Epileptic spasms

Overview

  • Epileptic Spasms (also known as West Syndrome) is an age-related epilepsy syndrome characterized by epileptic spasms, and chaotic EEG abnormalities, associated with modification of behaviour and cognitive decline.
  • The ILAE Commission on Classification and Terminology (2010) reclassified this group from Infantile Spasms to Epileptic Spasms, because spasms may continue past or even occur de novo after infancy.
  • Epileptic Spasms may be classified as focal, generalized or unknown.
  • Epileptic Spasms is the prototype of an epileptic encephalopathy - a condition in which epileptic abnormalities themselves contribute to the progressive disturbance in cerebral function.
  • There can be a profound impact on neurological development, particularly cognition and behaviour.

According to the NICE Guideline: The Epilepsies:

  • The seizure type(s) and epilepsy syndrome, aetiology, and co-morbidity should be determined.
  • If there is diagnostic uncertainty, individuals should be referred to tertiary services soon (within 4 weeks) for further assessment.

Demographics

  • Prevalance: 0.25-0.4 / 1000. 
  • Commonest syndrome in the first year of life.
  • Age of onset: Peak age: 3-7 months, 90% present in the first year, rare after 18 months of age.
  • 90% have impaired cognitive, communication, motor skills at presentation (Ref: DCMN 2019, 61:11, 1295-1301).

Aetiology:

The aetiologies in about 50% of cases are prenatal (malformations, intrauterine insults, neurocutaneous syndromes - including Tuberous Sclerosis, metabolic and genetic disorders).

Infantile spasms are aetiologically heterogeneous. 70% abnormal brain imaging.

Examples of aetiologies include:

  • Tuberous Sclerosis: Epilepsy is the most common neurological symptom of Tuberous Sclerosis (80-90%), with frequent presentation of Infantile Spasms in the first year of life (33%).
  • Hypoxic Ischemic Encephalopathy (HIE): Prolonged depression of EEG over 21 days of age in term or near-term infants with HIE is a valuable predictor of later development of Infantile Spasms.
  • Mitochondrial disorders: Spasms are the most common presenting seizure type in children with probable and definite mitochondrial disease.
  • Genetic: Epileptic spasms can be caused by single de novo gene mutations but less commonly than in epileptic encephalopathies in general. Genetic consultation is required to explore this aetiology. In a study of 44 unsolved infantile spasm cases: 7% had a de novo chromosomal rearrangement and pathogenic mutation with exome sequencing in 28% of the remainder (Ref: Hum Molec Genet. 23, 4846-4858, 2014).

Signs | Symptoms

Seizure semiology

  • Epileptic spasm: Sudden, bilateral and symmetric contraction of muscles of the neck, trunk, and extremities. The type of seizure depends on muscles (flexor or extensor) affected and on extent of contraction. The intensity of contractions and number of muscle groups involved vary considerably.
  • The episodes are grouped in series or clusters, 5-30 secs apart, mainly on awakening or during the transition from NREM to REM sleep.
  • Asymmetric spasms may occur.

Differential Diagnosis

 Other non-epileptic events e.g.: shudders.

 Benign myoclonus of early infancy:

  • Spells begin in less than 1 year, self-limited.
  • Clusters of head, trunk or extremity spasms, eye-blinking, brief jerking of upper extremity or trunk, and head-nodding episodes.
  • EEG invariably normal, neurologic development is not affected.
  • Complete resolution 2 weeks to 8 months after onset.

Investigations

Tailor investigations depending on the clinical phenotype.

EEG

  • Classic hypsarrhythmia: Very high voltage asynchronous, random and independent spike and sharp wave discharges with periods of electro-decrements. Discharges are worse in NREM sleep.
  • Modified hypsarrhythmia: Focal or asymmetric discharges, episodes of voltage attenuation and some inter-hemispheric synchronization.
  • There is no difference in prognosis or treatment with these EEG patterns.

