Taking West syndrome by a storm of fast EEG oscillations (FOs)
Rajalaxmi Natarajan, PhD
West syndrome is a rare epilepsy syndrome that affects about 1 in 3000 infants. It is diagnosed based on a triad of symptoms: infantile spasms, a high-voltage, chaotic electroencephalogram (EEG) pattern called hypsarrhythmia and cognitive impairment.
Although the spasms of West syndrome infants are briefer compared to other seizure disorders, they are considered ‘catastrophic’ because of the enormous negative impact they appear to have on cognitive development. Almost 90% of the patients diagnosed with West Syndrome suffer from various degrees of developmental delays and cognitive disability. In general, treatment of infantile spasms remains enigmatic but the most commonly prescribed treatments include hormones (ACTH or corticosteroids), anti-convulsants (vigabatrin) or focal brain surgery. However, they are not always effective in halting the spasms or the cognitive decline.
The goal of treatment for infants suffering from West syndrome is to reduce the frequency of spasms and hypsarrhythmia as quickly as possible because suppressing one or both of them is thought to result in cognitive improvement or at least prevent further damage. However, pathophysiological mechanisms by which spasms and hypsarrhythmia disrupt normal processes of brain development have remained a mystery.
A recent paper1 in the Annals of Neurology by Kobayashi et al., provides a clue to how hypsarrhythmia may be contributing to the progressive loss of cognitive functions in infants suffering from West syndrome. While investigators in the Cain Laboratories at Baylor College of Medicine had previously reported the presence of very frequent pathological high-frequency oscillations during hypsarrhythmia in an animal model of infantile spasms2, this is the first study to document the presence of such a ‘storm’ of pathogenic fast oscillations (FOs) in EEG recordings during hypsarrhythmia in West syndrome patients.
Certain high-frequency oscillations, termed physiological high-frequency oscillations (HFOs) or ripples, do occur under normal circumstances and have frequently been linked to the development of higher-order brain functions such as language and memory. However, identification of these exceedingly abnormal FOs during hypsarrhythmia leads the authors to suggest that these aberrant FOs may interfere with the processing of physiological HFOs and thereby derail normal development. The authors report that on average 66 FOs occur every minute during hypsarrhythmia in West syndrome patient brains. However, in comparable recordings from normal infants they were only able to detect 1 event per minute.
Finally, the authors found that the frequency of pathological FOs decreased dramatically when the children were treated with ACTH or vigabatrin. In these patients, the frequency of hypsarrhythmia and epileptic spasms were also reduced dramatically after ACTH/vigabatrin treatment. Together, these observations implicate detrimental fast oscillations (FOs) in the pathophysiology of West syndrome. However, since these pathological FOs were suppressed at the same time as spasms and hypsarrhythmia, it is not possible to definitively conclude that the beneficial effects of these drugs are solely due to the suppression of FOs. Further work is warranted in this regard.
This study provides a hint into a possible mechanism by which hypsarrhythmia may cause severe cognitive deficits in West Syndrome patients and implicates aberrant FOs in disease progression. While this is a significant step forward in understanding an under studied catastrophic epilepsy, specific cellular mechanisms and molecules that mediate the generation of FOs need to be identified in order to develop ways to eliminate them and possibly treat West syndrome patients more effectively.
1. Kobayashi et al., Annals of Neurology, 2015 Jan;77(1):58-67. A storm of fast (40-150Hz) oscillations during hypsarrhythmia in West syndrome.
2. Frost et al., Neurobiol Dis. 2012 May;46(2):377-88. Interictal high frequency oscillations in an animal model of infantile spasms.