44) infants when serial video-EEG was used.
      • Gaily E.
      • Liukkonen E.
      • Paetau R.
      • Rekola M.
      • Granström M.-L.
      Infantile spasms: diagnosis and assessment of treatment response by video-EEG.
      Persistent spasms at age one year may predict long-term intellectual disability.
      • Granström M.-L.
      Prognosis of infantile spasms.
      ,
      • Gaily E.
      • Liukkonen E.
      • Paetau R.
      • Rekola M.
      • Granström M.-L.
      Infantile spasms: diagnosis and assessment of treatment response by video-EEG.
      Persistence or worsening of epileptic discharges in EEG, especially multifocal discharges, are highly predictive of spasms, a warning sign.
      • Gaily E.
      • Liukkonen E.
      • Paetau R.
      • Rekola M.
      • Granström M.-L.
      Infantile spasms: diagnosis and assessment of treatment response by video-EEG.
      The appearance of epileptic discharges after ACTH therapy has been related to seizure relapse.
      • Hayashi Y.
      • Yoshinaga H.
      • Akiyama T.
      • Endoh F.
      • Ohtsuka Y.
      • Kobayasi K.
      Predictive factors for relapse of adrenocorticotropic hormone therapy in West syndrome.

      Quality of life

      One hundred twenty Japanese patients with a previous diagnosis of infantile spasms were assessed at an average age of 25 years with a questionnaire to measure social outcome.
      • Kumagai T.
      • Ito M.
      • Yamazaki Y.
      • et al.
      Long-term prognosis of patients of patients with West syndrome in Japan; social aspects.
      Most patients had attended school in a special education setting, but at follow-up 20% still had very limited independence for activities of daily living. Only 9% had full-time work as adults. Sixty per cent were judged to have a reasonable quality of life (such as being able to walk, communicate, eat, dress, and use the toilet) and could enjoy daily life. Very few could lead an independent life. Another Japanese study addressed 117 patients by questionnaires, completed by primary care givers 20 years after the onset of spasms. The response rate was only 45%.
      • Ito M.
      • Kumagai T.
      • Yamazaki Y.
      • et al.
      Long-term prognosis of patients with West syndrome in Japan.
      Two patients were deceased, 40% still had daily or weekly seizures, and 25% were seizure-free. Only half of the patients were able to walk by age three years. By age six years, 41 were able to communicate. Most adult patients needed assistance in their everyday life.

      Mortality

      Mortality rates in different long-term studies are summarized in Table 5. In the 10-year follow-up of a cohort of patients born from 1994 to 1999 from the University Hospital of Helsinki, Finland, the mortality rate was 13% by age three years (seven of 55 patients, 13%),
      • Granström M.-L.
      Prognosis of infantile spasms.
      which is similar to the mortality at three years in the study by Riikonen.
      • Riikonen R.
      Long-term outcome of West syndrome: a study of adults with a history of infantile spasms.
      ,
      • Riikonen R.
      A long-term follow-up study of 214 children with the syndrome of infantile spasms.
      It is to be noted that all patients with newly diagnosed infantile spasms had first received VGB treatment in the Helsinki study.
      However, in a recent study from the Netherlands
      • Krijgh E.
      • Catsman C.
      • Neuteboom R.
      Early seizure freedom is a prognostic factor for survival in patients with West syndrome.
      the cumulative mortality at age three years was 31%, even higher than in the Finnish study. Freedom from seizures was an independent predictor of survival.

      Can we improve the outcome? Lead time to treatment, response to treatment, duration of hypsarrhythmia, and correlation to outcome

