Multiple Sclerosis Prodrome Holds Promise of Earlier Diagnosis

September 13, 2020

"It is time that the prodromal phase of multiple sclerosis is formally recognized."

That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the 8th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

"There is now no doubt that there is an MS prodrome measurable by increased healthcare usage and lifestyle changes that are recognizable 5 to 10 years before the clinical recognition of MS. There is a myriad of prodromal features but none that are specific to MS," Tremlett said.  

"These findings show that in future there could be an earlier window of opportunity to identify and manage MS," she suggested.

In an interview with Medscape Medical News, Tremlett, who is Professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, explained that for multiple sclerosis (MS), a prodrome is a relatively new concept.

"Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist," she said. "But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis."

Helen Tremlett, PhD

In her plenary talk, Tremlett summarized the available evidence showing that in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.

In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS compared with controls.

This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome.

In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.

"There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated," Tremlett told Medscape Medical News.  

"We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected."

The researchers found that dermatology referrals increased in patients who went on to develop relapsing/remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.

In a large UK population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors' records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions compared with controls, Tremlett reported.

Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (odds ratio compared with controls, 1.2).

The increase in pain seemed to be greater with age, with odds ratios compared with controls of 1.8 for those younger than 30 years, 2.1 for those age 30 to 49 years, and 2.4 for those older than50 years.

A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS.

"This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious," Tremlett commented.  

A study in pediatric MS found that the mothers of the patients had higher use of healthcare (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event. 

A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that "many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event," with the implication that this is evidence of missed opportunity for earlier diagnosis, Tremlett noted.  

In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).

 "This is evidence for shared prodromal features across immune diseases, but there isn't a single feature specific to MS," Tremlett said.   

She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS compared with 30 matched controls.

What Are the Implications?

Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS.

"If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors."

She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception.

"This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant."

She believes the longer-term impact of the prodrome is going to require much thought. 

"There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations."

"We can't automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common."

On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.

"Yes, we do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice," she said. "But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS — many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully."

Following in the Footsteps of Parkinson Disease

She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS.

"We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study."

Tremlett points out that in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. "This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I'm hoping that MS will follow in their footsteps."

Commenting on the presentation for Medscape Medical News, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said, "There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS)."

He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5 to 10 years before presentation to a neurologist. 

"Those symptoms are ones that are common in MS, though not specific for MS," Cohen noted. "The main implication is that the timeline for MS needs to be moved earlier — for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS."

New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence, Italy, added: "The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment."

Tremlett reports an investment in Precision NanoSystems Inc.

8th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020. Presented September 11, 2020.  Session number PL01.  

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