Neuroimaging

  • MRI/MRS

Genetic

  • Chromosomes, CGH array, and when indicated, gene panel and next-generation sequencing.
  • In consultation with a geneticist, an early gene panel or next-generation sequencing may give a diagnosis, limiting the need for other extensive investigations. This is particularly important in the group of children where history and imaging do not provide the aetiology. 

Ophthalmological evaluation

  • Recommended

Hearing assessment

  • Recommended

TORCH screen

  • Recommended in an appropriate setting

Metabolic: explains a small subset

  • It is important to treat treatable conditions (B12, copper, UMS, CSF glucose).
  • First-line investigations include Urine metabolic screen (including P6C), biotinidase, Vitamine B12, Lactate, ammonia, LFTs.
  • Second-line investigations to be considered in consultation with a Paediatric Neurologist include copper, transferrins, CSF analysis including glucose, amino acids, lactate, neurotransmitters (if clinically indicated), plasma amino acids.
  • Glucose transporter disorder has been reported as a cause of epileptic spasms.

Prognosis

A population-based, 10-yr follow-up observational study of 18 infants (Trevathan et al., 1999), found:

  • 80% of 10-year-olds had developmental delay, often severe
  • 40% - cerebral palsy
  • 94% - active epilepsy, with 50% Lennox Gastaut (other series 15-20%)
  • 15% - died before 11 years.

In addition, others have shown:

  • There is a very high incidence of neuropsychiatric difficulties, and
  • There is a significant increase in Autistic Spectrum Disorder.

Poor prognostic factors

  • Adverse neonatal history
  • Symptomatic aetiology
  • Partial seizures
  • Asymmetric EEGs
  • Age of onset <4months
  • Seizures preceding spasms (outside neonatal period)
  • Delayed development prior to the onset of spasms
  • Time delay in treating > 1 month

Mortality in Infantile Spasms (based on a hospital-based study) (Epilepsia 2020):

  • 150 patients with IS were followed for 12 years in single-centre.
  • Mortality was 17% with major risk factors: persistence of spasms and comorbid respiratory system disorders.
  • Early deaths were related to neurological impairments/comorbidities.
  • Mortality was epilepsy-related in 1/3 patients with SUDEP accounting for 88% of epilepsy-related deaths.
  • Most deaths in children <5y were related to respiratory failure, SUDEP (17%) was less common in this age group,
  • In children > 5y, SUDEP was more common (45%). 

Management

Aim for:

  • Cessation of seizures
  • Resolution of hypsarrhythmia on EEG
  • Preserved development
  • Short lag time to treatment leads to better long-term developmental outcome

Treatment options

  • Hormone (ACTH / prednisolone)
  • Vigabatrin: (see section below).
  • First-line treatment with standard therapy (vigabatrin, prednisone, ACTH) is the most important variable in determining the likelihood of response to treatment of epileptic spasms with or without hypsarrhythmia.
  • If patient fails one option, try other (e.g. if patient fails Vigabatrin try hormonal treatment and vice versa).

UK Infantile Spasm Study (UKISS) (2004)

  • The multicentre study compared the treatment effects of Vigabatrin with hormonal treatment (prednisolone and tetracosactide) in infantile spasms.
  • Cessation of spasms by 2 weeks was more likely with hormonal treatment than vigabatrin
  • Generally, development and epilepsy outcomes were not significantly different between the two treatment groups at 4 years of follow up
  • Better development was seen at 14 months and 4-year follow up in those with no identified aetiology allocated hormonal treatment.
  • If the patient fails one drug (for example hormonal), may respond to other (for example vigabatrin) or vice versa.  

ICISS: Follow-up to UKISS (2017)

  • In this study, the efficacy of combined treatment (hormonal and vigabatrin) was evaluated compared to hormonal treatment alone.
  • Cessation of spasms significantly greater in combination treatment 72% vs 57% (p=0.002). High risk of developmental impairment was associated with the primary outcome (cessation of spasms).
  • Treatment response was faster on combination therapy (p=0.015).
  • Electroclinical outcome: combination treatment significantly better outcome (p=0.015).

