Reduction in Glutamine/Glutamate Levels in the Cerebral Cortex after Adrenocorticotropic Hormone Therapy in Patients with West Syndrome

Abstract

West syndrome (WS), an intractable epileptic encephalopathy of infancy, is refractory to many antiepileptic drugs; however, adrenocorticotropic hormone (ACTH) is an effective treatment for WS. The mechanism behind the efficacy of ACTH is mediated by biochemical processes that remain unknown. We examined the effects of ACTH therapy with tetracosactide (TCS), a synthetic ACTH analogue, on brain metabolism in patients with WS, using 1 H magnetic resonance spectroscopy ( 1 H-MRS). In six patients with cryptogenic WS, we performed single-voxel 1 H-MRS at the occipital lobe cortex. Measurements were taken prior to TCS treatment, a few days after therapy, and several months after therapy. Data were also compared with subjects having only mild psychomotor delays. The metabolites measured were glutamine plus glutamate (Glx), N-acetylaspartate (NAA), choline (Cho), and myoinositol (mI); each was expressed as a ratio with creatine plus phosphocreatine (total creatine: tCr). The Glx/tCr ratio was significantly reduced after the TCS treatment. The NAA/tCr ratio was also significantly reduced after the treatment compared with the control group, although the change in NAA signal was heterogeneous among patients, correlating with respective outcomes. The Cho/tCr and mI/tCr ratios were not affected by TCS treatment. The reduction in Glx suggests a decrease in the glutamate-glutamine cycle, which plays a pivotal role in synthesizing neurotransmitters such as glutamate and GABA. TCS-induced Glx reduction may induce changes in synaptic signal transduction, thereby accounting for the effect of TCS on WS. The change in NAA indicates altered neuronal activity, which may be correlated with outcome in WS patients.

Catatonia Associated With a SCN2A-Related Disorder in a 4-Year-Old Child

“…Epilepsy linked to an SCN2A mutation has previously been successfully treated with PEDIATRICS Volume 142, number 5, November 2018 3 adrenocorticotropic hormone, 22 which also supports a link between E/I balance and the hypothalamopituitary-adrenocortical stress pathway. 23 Because treatment with adrenocorticotropic hormone in these disorders is not typical, we could not fully exclude an autoimmune disorder. Nevertheless, this hypothesis appeared unlikely because (1) no specific markers were found, (2) no response to plasma exchange was observed, and (3) this hypothesis did not match with the positive effects of vigabatrin.…”

The Impact of H Ypothalamic-Pituitary-Adrenal System Hormones on Epileptogenesis

“…Существу-ет также мнение, что АКТГ увеличивает способность нейронов усваивать витамины группы В, а имен-но витамин В 6 , который является непосредствен-ным активатором созревания нервной ткани [30]. АКТГ оказывает влияние и на выработку возбужда-ющих нейротрансмиттеров (в частности, глутамата), а именно удлиняет цикл их синтеза, снижая таким образом концентрацию данного нейромедиатора в ЦНС [28]. АКТГ способен действовать в качестве модулятора внутриклеточных нейростероидов; в ре-зультате такой модуляции увеличивается продукция аденозина, косвенно воздействующего на рецепторы гамма-аминомасляной кислоты (ГАМК), что приво-дит к инактивации кальциевых каналов в мембране нейронов [7].…”

GABAergic Interneurons in Severe Early Epileptic Encephalopathy with a Suppression-Burst Pattern: A Continuum of Pathology

“…• Adrenocorticotrophic hormone and oral corticosteroids: Pituitary-adrenal hormones have long been known to affect epileptogenesis. Even though the mechanism behind the efficacy of ACTH is mediated by biochemical processes that remain unknown, a reduction in glutamine/glutamate levels in the cerebral cortex after ACTH therapy in patients with WS has been shown [227]. Systemic administration of ACTH causes an increase in midbrain and striatal GABA receptor binding [228].…”