Symptoms Prior to Diagnosis of Multiple Sclerosis in Individuals Younger Than 18 Years
Authors: Manas K. Akmatov, Jonas Graf, Claudia Kohring, David Ellenberger, Jörg Bätzing, Helen Tremlett, Jakob Holstiege
Journal: JAMA Network Open (2024)

A growing body of literature suggests the presence of a prodromal period with nonspecific signs and symptoms before onset of multiple sclerosis (MS). To systematically assess diseases and symptoms diagnosed in the 5 years before a first MS- or central nervous system (CNS) demyelinating disease-related diagnostic code in pediatric patients compared with controls without MS and controls with another immune-mediated disorder, juvenile idiopathic arthritis (JIA). This population-based, matched case-control study included children and adolescents (aged <18 years) in Germany with statutory health insurance from January 2010 to December 2020. The study population consisted of 3 groups: case individuals with MS, control individuals without MS, and control individuals with JIA. Data were analyzed from November 2023 to April 2024. Diagnoses coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, German Modification (ICD-10-GM). The main outcome was incident cases of MS, defined as the first confirmed diagnosis of MS (ICD-10-GM code G35) in 1 quarter between 2013 and 2020 and at least 1 additional diagnosis in the following quarters. In total, 163 ICD-10-GM codes before a first MS diagnosis were assessed using univariable and multivariable logistic regression analyses. The study population consisted of 1091 children and adolescents with MS, 10 910 without MS, and 1068 with JIA. Of the children and adolescents with MS, 788 (72.2%) were female. Mean (SD) age at disease diagnosis was 15.7 (1.7) years. Nine ICD-10-GM codes were present more frequently among children and adolescents with MS in the 5 years before their first MS diagnosis than among controls without MS: obesity (adjusted odds ratio [AOR], 1.70; 95% CI, 1.42-2.02), disorders of eye refraction and accommodation (AOR, 1.26; 95% CI, 1.09-1.47), visual disturbances (AOR, 1.31; 95% CI, 1.10-1.55), gastritis and duodenitis (AOR, 1.35; 95% CI, 1.08-1.70), patella disorders (AOR, 1.47; 95% CI, 1.13-1.90), heartbeat abnormalities (AOR, 1.94; 95% CI, 1.27-2.96), flatulence (AOR, 1.43; 95% CI, 1.01-2.01), skin sensation disturbances (AOR, 12.93; 95% CI, 8.98-18.62), as well as dizziness and giddiness (AOR, 1.52; 95% CI, 1.22-1.89). Four of these ICD-10-GM codes were significantly more prevalent in children and adolescents with MS than in controls with JIA: obesity (AOR, 3.19; 95% CI, 2.03-5.02), refraction and accommodation disorders (AOR, 3.08; 95% CI, 2.33-4.08), visual disturbances (AOR, 1.62; 95% CI, 1.13-2.33), and skin sensation disturbances (AOR, 27.70; 95% CI, 6.52-117.64). In this population-based, matched case-control study, children and adolescents with MS had diverse metabolic, ocular, musculoskeletal, gastrointestinal, and cardiovascular symptoms, signs, or diagnoses within 5 years before their first MS diagnosis. Better characterization of early symptoms and/or risk factors, comorbid disorders, and possible prodromal features of MS may have considerable implications for early recognition and subsequent progression of the disease.