      Lead time to treatment

      Several studies have found a relationship between short time to treatment and improved mental outcome.
      • Cohen-Sadan S.
      • Kramer U.
      • Ben-Zeev B.
      • et al.
      Multicenter long- term follow-up of children with idiopathic West syndrome: ACTH versus vigabatrin.
      ,
      • Kivity S.
      • Lerman P.
      • Ariel B.
      • Danziger Y.
      • Mimouni M.
      • Shinnar S.
      Long-term cognitive outcomes of a cohort of children with cryptogenic infantile spasms treated with high-dose adrenocorticotropic hormone.
      ,
      • Lombroso C.T.
      A prospective study of infantile spasms: clinical and therapeutic correlations.
      ,
      • Jeavons P.
      • Bower M.
      • Dimitracoudi M.
      Long-term prognosis of 150 cases of West syndrome.
      ,
      • O’Callaghan F.
      • Lux A.
      • Darke K.
      • et al.
      The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study.
      • Auvin S.
      • Hartman A.
      • Desnous B.
      • et al.
      Diagnosis delay in West syndrome. Misdiagnosis and consequences.
      • Primec Z.
      • Stare J.
      • Neubauer D.
      The risk of lower outcome in infantile spasms increases after three weeks of hypsarrhythmia duration.
      Furthermore, Kivity et al.
      • Kivity S.
      • Lerman P.
      • Ariel B.
      • Danziger Y.
      • Mimouni M.
      • Shinnar S.
      Long-term cognitive outcomes of a cohort of children with cryptogenic infantile spasms treated with high-dose adrenocorticotropic hormone.
      documented normal cognitive outcome in all 22 patients with an unknown cause for infantile spasms when they received ACTH within one month of onset. Fifteen other patients had a longer lead time before ACTH, and normal cognition was seen in only 40%. The UKISS showed a stepwise decline in intellectual outcome with longer lead time to treatment in the group of unknown etiology at age four years.
      • Auvin S.
      • Hartman A.
      • Desnous B.
      • et al.
      Diagnosis delay in West syndrome. Misdiagnosis and consequences.
      Intellectual outcome was assessed using the Vineland Adaptive Behavioral Scores.
      Furthermore, in a recent multicenter prospective study
      • Knupp K.
      • Coryell J.
      • Nickels K.
      • Ryan N.
      • Leister E.
      Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort.
      of 118 patients who had failed their first treatment for infantile spasms, the response to a second treatment was better when the initial treatment lead time was less than four weeks.

      Response to treatment

      Important information came from the UKISS. Patients with unknown cause who were primarily allocated to hormonal therapy had a better cognitive outcome at age four years than those allocated to VGB.
      • Darke K.
      • Edwards S.W.
      • Hancock E.
      • et al.
      Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multicentre randomised trial.
      The authors concluded that ACTH should be given as the first-choice drug for patients with an “unidentified” etiology. Prompt control of spasms and improvement in the concomitant EEG appear to be important in achieving optimal long-term cognitive development.

      Duration of hypsarrhythmia

      It seems highly likely that the duration of hypsarrhythmia is responsible, at least in part, for the cognitive decline, irrespective of other seizure types. In a retrospective study of 48 patients, Primec et al.
      • Primec Z.
      • Stare J.
      • Neubauer D.
      The risk of lower outcome in infantile spasms increases after three weeks of hypsarrhythmia duration.
      showed that the risk of intellectual disability increases after three weeks of hypsarrhythmia.

      Prevention of infantile spasms

      Some causes of infantile spasms may be preventable. It is likely that reduction of the numbers of babies born small for gestational age, prompt treatment of hypoglycemia, and early treatment of herpes encephalitis will reduce the number of cases of infantile spasms. Furthermore, some metabolic disorders that cause infantile spasms may be preventable or cured by early detection.
      A study of infants with TSC by Jozwiack et al.
      • Jozwiack S.
      • Kotsulska K.
      • Domanska- Pakiela D.
      • et al.
      Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex.
      suggested that the severity of cognitive impairment and epilepsy might be reduced by starting VGB when spike discharges appear on the EEG before the onset of clinical seizures. There were 10 infants in this early “prevention” group who were compared with 31 retrospective controls who had received conventional treatment only after clinical seizures had developed. At age 24 months “psychomotor retardation” and drug-resistant epilepsy was significantly less frequent and less severe in the “prevention” group. This original report has led to ongoing large clinical trials in the United States (Clinical Trials Gov.) and the EPISTOP (http://epistop.eu) study in Europe.
      Curatolo et al.
      • Curatolo P.
      • Nabbout R.
      • Lagae L.
      • et al.
      Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations.
      concluded that administration of VGB may be considered in children with TSC with subclinical epileptiform discharges, but recommendations for clinical practice should await the results of the US and European randomized trials. Repeated monitoring of EEG during the first months of life before onset of seizures may be crucial for early preventive treatment.
      About 10% patients with TSC are diagnosed prenatally with the finding of cardiac rhabdomyomas. When repeated EEGs have been recorded in these babies, spikes and sharp waves have indicated a high risk of subsequent seizures. The time between detection of abnormalities on EEG and the onset of clinical seizures varied from one to eight days in five patients who were diagnosed with TSC pre- or perinatally and had regular EEG monitoring every four to six weeks.
      • Domańska-Pakieła D.
      • Kaczorowska M.
      • Jurkiewicz E.
      • et al.
      EEG abnormalities preceding the epilepsy onset in tuberous sclerosis complex patients - a prospective study of 5 patients.
      Another high-risk group for infantile spasms is preterm babies with PVL.
      • Yoshinaga H.
      • Endo F.
      • Kikumoto K.
      • et al.
      Epilepsy development in infancy with epileptic discharges.
      Japanese authors propose that the preterm infants with PVL who show epileptic discharges before corrected age three months should be treated by antiepileptic drugs to prevent the onset of West syndrome, although it is not easy to identify patients for prevention of West syndrome with sufficient antecedence.
      • Yoshinaga H.
      • Endo F.
      • Kikumoto K.
      • et al.
      Epilepsy development in infancy with epileptic discharges.
      Improving cognitive and seizure outcome in infantile spasms remains a demanding task. Widjaja et al.
      • Widjaja E.
      • Go C.
      • McCoy B.
      • Snead 3rd, O.C.
      Neurodevelopmental outcome in infantile spasms: a systematic review and meta-analysis.
      noted no improvement in neurodevelopmental outcome in studies published before, during, and after 2004. In general, the outcome remained poor even for the unknown cause group. Most of the reviewed studies had relatively short follow-ups and were retrospective.
      There are certain things that can be done to prevent infantile spasms or improve the patients’ outcome: good maternal care (avoiding infections, toxemia, hypoxia, and small for gestational age babies); early recognition of spasms and prompt treatment; timely EEG evaluation of response to therapy and change to other antiepileptic drugs when necessary, or use of combination therapy; avoidance of side effects of therapy including consideration of the risks and benefits of some treatments, especially with combination therapy
      • Riikonen R.
      Combination therapy for treatment of infantile spasms.
      ; early treatment of relapses and epileptic discharges in EEG (especially multifocal spikes); treatment of pre-hypsarrhythmic EEG in high-risk infants like those with TSC; use of ACTH for patients without known etiology; and considering ketogenic diet, brain stimulation, or surgery in refractory patients.

      Conclusions

      Numerous factors have been shown to influence the short- or long-term outcomes of children with infantile spasms. A majority of the studies have been retrospective and have included different populations and different treatment regimens. It is difficult to know if the prognosis has changed over time.
      The most important prognostic factors are the underlying etiology and presence or absence of developmental abnormalities at spasm onset. Improved etiologic diagnostics should allow more accurate prognostic counseling.
      Early cessation of the spasms is important for cognitive outcome. A short duration of hypsarrhythmia is important regardless of etiology but may be especially important in the unknown cause group. ACTH still seems to be the most effective single treatment, but combination of the hormonal treatment with VGB either simultaneously or sequentially shows promise. The role of prednisolone requires further study. Recurrence of the spasms does not seem to be heavily dependent on the type of medication used. Smaller ACTH doses might bring better cognitive outcome than large doses. EEG findings at cessation of epileptic spasms are of prognostic importance for recurrence.
      The adverse effects of treatments are now well known, as are the means to avoid or treat them. Risk-benefit considerations are important for the choice of treatment. An important principle is to use drugs at their lowest effective dose for the shortest duration, although defining the best treatment regime requires more study.
      There are only few long-term outcome studies, and they show that at most, a quarter of patients have a favorable long-term cognitive outcome and a third remain seizure-free. Many comorbidities are associated with infantile spasms (autism, cerebral palsy, sensory defects), and mortality is high throughout life. Early treatment may be the most important way to improve neurodevelopmental outcome.
      In the long run it will be necessary to learn more about brain maturation, neural networks, cellular pathomechanisms, genetic etiologies and mechanisms, and genetics. This knowledge may facilitate development of novel pharmacologic interventions with the ultimate goal of improving the cognitive outcome. With advancing genetic and molecular data, it should be possible to directly target pathogenetic mechanisms as in specific disorders such as TSC. Follow-up studies of interventions in specific etiologic subclasses will be important. Novel treatments such as melanocortin receptor agonists, neuroprotective treatment, rapamycin, and medical cannabinoids should be addressed in further studies.

      Acknowledgments

      I thank Dr. Jaana Lähdetie for help in writing and Dr. Peter Camfield for editing this manuscript.

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