RELAPSING & REMITTING MS

 When MS is still in the inflammatory stage, it does behave in different phases depending on the status at the moment. If MS is active(inflammatory), then it does act accordingly. Most of the common symptoms of MS for each patient become more troublesome (angry), and that patient becomes symptomatic and would seek help. Fatigue gets worse, sensory symptoms become more troublesome, limb weakness becomes more disabling, and balance would be affected as well. The patient loses his/her ability to perform as before this episode of relapse.

Some patients develop new significant symptoms of any nature, but mainly pain, muscle weakness, reduced walking ability, and increasing fatigue. Memory can be affected as a result.

In these circumstances, any patient with MS must seek advice from MS specialist nurse, general practitioner, or his/her neurologist via secretary or directly. 

Any of those three three teams would at first exclude any conditions might affect MS but not necessarily to a relapsing status such as infections (urinary or chest as commonest, but any other infections). MS relapse basically means: Exacerbation of the current symptoms or developing new symptoms lasting between 3 days and three months followed by at least 70% improvement with or without treatment. There is a flexibility among neurologists about the timing as some consider 2 days as least and up to six months as most. Every patient with a possible relapse must be assessed ideally by a neurologist to confirm the diagnosis of relapse, as this stage is very important on two aspects:

1. Considering medical intervention such as the use of steroids.
2. Considering disease modifying treatment according to the know criteria for this type of treatment.

A supportive measure for clinical judgement is Gadolinium enhanced MRI scan of the brain and at least cervical spine. Any signs of enhancement is indicative of active MS even when the clinical picture is not very strong.

Once the diagnosis is made for a relapse in MS, treatment must be considered as soon as possible to reduce the chances of further axonal(nerve fibre) damage which is irreversible and becomes cumulative which means increasing MS permanent disabilities.

In this space, I will try to mention available treatments at different stages of MS, and will try my best to make it simple and easy to understand.

There are many ways on how to tackle this subject, but I would expect the reader to seek information on the first instance then to learn some more details about the available medications, how they work, how much benefit, and what will be the long course effects and side effects. The reader in my view would also seek to learn about the new advances in this area.

 To start with, we need to be clear and honest in the field of treatment. We don’t know the causes of MS, hence, we don’t know in reality how to treat it. We are treating symptoms, and trying hard to slow down the disease course. We are also trying hard to make life for MS sufferers easier and more comfortable.

I think it is probably worth mentioning that, most of our efforts in the field of MS management have been concentrated on trying different medications and remedies based on our experience with these medications in other conditions, hence, the currently available medications are non-specific for MS, and obviously are not offering cure for this condition.

It is much easier to try a new treatment in a controlled 3-6 month study, as it is easy to do, has an expected positive outcome, and can be repeated some where else (re-producible).

In this scenario, I feel we are taking the easy option, and relying too much on the financial aspect as most of these studies are sponsored by drug companies whose main interest is profit. We don’t rely that much on scientific organisations or governmental institutions, who would be more interested in the outcome and better “real” choices for disease management.

I would be much happier to see more concentration on disease pathology and pathophysiology with special interest on finding the aetiology (causes) of the disease, then treat the condition by eliminating the offender. That way, we can achieve our real goal in MS… cure !.

I remember, in the early 80s, HIV was a horrible disease and it was frightening. initially, there were real efforts to control the disease, then more attention was paid to finding the cause of HIV, and it was found. Nowadays, HIV is not a big threat anymore, and there are very strong possibilities on curing the disease all together. Why we don’t do the same with MS?. 

I think, we need to spend more money and time looking for the real causes of MS, which, despite of the available theories, I believe is going to be viral in nature. Knowing the virus would obviously open the way for finding a cure. That is the way forward in my view, instead of dreaming about stem cell transplant and thinking of curing MS via enabling the damaged nerves to regrow. That way may help the current sufferers, but would not help preventing the disease.

Anyway, let me live with the reality and accept facts as they are !. I will mention about the currently available treatments for MS, and will consider that through the following three categories, leaving the rest in this connection to be mentioned under “advances” in managing MS. 

Treatment of MS can be discussed through the following 3 categories:

1. Treatment of MS exacerbations (relapses).
2. Treatment of MS complications.
3. Disease modifying therapy (DMT).

TREATMENT OF MS RELAPSES

The acute exacerbation of MS is called relapse. A relapse in MS is defined as: new significant symptoms lasting between 3 days and 3 months followed by at least 70% recovery to the previous status.

We do allow margins to this definition by accepting 2 days of genuine symptoms, and 6 months as the upper limit if the new symptoms are considered genuine.

Following a qualified clinical assessment by the neurologist and an outcome decision for a relapse, the next step is to try and identify the possible cause of this relapse when possible. We always try to exclude infection or treat it if it is identified.

The commonest infections in MS those lead to a relapsing episode are urinary tract infections and respiratory infections. Any other acute infection can cause relapse in MS.

Other possible causes of a relapse in MS include:

1. Major surgery.
2. Aggressive chemotherapy.
3. Extensive radiotherapy.
4. Major trauma.
5. Severe stress.
6. Post partal period of 2-3 weeks.
7. Withdrawal of any of the DMT.

Once a diagnosis of MS relapse is made, treatment must be started as soon as possible. The longer the relapse time with no treatment the more chance of developing new irreversible axonal degeneration.

The available treatments of an MS relapse include:

1. Steroids: Oral prednisolone, oral methyl prednisolone, and possible dexamethasone. Intravenous methyl prednisolone was probably the most commonly used steroids for MS relapses, but following the iv/oral methyl prednisolne study in 2014, it was found that both ways of delivering steroids proved to be more or less equivalent in both efficiency and side effects. The regimen we follow here is oral methyl prednisolone 500mg per day for 5 days, or intravenous methyl prednisolone 1000mg per day for 3 days. We are still using gastric mucosal protection when we give steroids, such as H2 receptor blockers e.g Ranitidine, or proton-pump inhibitors e.g Lansoprazole. I have to mention here that prednisolone is water soluble, hence, it has less bio-availability in the nervous system, and it lasts for shorter time within the body. Methyl prednisolone on the other and is a fat soluble, hence, its bio-availability in the nervous system is much better and it does last longer in the body. Another important point for MS patients to know: steroids in principle are anabolic (energy producers) and they do have anti-inflammatory effects. If steroids are used for any purpose, they can make you feel better for 5-7 days. That is not necessarily anti-inflammatory. It could be anabolic, hence, a positive effect for steroids is not an indication that it has improved a relapse in MS. Most of the time, the anti-inflammatory benefits of steroids in MS can last for up few weeks or even longer, by rendering a relapse into remission. Steroids can increase blood sugar (diabetes mellitus), and can affect the blood pressure control. They can also disturb sleeping at night, and they may make you feel hot and flushed. In connection to weight gain, I don’t think 3 or 5 days course would cause any significant weight gain in normal circumstances, and it is unlikely to affect bone metabolism or require bone protection if not given many times/year. Any other questions or queries in connection with steroids in MS will be answered once received. Oral prednisolone can be used. The regimen we follow is very simple: 40mg/day for 5 days, 25mg/day for 5 days, and 15mg/day for 5 days, then stop. Other regimens can be considered as long as between 2-3 weeks tapering done of steroids is followed.
2. Immunoglobulins e.g Vigam 400mg/Kg body weight/day for 5 days. Intra-venous IgG is not the best choice for relapsed MS, but there are conditions when they could be considered instead of steroids such as contra-indications for using steroids. They are very expensive in comparison with steroids.
3. Plasmapheresis (plasma exchange): plasma exchanges may reduce the amount of antibodies against the myelin sheath as well as some of the acute phase proteins which could induce a relapse in MS. Plasma exchange can prove to be more effective than steroids and immunoglobulins, but can some times be associated with dangerous side effects such as pulmonary embolism. Plasmapheresis can be reserved for few selected cases with  bad relapse, but the neurologist is probably the best person to decide about this type of treatment.

I have to mention here that, some times a relapse in MS can be resolved spontaneously with no need for intervention, especially the mild or sensory type of relapses.

DISEASE MODIFYING THERAPY (DMT)

There are two basic appraoches towards treating MS:

1. Stimulating remyelination:  Under research at the moment, but this is a very promising approach, and may lea to a full cure or at least full prevention of demyelinating diseases in the future. It is known from previous research work that LINGO-1 is a receptor expressed on oligodendrocytes(oligodyndrocytes are the myeline producing cells in the central nervous system). Activation inhibits oligodendrocyte differentiation and remyelination. On the other and, antagonising this inhibitor should therefore enhance remyelination, and anti-LINGO-1 antibodies augment myelin repair in various in vitro and animal models. Currently the known anti-Lingo-1 antibody known as Opicinumab is under trials for optic neuritis, but despite of the disappointing outcome from phase-II recent RENEW trial (The Lancet Neurology. Vol. 16, No. 3p189–199, March 2017), but it does open the way for more research on this area and the future will only be better and promising for MS sufferers.
2. Blocking inflammation: Via the use of different inflammatory blocking agents currently used in DMT.

DISEASE MODIFYING THERAPY (DMT)

Currently, there are three types of DMT available for therapeutic use:

1. The injectable preparations: Subcutaneous or intra-muscular.
2. The oral preparations.
3. The infusible(iv) preparations.

INJECTABLE PREPARATIONS

1. Glatiramer Acetate: Copaxone.
2. BIF type 1a: Avonex, Rebif.
3. BIF type 1b: Betaferon, Extavia.
4. Long acting preparations: Plegridy, Copaxone 40mg, and Glatiramer Acetate Depot 80mg.   

INFUSIBLE PREPARATIONS

1. Mitoxantrone (Novantrone)
2. Natalizumab (Tysabri)
3. Alemtuzumab (Lemtrada).
4. Rituximab (Mabthera).

5. Ocrelizumab (Ocrevus)

ORAL PREPARATIONS

1. Fingolimod(Gilenya).
2. Dimethyl Fumarate (Tecfidera).
3. Teriflunomide (Aubagio).
4. Cladribine (Mavenclad).
5. Ozanimod(Zeposia).