I have been diagnosed with relapsing-remitting MS. What can happen?
If you are diagnosed with relapsing-remitting MS, you can expect to have relapses with worsening neurological symptoms, remissions when these symptoms improve and, at some point develop secondary progressive MS. Relapses are new or worsening neurological symptoms with objective changes in the neurological exam in the absence of fever and last for more than 24 hours which have been preceded by a period of clinical stability of at least 30 days (Uitdehaag, 2017). When a relapse will occur is unpredictable. In a relapse, symptoms come on acutely or sub acutely over a period of days with maximum deficits within one month and then spontaneously and progressively improve. (Brownlee et al, 2017)
Relapses can affect a single location or multiple locations in the central nervous system. A relapse in a single location will cause a single symptom such as weakness, numbness, or loss of vision while a relapse in multiple parts of the central nervous system may cause a multitude of symptoms at the same time. Relapses may also affect more complex systems in the CNS and cause cognitive impairment or emotional distress. Symptoms may be subtle and not easily recognized, or severe, requiring expedient treatment. Although technically the diagnosis of a relapse requires new or worsening neurological symptoms with objective changes on the neurological exam, I would consider one or more new lesions on a brain or spinal cord MI evidence of a clinically “silent” relapse.
Relapses generally improve (remit) but a person’s neurological condition may not always return to their baseline. The principal prognostic factor for recovery after relapse is the length of time the relapse persists. About 16 to 30% of patients will have incomplete recovery after a relapse and be left with some permanent symptoms or signs of the relapse (Confavreux and Vukusic 2014).
The contribution of relapses to disability is not straightforward (Confavreux and Vukusic 2014). Multiple relapses can contribute to the development of permanent disability and some permanent disability can occur as a result of a single relapse. Certain relapse related factors such as incomplete recovery from the initial attack, short interval between first and second attack, and a high rate of relapses in the initial years is associated with more rapid development of disability (Confavreux and Vukusic 2014).
If you become severely disabled in one functional system (an EDSS of 4), [see Outcomes in MS for details on functional systems and the EDSS] data from a large study in Lyon, France suggests that further relapses will not affect the course of subsequent disability (Confavreux and Vukusic 2014). Further worsening can occur in the presence or absence or relapses.
How are relapses treated?
Major relapses should be treated but some neurologists may not recommend treatment for minor or subtle relapses as the risk of treatment may outweigh its benefits. Treatment for a relapse may include adrenocorticotropic hormone (ACTH), methylprednisolone, oral steroids, or in the case of a severe relapse that does not respond to these medications, plasma exchange. Treatment for a relapse should speed up recovery time (Rose, et al. 1970). ACTH given by injection into a muscle was the first treatment discovered to improve symptoms after a relapse (Murray 2005). Subsequently, high dose methylprednisolone, given by an infusion into a vein in the arm, was shown to be equally effective as ACTH.
Some early studies showed that methylprednisolone may also be a more reliable treatment than ACTH. ACTH works by stimulating the body to produce cortisol and the pathway in the body by which this occurs may not function as well in people with MS compared to people without MS.
Currently, methylprednisolone is much less expensive than ACTH. A 3 to 5-day course of high dose intravenous methylprednisolone is usually prescribed for a significant MS relapse.
More recently, oral steroids have been shown to be equally as effective as intravenous methylprednisolone (Barnes D et al. 1997) (Alam SM et al 1993). Oral steroid treatment is much more convenient than intravenous methylprednisolone and also less expensive.
Side effects of ACTH and high dose steroids include: weakening bone; elevated glucose levels; upset stomach; anxiety, depression, and psychosis (difficulty in determining what is real and unreal associated with false beliefs and seeing or hearing things that other people to not see or hear); insomnia; weight gain; avascular necrosis of the shoulder or hip; and cataracts (Jacqueline F. Marcus 2013 ).
Avascular necrosis, the death of bone tissue due to low blood flow in a bone, is one of the most feared side effects of repeated steroid use which tempers its frequent use. It may cause mild or severe pain in bones and if severe can cause joints to collapse and become unusable.
To help minimize the potential for side effects, when I prescribe steroids to treat an MS relapse, I generally prescribe a medicine such as famotidine (Pepcid®) to prevent stomach upset, check glucose frequently and give insulin as needed, and use a medication such as lorazepam (Ativan®) to help with anxiety or insomnia.
For a severe relapses that hasn’t responded to steroid treatment, plasma exchange therapy may help. (Jacqueline F. Marcus 2013 ) In this therapy, the liquid portion of your blood called plasma is removed every other day for 14 days and replaced with new plasma.[vi]
If you think you are having a relapse that your neurologist does not wish to treat, it is important to consider having an MRI of the brain (and spinal cord if your symptoms are suggestive of spinal cord involvement) as it may show more inflammation than your symptoms suggest and may indicate the need for treatment of the relapse or consideration of a change in your disease modifying therapy.
The natural history of relapsing-remitting MS
Aside from relapses, we know that most people with relapsing-remitting MS will at some point develop secondary progressive MS. Three large natural history studies showed an estimated time to progressive disease of about 19 years and, that the best predictor of shorter time to progressive disease is your age at onset of MS (Confavreux and Vukusic 2014). The older you are when you are diagnosed with relapsing-remitting MS, the sooner you are likely to start progressive disease (secondary progressive MS). We are concerned about a change from relapsing-remitting MS to secondary progressive MS because once an individual’s course become progressive it follows the time line of progressive patient who show faster deterioration than relapsing-remitting MS patients.
Koch et al (Marcus Koch 2010) reported on relapsing-remitting MS patients who were enrolled in an MS database in British Columbia, Canada from 1 September 1980 to 31 July 2003. They found the onset of secondary progression to be a gradual process in the group as a whole, with a steady increase of conversions to secondary progressive MS observed over follow-up. The times it took for individual patients to convert were widespread, with secondary progressive MS being reached within 1 year of MS onset through to more than 50 years post-onset, and in individuals from 11 to 82 years of age. Overall, the median time to secondary progression was 21years from onset and the median age 54. There was a lot of variability in both the time to and the age at secondary progression: while the 25% of patients with the quickest disease progression reached secondary progression in less than 11 years and at a younger age than 45years; the 25% with the slowest progression reached secondary progression after more than 32 years and at an age of more than 63 years. Men and patients who started their MS with complaints of limb weakness developed secondary progressive MS after a shorter time and at a younger age. Patients with a younger age at onset took a longer time to secondary progressive MS but reached secondary progressive MS at a younger age.
Although the age when you get MS is the best predictor of faster conversion to secondary progressive multiple sclerosis, other, weaker, predictors of a shorter time to secondary progressive multiple sclerosis include being a male, having spinal cord related symptoms, incomplete recovery from the first episode, shorter time between first and second attack, a greater attack rate in the first two to five years, and having higher disability in the first 5 years of your illness. (Confavreux and Vukusic 2014)
Note that disease modifying therapy may delay the time before someone with relapsing-remitting MS converts to secondary progressive MS
Confreaux and Vukusic note that about 30% of patients with multiple sclerosis have a benign form of the disease which they defined as being “fully functional in all neurologic systems 15 years after disease onset” (Confavreux and Vukusic 2014). Others have disputed the concept of benign disease arguing that it can only be diagnosed in retrospect after one has had MS for 10 or 20 years, that there are no early predictors of who will have a benign course and that studies in the past looking at benign disease did not evaluate cognitive function. Many patients defined as having benign disease do have problems with memory, concentration, and planning (Multiple Sclerosis Trust 2017).
The most common definition of benign MS is having an EDSS of 3 or less (moderate disability in one functional system but without impairment in walking) 10 years after the first sign of MS. [see Outcomes in MS for details on the EDSS] Sartori et al. reviewed more than 5000 records in the Ottawa Hospital MS clinic database and identified 175 people with an EDSS of 3 or less who had been assessed at 10 and 20 years. Of these 175 patients. 44% has worsened to an EDSS of greater than 3 by 20 years and thus were no longer benign (Sartori, Abdoli and Freed 2017).
I have been diagnosed with a clinically-isolated syndrome. What can to happen?
The first question to ask when you are diagnosed with clinically isolated syndrome is whether this is the first manifestation of MS. Your MRI and cerebrospinal fluid help to determine this. Since 2017, we can use guidelines, referred to as the 2017 McDonald Criteria, to diagnose clinically definite MS in someone with a single episode of demyelinating disease. MS can be diagnosed if your MRI shows evidence of inflammation which has occurred in more than one part of the brain, spinal cord, or optic nerve (dissemination in space) and at more than one time (dissemination in time). Evidence that inflammation has occurred in more than one location is the finding on a T2 weighted MRI of one or more lesions that are characteristic of multiple sclerosis in two or more of four specific areas of the CNS. These areas are next to the fluid filled spaces in the brain (periventricular); on or near the surface of the brain (cortical or juxtacortical); in the brainstem or lower part of the brain (infratentorial); and, the spinal cord. Dissemination in time can be demonstrated by the simultaneous presence of one or more gadolinium-enhancing lesions which indicate current inflammation and non-enhancing lesions which indicates inflammation that has occurred in the past.
