Epileptic spasms---175 years on

Jo M. Wilmshurst, Roland C Ibekwe and Finbar J.K. O’Callaghan.  Epileptic spasms — 175 years on: Trying to teach an old dog new tricks.  Seizure.  In press.

Abstract

Purpose

This text provides an overview of how the condition "infantile spasms" has evolved in the last 175 years.

Method

Key references are summarised to assimilate this review. Results: Infantile spasms, first described by Dr West in 1841, has undergone extensive investigation to understand the pathogenesis, aetiologies, optimal intervention and most likely prognosis for the affected child. The terminology has recently evolved such that the preferred term for the condition is now “epileptic spasms” in recognition of the fact that cases can present outside infancy. The aetiologies are diverse and can be structural, genetic, metabolic or acquired. Increasing numbers of presumed causative genetic mutations are now being identified. The condition is an epileptic encephalopathy such that without adequate control of the clinical seizures and correction of the abnormal EEG, ongoing neurological damage occurs. In some cases neuroregression is inevitable despite intervention. First-line treatments are either hormonal therapies, adrenocortcotrophic hormone or prednisolone, or vigabatrin. In the sub-group of patients with tuberous sclerosis complex, vigabatrin is the preferred treatment. High dose prednisolone may be a more viable option in resource limited settings. Recent research has suggested that combining hormonal therapies with vigabatrin will result in more patients achieving spasm cessation.

Conclusions

Despite extensive study, the pathogenic mechanisms remain an area of debate and in need of further exploration. The enigma, however, may be explained as the role of resting state and dysfunctional brain networks are elucidated further.

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From the article

A large single centre study of 150 infants with infantile spasms, assessed their long term outcome. The subsequent prognosis of this group was that 22% died, 16% attended normal school and the remainder required school learning support or day-care, with 34% severely affected. Fifty-five percent went on to develop other seizure types and 47% had abnormal neurological signs. Overall they illustrated the legacy of neurodisability associated with the majority of children who had infantile spasms. This was further supported by the findings of Riikonen in the epidemiological study of patients with IS in Finland. Poor prognosis related to early onset, long duration of spasms and presence of developmental delay at onset. But the infants with “cryptogenic aetiology” had a better prognosis…

The condition of late-onset infantile spasms is an accepted entity, to the extent that the preferred term is no longer infantile spasms but now referred to as late-onset epileptic spasms. This condition is often associated with focal cortical dysplasia type 1. Patients may have severe mental impairment but seizures can be remedial to surgical interventions. These late-onset epileptic spasms (ES) are distinct from West syndrome and Lennox–Gastaut syndrome…

Epileptic spasm is an age related disorder. It is the most common epileptic syndrome in infancy. The incidence of IS has been estimated to range 2–5/10,000 newborne. Studies from high income countries showed wide range incidence rate (0.05–0.6/1000 liveborne) higher reported incidence were reported from the higher geographic latitudes; Sweden, Finland and Denmark and lowest incidence in United States of America, Britain and Korea. It is not clear if this difference were due to environmental factors or specific genetic predisposition…

Twenty-one United States paediatric epilepsy centres prospectively enrolled infants with newly diagnosed West syndrome in a central database. A total of 251 infants were enrolled (53% male). A cause was identified in 161 (64.4%) of 250 cases (genetic, 14.4%; genetic-structural, 10.0%; structural-congenital, 10.8%; structural-acquired, 22.4%; metabolic, 4.8%; and infectious, 2.0%). An obvious cause was found after initial clinical assessment (history and physical examination) and/or MRI in 138 of 161, whereas further genetic and metabolic studies were revealing in another 23 cases. Of 112 subjects without an obvious cause after initial evaluation and MRI, 81 (72.3%) had undergone genetic testing, which showed a causal abnormality in 23.5% and a variant of unknown significance in 14.8%. Although metabolic studies were done in the majority, these revealed an aetiology in only five cases (4.5%). The group concluded that the clinical evaluation and MRI provided a specific diagnosis in 55% of children presenting with West syndrome. They recommended a cost-effective workup for those without obvious cause, after initial clinical evaluation and MRI,that should include an array comparative genomic hybridization (aCGH) followed by an epilepsy gene panel if the microarray is not definitive, as well as serum lactate, serum amino acids, and urine organic acids…

The underlying pathogenesis of ES is not fully understood. The condition is proposed to be a derangement of a network, or a system epilepsy. The mechanism for the associated encephalopathy is still not fully elucidated. It is hypothesised that the encephalopathy is a reflection of the background slowing and disruption in the normal brain rhythms due to a disturbance in brain networks. The infant is especially vulnerable to the development of epileptic spasms based on their stage of brain maturation and the time window that this places them in. Hence a wide range of aetiologies have the capacity of leading to the same outcome, namely ES and often West syndrome, they have the equivalent mechanism of flipping a switch (which may have been predestined in a vulnerable child or directly operational in instigating the ripple effect of damage)…

Benign non-epileptic IS has been reported by some workers and these children have an excellent prognosis with a normal EEG. According to current knowledge a normal EEG excludes the diagnosis of IS…

In resource limited settings access to ACTH or vigabatrin may not be viable. Indeed even in many parts of the US the cost of ACTH often precludes its use as therapy. Data is evolving supportive of high dose prednisolone (8 mg/kg/day, or 40–60 mg per day, for 2 weeks of therapy followed by a 2 week taper) with equivalent responses to those seen with ACTH…

Another key factor associated with developmental outcome is the “lead time to treatment” i.e. the time from seizure onset to initiation of treatment  [65]  . In this study that looked at participants in UKISS  lead-time to treatment was categorised as 7 days or less, 8–14 days, 15 days–1 month, 1–2 months and greater than two months. The study showed that the earlier the intervention the better, each increase in category of lead time duration was associated with a 3.9 (95% CI 0.4–7.3, p = 0.014) decrease in VABS score…

The prompt response to treatment and a short duration of hypsarrythmia is also an indicator. This has also been reported in patients with infantile spasms and TSC  [68]  as well as those with IS and Trisomy 21…

Epileptic spasms remain in many ways a connundrum, the ideal intervention is still unravelling, as well as how to best to screen patients with the intent for optimal care, and certainly with regards to the genetic causative mutations, the list could be exhaustive. As the vast range of genetics causes for ES evolve, it will be important to structure cost effective screening tools and to assess where the results will alter management i.e. precision medicine. However in most settings early recognition and intervention remain the priority of care to aim for optimal outcome for the infant.

See:  http://childnervoussystem.blogspot.com/2016/03/acth-is-more-effective-than-other.html
http://childnervoussystem.blogspot.com/2015/08/high-dose-prednisolone-for-infantile.html
http://childnervoussystem.blogspot.com/2015/06/west-on-west-syndrome.html