Influence of Age at Onset and Obesity on Pediatric Multiple SclerosisDoctoral thesis
Date of Examination:2024-02-08
Date of issue:2024-01-19
Advisor:Prof. Dr. Jutta Gärtner
Referee:Prof. Dr. Jutta Gärtner
Referee:Prof. Dr. Martin Weber
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EnglishPediatric multiple sclerosis has many parallels to adult multiple sclerosis, however, the initial disease course is generally associated with more relapses yet better recovery and slower disability progression than in adults. Two distinctive features of pediatric multiple sclerosis indicate that age at onset in children has clinical relevance. Firstly, female preponderance, a hallmark of adult multiple sclerosis, first becomes apparent after puberty suggesting that multiple sclerosis risk in girls is unfavourably influenced by sexual maturation, Secondly, in younger pediatric patients the first attack can be difficult to distinguish from other inflammatory central nervous system demyelinating disorders often leading to delays in diagnosis and treatment initiation. A relatively recent link between obesity in adolescence and increased multiple sclerosis risk in adulthood also appears relevant for pediatric multiple sclerosis but studies are very limited. Moreover, almost nothing is known about the influence of obesity on disease modifying therapy and disease course in children. This thesis presents the findings of two retrospective single center cohort studies which explore firstly, the effect of a pre-pubertal onset of multiple sclerosis on clinical features and, secondly, the influence of obesity on pediatric multiple sclerosis risk, treatment response and disease course. In the first study, presenting features, relapse rate and disability progression of 47 pre-pubertal children at disease onset were compared with 41 adolescents aged 14 to 16 years at onset. Findings showed a specific pattern of symptoms at clinical manifestation in both patient groups that was maintained over the first two years of disease suggesting that regional changes in vulnerability to inflammatory processes in the developing brain affect presentation. Multifocal symptoms, a propensity for motor and brainstem symptoms and encephalopathy were all more common in pre-pubertal cases at clinical onset compared to sensory and visual symptoms in adolescent cases. Less favourably, children with a pre-pubertal onset had a higher likelihood of a severe first attack, a higher frequency of mild sequelae following the attack and a greater vulnerability for cognitive involvement in the early course of disease. Nevertheless, relapse rate and disability progression after five disease years, were not significantly different between pre-pubertal and post-pubertal onset cases. In the second study, a cohort of 453 children with multiple sclerosis were categorized as non-overweight, overweight or obese according to their body mass index within six months of their first multiple sclerosis attack. The weight groups were then compared with body mass index data of 14,747 healthy German controls. Resultingly, obesity was associated with significant twofold odds of multiple sclerosis in both sexes. Weight categories were then compared within the multiple sclerosis cohort. Obese children with multiple sclerosis were significantly more likely to relapse on first-line therapy with interferon beta and glatiramer acetate and, subsequently had a higher switch rate to a second-line therapy. Furthermore, patients who were obese at onset were likely to remain obese. Findings did not indicate a more inflammatory underlying disease process or worse disability progression in obese patients, suggesting a possible role of altered pharmacokinetics in poor treatment response.
Keywords: Pediatric multiple sclerosis; Obesity; Puberty