Appearance of fetal pain could be associated with maturation of the mesodiencephalic structures

Slobodan Sekulic,1 Ksenija Gebauer-Bukurov,1 Milan Cvijanovic,1 Aleksandar Kopitovic,1 Djordje Ilic,2 Djordje Petrovic,2 Ivan Capo,3 Ivana Pericin-Starcevic,4 Oliver Christ,5 Anastasia Topalidou6 1Department of Neurology, Faculty of Medicine Novi Sad, University of Novi Sad, 2Department of Obstetrics and Gynecology, Faculty of Medicine Novi Sad, University of Novi Sad, 3Department of Histology and Embryology, Faculty of Medicine Novi Sad, University of Novi Sad, 4Department of Developmental Neurology and Epilepsy, Institute for Child and Youth Health Care of Vojvodina, Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia; 5School of Applied Psychology, Institute Humans in Complex Systems, Olten, Switzerland; 6Department of Orthopaedics and Traumatology, University Hospital of Heraklion, Faculty of Medicine, University of Crete, Heraklion, Greece Abstract: Fetal pain remains a controversial subject both in terms of recognizing its existence and the time-frame within which it appears. This article investigates the hypothesis that pain perception during development is not related to any determined structures of the central nervous system (CNS), on the contrary, the process of perception could be made with any structure satisfying conditions that the perception of pain is the organization, identification, and interpretation of sensory information in order to represent and understand the environment. According to this definition, chronic decerebrate and decorticate experimental animals, anencephalic, and hydranencephalic patients demonstrate that the basic, most general, appropriate interaction with the environment can be achieved with a functional mesodiencephalon (brain stem, and diencephalon) as the hierarchically highest structure of the CNS during development. In intact fetuses, this structure shows signs of sufficient maturation starting from the 15th week of gestation. Bearing in mind the dominant role of the reticular formation of the brain stem, which is marked by a wide divergence of afferent information, a sense of pain transmitted through it is diffuse and can dominate the overall perception of the fetus. The threshold for tactile stimuli is lower at earlier stages of gestation. The pain inhibition mechanisms are not sufficiently developed during intrauterine development, which is another factor that leads to increased intensity of pain in the fetus. As a conclusion it could be proposed that the fetus is exposed to rudimentary painful stimuli starting from the 15th gestation week and that it is extremely sensitive to painful stimuli. Keywords: pain, fetus, perception, brain stem, thalamu

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis

BACKGROUND: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). CONCLUSIONS: Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .)