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The MS prodrome; how real is it? 


Multiple sclerosis has a preclinical phase during which irreversible damage occurs. This phase is typically associated with subtle symptoms and signs that aren’t enough to warrant a diagnosis of MS and we, therefore refer to this as the MS prodrome. Identifying a prodrome is important as it may allow you to diagnose MS earlier. With the emergence of disease-modifying therapies identifying patients in the preclinical phase of the disease provides the potential to improve disease outcomes; the earlier you modify the course of MS the greater will be the impact on the long-term trajectory. In addition, preservation of brain reserve should reduce the inevitable impact that ‘normal ageing’ has on MS outcome over your life.


Helen Tremlett’s group in British Columbia have cleverly used health administrative and clinical databases in Canada, show increased healthcare utilization prior to the development of a first demyelinating event, compatible with MS. The so-called rate ratios increased steadily between five years and one year before the first demyelinating disease claim, which is an indicator that the increase healthcare utilization was due to the MS prodrome. The study findings support other published observations describing an MS prodrome.


It should not be a surprise that physician or neurologist generated codes that were associated with MS included disorders of the central and peripheral nervous system, disorders of the eye and cerebrovascular disease. Hospital and prescription data were poor predictors, however, hospitalizations related to the urinary system or spinal cord diseases, or prescriptions for urinary antispasmodics or anti-vertigo preparations, were associated with 2 to 3-fold higher odds of developing MS in the future.


MS in common with other neurodegenerative diseases also has a latent, or pre-disease, state prior to the preclinical and clinical phases. The latency phase refers to the so-called ‘at risk’ period prior to the onset of focal inflammatory lesions that defines MS pathologically. Migration studies, between areas of high and low prevalence, indicate that from exposure to the putative environmental risk factors and the onset of the disease is somewhere between 10 and 20 years. Similarly, pathological studies indicate that the preclinical phase of MS could potentially be decades. A large Danish series found that approximately a quarter of cases with pathological evidence of MS at post-mortem were never diagnosed with MS in life. Either these subjects had asymptomatic MS or their symptoms were put down to some other ailment.


In general, MS begins before the first clinical attack; the majority of patients presenting with a clinically isolated syndrome (CIS) have older, inactive, lesions on their MRI that does not account for the CIS. Familial studies demonstrate that some siblings, including unidentical and identical twins, have lesions on MRI compatible with demyelination and/or the presence of oligoclonal IgG bands in their CSF; this is despite the majority of these siblings never going onto to develop MS. The MS endophenotype is the term that we use to capture the ‘at risk’, ‘asymptomatic’, ‘prodromal’ and ‘clinical’ phases of MS.


Redefining MS to capture the different phases of the disease should allow us to study the impact of DMTs on both the asymptomatic (radiologically isolated syndrome – RIS) or prodromal phases. Recent studies have demonstrated that even at these earlier stages of MS there is evidence of end-organ or brain damage.


There is an ongoing debate whether, or not, we should extend the diagnosis of MS into this asymptomatic, and now the prodromal, phases of the disease and to offer these people DMTs. I have little doubt about this and hope the next rendition of the McDonald MS diagnostic criteria will extend the diagnosis of MS into the asymptomatic phase of the disease. Redefining when MS begins will allow us to test whether very early intervention in the disease course improves long-term outcome rather than waiting for the disease to become symptomatic.

 
 

Högg et al. Mining healthcare data for markers of the multiple sclerosis prodrome. Mult Scler Relat Disord. 2018 Aug 8;25:232-240.


BACKGROUND: Previous studies suggest the existence of a prodromal period in multiple sclerosis, but little is known about the phenotypic characteristics. This study aims to characterize the multiple sclerosis (MS) prodrome using data mining analytics in the healthcare setting.



METHODS: We identified people with MS and matched general population controls using health administrative data in two Canadian provinces (British Columbia and Saskatchewan). Using a training dataset (66.6% of British Columbia’s cohort), L1 penalized logistic regression models were fitted to predict MS from physician and hospital encounters (via International Classification of Diseases [ICD] codes) and prescriptions filled (as drug classes) during the five years before the MS case’s first demyelinating event. Internal and external validation of identified predictors was performed using logistic regression on the remaining British Columbia (33.4%) and Saskatchewan data. Adjusted odds ratios (aORs) and Area under the Curve (AUC) metrics for the models’ predictive performance were reported.


RESULTS: We identified 8,669 MS cases and 40,867 controls. Good predictive performance was observed for physician data (internal/external validation AUC = 0.81/0.79). Physician-generated ICD codes that were associated with MS and validated in both provinces included disorders of the central and peripheral nervous system, disorders of the eye, and cerebrovascular disease (aOR = 1.3-7.0). Overall, hospital and prescription data showed very poor and poor predictive performance (internal/external validation AUCs = 0.54/0.55 and 0.66/0.61, respectively). However, hospitalizations related to the urinary system or spinal cord diseases, or prescriptions for urinary antispasmodics or anti-vertigo preparations, were associated with 2 to 3-fold higher odds of MS (aOR = 2.3-3.3).


CONCLUSIONS: Findings provide insight into the clinical characteristics of the MS prodrome. Diagnostic codes from physician encounters were capable of differentiating between MS cases and controls.


CoI: none in relation to this post

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

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