The finding of certain markers called oligoclonal bands in your cerebrospinal spinal fluid can be used as a surrogate marker of dissemination in time to confirm the diagnosis of relapsing-remitting MS in people with a clinically-isolated syndrome and MRI evidence of dissemination in space. (Thompson AJ 2018)
If you don’t have these characteristic MRI findings on your initial MRI scans, a new MS lesion on a follow-up MRI, compared to your baseline scan, will give you the diagnosis of clinically definite MS (Brex P 2018) A repeat MRI scan is usually done in 3 or 6 months.
The second question if you do not have MS based upon your history, examination, MRI and cerebrospinal fluid analysis is whether or not you will develop a diagnosis of clinically definite multiple sclerosis in the future. The diagnosis of clinically definite multiple sclerosis can be made when a person with a clinically isolated syndrome has a second episode of neurologic symptoms and/or signs on a neurological exam or new characteristic lesions on a follow-up MRI scan.
The natural history (prognosis) of clinically isolated syndrome
In clinically isolated syndrome the likelihood of a second relapse is greatest in the immediate aftermath of the initial episode and then lessens with time. (Confavreux and Vukusic 2014) From studies of patients with a clinically isolated syndrome, the median time to have a second episode of neurological signs or symptoms or have new characteristic brain lesions on MRI (leading to a definite diagnosis of multiple sclerosis) is about 2 years. These clinical studies indicate that there are no clinical parameters such as age, sex, single or multi focal signs or symptoms, or degree of recovery from the first attack that predict a second clinical attack. The presence of brain MRI abnormalities, however, does influence the likelihood of another attack and the diagnosis of clinically definite MS. A normal MRI with clinically isolated syndrome reduces the risk of developing MS by 20 years from 82% if MRI abnormalities are present to 21% if not (Swanton, Fernando and Miller 2014 ).
I have been diagnosed with primary progressive MS. What can happen?
Primary progressive MS is less common than relapsing-remitting MS and comes on more slowly and insidiously than relapsing-remitting MS. It is more difficult to diagnose. If your neurologist diagnoses you with primary progressive MS, several other disorders need to be ruled out and you may need a spinal tap to be sure of the diagnosis. As the term progressive implies, the prognosis for primary progressive MS is not as favorable as relapsing-remitting MS. This may be due to the fact that relapsing-remitting MS generally occurs at a younger age than primary progressive MS. Both relapsing-remitting MS and primary progressive MS seem to have a similar prognosis by the time someone with relapsing-remitting MS reaches the same age as someone with primary progressive MS.
Progressive forms of MS include either secondary progressive MS and primary progressive MS. In patients with progressive forms of multiple sclerosis, progressive disability ensues in contrast to the remitting forms of multiple sclerosis where people usually get better after a relapse though may not return to their prior baseline. In progressive forms of multiple sclerosis, relentless worsening occurs. In the best-case scenario this progression occurs very slowly but in the worst-case more rapidly Long-term studies indicate that primary progressive patient become severely disabled in one functional system more quickly than relapsing-remitting MS patients but that once this milestone (EDSS 4) is reached, both primary progressive and relapsing-remitting MS patients progress to the use of a cane (EDSS 6) at a similar rate. (Confavreux and Vukusic 2014).
In the MS natural history study in London, Ontario, 1099 untreated patients with MS were followed from 1972 to 1998. At the onset of disease, 65% had relapsing remitting disease, 15% relapsing progressive disease, and about 20% had primary progressive disease. Patients with progressive disease from the start took a much shorter time to reach MS milestones than those with relapsing-remitting MS. These with progressive disease from the start took a median time of 1.4 years to become moderately disabled in one functional system but still is able to walk without a problem (EDSS 3) and only 4.5 years to require the use of a cane or walker (EDSS 6)(Ebers 1998).
I have been diagnosed with a radiological isolated syndrome . What can to happen?
A recent article by Lebrun-Frenay, C et al. discusses the likelihood of developing MS if you are diagnosed with a radiological isolated syndrome (Lebrun-Frenay, 2020). In this article, 451 patients diagnosed with a radiological isolated syndrome were evaluated. After 10 years. 51% had developed MS. 21 of the 173 patients who developed symptoms fulfilled criteria for PPMS. The risk of MS was higher if you were younger (age less than 37 years), had initial cerebrospinal fluid results characteristic of MS, or if your initial MRIs showed brainstem or spinal cord lesions. The probability of developing MS was 29% with one or more risk factors, 54% with 2 risk factors, 68% with 3 risk factors, and 87% with all four risk factors. The presence of gadolinium enhanced lesions on the baseline MRI was not associated with the risk of conversion but having gadolinium enhanced lesions on a follow up scan was associated with increased risk of having neurological symptoms and being diagnosed with MS.