Monoamine neurotransmitters in early epileptic encephalopathies: New insights into pathophysiology and therapy

Abstract

AimTo study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients.MethodTwo hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0–3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non‐progressive disorders, infantile spasms, Doose syndrome, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments.ResultsAbnormal neurotransmitter values were identified in 68 (33%) patients. 5‐Hydroxyindoleacetic acid (5‐HIAA) deficit was the most prevalent alteration (91%). Low CSF 5‐HIAA levels were significantly higher in 1‐ to 3‐year‐old children. A negative significant correlation was found between 5‐HIAA levels and epilepsy duration before CSF study (Spearman's ρ=−0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5‐HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills.InterpretationA considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy.What this paper adds 5‐Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.

Metabolic characterization of neurogenetic disorders involving glutamatergic neurotransmission

“…Similar decreases in peripheral tryptophan metabolism had been previously described in plasma of Rett syndrome patients 34 and animal models 42 . Likewise, alterations in tryptophan metabolism had been previously reported in developmental and epileptic encephalopathy patients, in which abnormal concentration of neurotransmitter was identified in 33% of the samples, being 5‐HIAA deficit was the most prevalent alteration (91%) 43 . It has also being studied in other diseases with unclear genetic etiology as diverse as migraine, schizophrenia, suicidality or autism spectrum disorders 44–47 …”

“…42 Likewise, alterations in tryptophan metabolism had been previously reported in developmental and epileptic encephalopathy patients, in which abnormal concentration of neurotransmitter was identified in 33% of the samples, being 5-HIAA deficit was the most prevalent alteration (91%). 43 It has also being studied in other diseases with unclear genetic etiology as diverse as migraine, schizophrenia, suicidality or autism spectrum disorders. [44][45][46][47] On the other side, although not neurotransmitter-producing, the kynurenine pathway plays essential roles in cell function: it has a key function in energy metabolism by regulation of the coenzyme nicotinamide adenine dinucleotide (NAD+) 48 and has been implicated in the process of inflammation, 49,50 along with the neuroprotective role of kynurenic acid, an intermediate metabolite of the kynurenine pathway that acts as an antagonist to the N-methyl-D-aspartate receptors (NMDARs).…”

Neuroprotective efficacy of Marsilea quadrifolia leaf extract against pentylenetetrazole-induced seizure in rat model of epilepsy.

“…In the present study, PTZ-treated groups showed a significant increase ( p < .05) in brain 5-HT and 5-HIAA metabolite concentrations with a reduction in 5-HT level in the hippocampus after MQLE co-supplementation following PTZ administration, suggesting a restoration of spatial learning and memory system. Therefore, the extent of toxicity induced by PTZ may be sufficient to alter the homeostatic state of the growing complex neuronal system (Giachello & Baines, 2017; Juliá-Palacios et al, 2022) leading to integrated neurobiological functions and behavioral responses specifically related to alteration of 5-HT like neurotransmitter and its metabolite (5-HIAA). Although large number of models available for screening anticonvulsant activity, we used PTZ (ip) methods for direct assessment of antiepileptic effects of MQLE on nervous system function.…”

Neurotransmitters—Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System

“…Monoamines are a representative group of NTs with clinical significance in motor functions, emotional responses, motivations, and behavioral functions [ 3 , 56 ]. These substances are synthesized from presynaptic neurons and bind to the corresponding receptors on the postsynaptic membrane in order to exert their functions.…”

“…or catechol-O-methyltransferase (EC 2.1.1.6) or undergoes reuptake into the presynaptic terminal by monoamine transporters [ 11 ]. Severe neurological diseases (e.g., AD, PD, HD, schizophrenia) can occur when this equilibrium is dysregulated [ 56 , 57 ]. Thus, given their importance, the most representative NTs of this class are individually described in the next paragraphs.…”