 

  • 88% response rate to combination therapy if patients were from the group considered low risk of developmental impairment.
  • At 18 months there was no difference in developmental outcome comparing combined therapy group to hormonal treatment alone.   
  • Early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months.
  • Longer lead-time to treatment was associate with poorer outcomes (>2months).
  • No difference in side effects.

 

Fulminant vigabatrin toxicity when used in combined therapy (with ACTH) for Infantile Spasms (Epilepsia 2020; 61, e159-e164)

  • 3 cases described with symptomatic vigabatrin associated MRI changes characterised by encephalopathy, dyskinesia and dysautonomia.
  • Literature review suggests a high risk of the above phenomenon with infantile spasms in Down Syndrome managed with combination treatment.

 

Infantile Spasms and Tuberous Sclerosis

  • Vigabatrin is considered the drug of choice for patients with Tuberous Sclerosis Complex. There is a discussion in the literature regarding treatment pre-seizures based on EEG.
  • Duration of treatment is an important consideration. Potential side-effects are visual field defects and Vigabatrin Associated Reversible MRI Signal changes. 
  • Monitor for visual field defects – Electroretinography (ERG) at baseline and every 3 months.
  • Patients with vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM) may become symptomatic (see above).

 

Other options include:

  • Ketogenic Diet: is a strong consideration if the patient fails first-line treatments of ACTH, prednisone and vigabatrin and is associated with significant efficacy. In one specialised centre: authors (Dressler 2019) showed comparable efficacy of the ketogenic diet to high dose ACTH in the group with pre-vigabatrin, but the study was underpowered.    
  • Epilepsy surgery is indicated early in drug-resistant patients with a resectable lesion.
  • Other antiepileptics are not considered first-line treatment and efficacy overall is frequently low. These include nitrazepam, topiramate, levetiracetam, felbamate, lamotrigine, zonisamide, clobazam, sulthiame. 

References

  • Arce-Portillo E, Rufo-Campos M, Munoz-Cabello B, Blanco-Martinez B, Madruga-Garrido M, Ruiz-Del Portal L, et West syndrome: Aetiology, therapeutic options, clinical course and prognostic factors. Rev Neurol 2011;52(2):81-9.al.
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  • Bhalla, S, Skjei, K. Fulminant vigabatrin toxicity during combination therapy with adrenocorticotropic hormone for infantile spasms: Three cases and review of the literature. Epilepsia. 2020; 61: e159– e164. https://doi.org/10.1111/epi.16663
  • Darke K, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Lux AL, et al. Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: A multi-centre randomised trial. Arch Dis Child 2010;95(5):382-6. doi: 10.1136/adc.2009.160606
  • Demarest ST, et al,; Pediatric Epilepsy Research Consortium. The impact of hypsarrhythmia on infantile spasms treatment response: Observational cohort study from the National Infantile Spasms Consortium. Epilepsia. 2017 Dec;58(12):2098-2103. doi: 10.1111/epi.13937
  • Dressler A, Benninger F, Trimmel-Schwahofer P, Gröppel G, Porsche B, Abraham K, Mühlebner A, Samueli S, Male C, Feucht M. Efficacy and tolerability of the ketogenic diet versus high-dose adrenocorticotropic hormone for infantile spasms: A single-center parallel-cohort randomized controlled trial. Epilepsia. 2019 Mar;60(3):441-451. doi: 10.1111/epi.14679
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  • Harini, C, Nagarajan, E, Bergin, AM, et al. Mortality in infantile spasms: A hospital‐based study. Epilepsia. 2020; 61: 702– 713. doi: 10.1111/epi.16468
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  • O'Callaghan FJK 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 Lancet Child & Adolescent Health, 2018, 2(10):715-725. doi: 10.1016/S2352-4642(18)30244-X
  • O’Callaghan FJK, Edwards SW, Alber FD, Hancock E, Johnson AL, Kennedy CR et al. Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial. The Lancet Neurology  2017;16(1):33-42. doi: 10.1016/S1474-4422(16)30294-0
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Content last reviewed November 2020.