A prodrome is an early symptom or set of symptoms that indicates the onset of a disease before more diagnostically specific signs develop. One of the most typical examples is a migrainous aura (i.e. flickerings in your visual field) half an hour before you develop a throbbing migrainous headache. However, very often prodromal symptoms are very unspecific. Clouds could be a prodrome of a storm, but – as Charlie Mackesy illustrated – could also just hide the sun.
Over the preceding years, several studies have reported about the existence of an ‘MS prodrome’. This is a period covering about 5-10 years before the official diagnosis of MS during which pwMS have more physician and hospital encounters for various reasons. Before diagnosis, pwMS were more likely to present with mood/mental health disorders and migraine for example, and reported more urinary, musculoskeletal or skin-related conditions. If a prodrome exists, it is important to characterise it as early recognition might open the window to early treatment. However, …
Gasperi et al. analysed the symptoms and diagnoses 5 years before official MS diagnosis registered in the medical records from 10,262 pwMS living in Bavaria (Germany), and compared them with the symptoms registered for people diagnosed with psoriasis, Crohn’s disease and healthy controls (HC). In a first analysis, they found that 43 symptoms were more frequent among pwMS such as visual disturbance, dizziness, motor impairment, disorders of the urinary system, abnormal skin sensation, …. When people with psoriasis or Crohn’s disease were used as controls, 35/43 and 19/43 symptoms were still more common among pwMS, respectively. As many of these 43 symptoms could be caused by a demyelinating event, the authors performed a more stringent analysis in which they excluded all patients with symptoms that could flag a demyelinating event (e.g. blurry vision > optic neuritis). In this second analysis, none of the remaining 20/43 symptoms/disorders were significantly associated with MS.
This study thus questions the presence of an MS prodrome, and suggests that all symptoms preceding the official MS diagnosis are potential unrecognised demyelinating events. On the MD side, one of the contributing factors might be that most symptoms before diagnosis were recorded by GP’s who potentially do not always recognise the ‘neurology’ in the symptom. On the pwMS and MD side, there is always a tendency to minimise the importance of symptoms that are transitory. In MS, we should all fear the “postdromal” silence after the storm. People’s brain tend to interpret transient symptoms as benign, which is a good rule of thumb for many other non-neurological symptoms.
Hence, we need to rethink the MS prodrome terminology because it suggests that the 5 years before MS are different from what comes after. In addition, it gives too much credit to neurologists for determining the onset of the disease. Timing of diagnosis is a moment on which all pieces of the puzzle come together rather than a biologically defined moment in the MS disease course. How do you think we should rebrand the prodrome? Let us know by filling out the survey!
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Neurology 2021 Apr 26;10.1212/WNL.0000000000012074.
Christiane Gasperi 1, Alexander Hapfelmeier 2 3, Tanja Daltrozzo 4, Antonius Schneider 3, Ewan Donnachie 5, Bernhard Hemmer 6 7
- PMID: 33903190
- DOI: 10.1212/WNL.0000000000012074
Objective: To explore the occurrence of diseases and symptoms in the five years prior to diagnosis in patients with multiple sclerosis (MS) in a case-control study. Methods: Using ambulatory claims data we systematically assessed differences in the occurrence of diseases and symptoms in the five years prior to first diagnosis in patients with MS (n=10,262) as compared to patients with two other autoimmune diseases – Crohn’s disease (n=15,502) and psoriasis (n=98,432) – and individuals without these diseases (n=73,430). Results: Forty-three ICD-10 codes were recorded more frequently for patients with MS before diagnosis as compared to controls without autoimmune disease. Many of these findings were confirmed in a comparison to the other control groups. A high proportion of these ICD-10 codes represent symptoms suggestive of demyelinating events or other neurological diagnoses. In a sensitivity analysis excluding patients with such recordings prior to first diagnosis, no association remained significant. Seven ICD-10 codes were associated with lower odds ratios of MS, four of which represented upper respiratory tract infections. Here, the relations with MS were even more pronounced in the sensitivity analysis. Conclusions: Our analyses suggest that patients with MS are frequently not diagnosed at their first demyelinating event but often years later. Symptoms and physician encounters before MS diagnosis seem to be related to already ongoing disease rather than a prodrome. The observed association of upper respiratory tract infections with lower ORs of MS diagnosis suggests a link between protection from infection and MS that however needs to be validated and further investigated.