Introduction
Current evidence
Author | Year | Country | Cases (n) | Controls (n) | Data source | Findings |
---|---|---|---|---|---|---|
Berger et al. [7] | 2013 | USA | 5305 | 0 | Medical insurance claims | 1534 (28.9%) were diagnosed with fatigue prior to the index new MS diagnosis. Among the patients diagnosed with fatigue, 10.4% were also prescribed a fatigue-related medication. Fatigue was the earliest symptom in nearly 40% of patients. 30.8% of patients experienced only fatigue (and no other MS-related symptoms) in the three-year period prior to the index new MS diagnosis |
Sinay et al. [17] | 2015 | Argentina | 75 | 75 | Clinical cohort linked to school records | There was no difference between cases and controls in rates of repeating a school year or dropping out of high school. Cases had lower marks in maths, language and overall average in the last three years of high school cycle compared to controls. This effect was largest for those with short time between finishing school and onset of MS. Similarly, no effect was seen for exam marks ≥ 3 years before the end of high school |
Hoang et al. [8] | 2016 | Denmark | 5084 | 24,771 | Health administrative records | There was an increased risk of anxiety and depression (combined) in the two years before MS diagnosis [OR 1.40, 95% CI 1.05–1.88) but not significantly increased in the two years after diagnosis (OR 1.23, 0.92–1.64). OR was 1.4 (1.18–1.62) for depression in the MS population compared with controls, and the OR was 1.1 (0.78–1.43) for anxiety compared with controls |
Wijnands et al. [9] | 2017 | Canada | 14,428 | 72,059 | Health administrative records, MS registry | More frequent hospital admissions, outpatient visits, and prescriptions for people who went on to develop MS compared to controls, detectable up to 5 years before MS onset |
Disanto et al. [10] | 2018 | United Kingdom | 10,204 | 39,448 | Health administrative records | People who went on to develop MS had a higher frequency of physical (nausea and vomiting, urinary dysfunction, headache, eye pain, fatigue, back/neck pain) and psychiatric symptoms (anxiety, depression, insomnia and eating disorders) in the years leading up to MS onset. There was a positive association between the number of symptoms recorded and risk of future MS, with a 51%, 29%, and 20% increased risk of MS for each additional symptom at 0 to 2, 2 to 5, and 5 to 10 years before index date, respectively |
Högg et al. [11] | 2018 | Canada | 8669 | 40,867 | Health administrative records | A physician encounter for a cerebrovascular, central or peripheral nervous system-related disease or disorder of the sense organs was associated with two to fivefold higher odds of MS |
Marrie et al. [12] | 2019 | Canada | 1155 CIS-MS cases, 20,638 CIS-non MS cases | 108,726 | Health administrative records | For both CIS-MS and CIS-non MS cases, there were higher rates of hospitalisation, physician visits and prescriptions than controls leading up to the CIS diagnosis. For CIS-non MS cases, this was detectable in all five years leading up to CIS diagnosis, and for CIS-MS cases was largely seen in the year before CIS diagnosis |
Wijnands et al. [14] | 2019 | Canada | 2058 | 9837 | Health administrative records and MS registry | 1887 R-MS cases, 171 PPMS cases. There was no difference in the number of physician encounters in the 5 years before MS onset. However, there was a difference in the outpatient specialties that patients visited: cases of PPMS had 92% more nervous system-related encounters and 71% fewer pregnancy/childbirth encounters relative to R-MS |
Wijnands et al. [13] | 2019 | Canada | 13,951 | 66,940 | Health administrative records | There was an increase in number of physician encounters in the cases compared to controls during the five years leading up to first MS symptom. When classified by physician speciality there was a threefold to ninefold increases in visits to a neurologist (RR = 9.02, 95% CI: 7.53–10.80), neurosurgeon (RR = 3.63, 95% CI:2.81–4.69), or neurorehabilitation (RR = 3.20, 95% CI: 2.86–3.57), as well as increased number of encounters with a urologist (80%), ophthalmologist or otolaryngologist (76%), psychiatrist (66%) and internal medicine physician (53%) |
Lebrun-Frénay et al. [19] | 2020 | Multi-country | 451 | Clinical RIS cohort | Mean age at RIS diagnosis was 37.2 years. Headache (42%) was the commonest reason for an initial MRI scan. The cumulative probability of a clinical event at 10 years was 51.2%. Of the 173 patients who developed MS symptoms, 21 (11.7%, 62% female) fulfilled criteria for primary progressive MS. In univariate analysis, factors associated with increased risk of a first clinical event were a younger age (than 37 years) at RIS diagnosis, positive CSF, and presence of either infratentorial or spinal cord lesions. Radiological activity during follow-up was also associated with increased risk of a clinical event (HR = 1.81 [95% CI 1.31–2.52], p < 0.001) | |
Yusuf et al. [15] | 2021 | Canada | 6,863 | 31,865 | Health administrative records and MS registry | This study investigated prevalence of pain, fatigue, sleep disorders and anaemia in the five years preceding MS onset compared to controls. Pain was the commonest symptom (50% in MS cases, 33% in controls), and all symptoms were more common in those who would go on to develop MS than controls (pain, odds ratio [OR] 2.15; sleep disorders OR 2.61; anaemia OR 1.53; fatigue OR 3.37) |
Yusuf et al. [16] | 2022 | Canada | 6863 | 31,865 | Health administrative records | During the five years preceding a first demyelinating event, relative rates for males were 15% greater for total physician visits, and 21% higher for total hospital admissions, than relative rates for females. Age-specific effects included a 17% higher relative rate among older people with MS for visits to a GP, while younger people with MS had a 15–45% increased relative rate for ophthalmologist and sensory-related visits, and a 18% higher relative rate for cardiovascular-related drug prescription |
Prodromal window
Lessons from other diseases
Disease | Prodromal symptoms | Pre-diagnostic symptoms | Biomarkers in prodromal phase | Pre-diagnostic disease |
---|---|---|---|---|
– | Radiologically isolated syndrome (RIS) Oligoclonal bands | Clinically isolated syndrome (CIS) | ||
Mild behavioural problems, psychiatric disorders | Mild cognitive symptoms | Aβ42, TAU, pTAU | Mild cognitive impairment (MCI) | |
REM sleep behavioural disorder (RBD), anosmia, non-motor features | DAT scan α-synuclein tissue deposition and seed amplification | Prodromal PD | ||
Depression, apathy, irritability, executive dysfunction | CAG triplet repeat expansion in the HTT gene Serum neurofilament light | Peri-manifest HD | ||
Arthralgia, fatigue, reduced mental health, cardiovascular diseases, carpal tunnel syndrome | Pain, stiffness swelling of the joint, joint tenderness, morning stiffness | Rheumatoid factor IgM, anti-CCP IgG | – | |
Depression | Irritable bowel syndrome | – | – | |
– | – | – |