Why is multiple sclerosis research so hard?

RESEARCH on MS

1. Why is MS research so difficult?

   MS seems to be an inherently difficult disease to research. MS is so variable between different people that there don't seem to be common patterns that would provide a starting place for research. All of the most likely factors in MS development such as diet, environment, infectious agents, genetics, etc. have been looked at with only confusing and contradictory results. MS is also variable within one person which makes trying to assess the effects of possible treatments difficult.
   
   Also, the relapsing-remitting nature of many peoples' courses of MS can cause people to move in and out of symptoms even with no treatment with such wide variability that large numbers of patients are needed to try to tell the difference between a good result and the typical course of the disease.
   
   Which brings us to the next point:

2. What is a double-blind placebo controlled trial and why is it so important?

   In attempting to examine the validity of any treatment for any problem, there are two well known effects that confound the assessment. The "placebo effect" is a real phenomenum in which a patient will subjectively feel better and may even perform better on tests when he or she thinks that he or she is being treated by an authority figure, or believes he or she is receiving the actual treatment. Another problem is that the researcher doing the trial really wants the treatment to be effective. The researcher will unconsciously evaluate people receiving the treatment as doing better than people not receiving the treatment if he knows which are which. The double blind trial is designed to prevent these effects.

   In its simplest form, patients are randomly assigned to either receive the treatment being evaluated, or a placebo, a sham treatment which mimics the real treatment. Neither the patient, nor the researchers know which patients are in which groups. This way, the evaluation of the patient's progress is unbiased by any preknowledge of the possible treatment, and the patients don't know whether they are receiving the real treatment or the placebo. The trial ends at some predetermined stopping point which is chosen when the study is designed. At that time, the blind is broken and the results of the trial can be evaluated. More elaborate forms of this method evaluate in a double-blinded fashion one standard treatment against a new treatment, or different dosages of the same medication.
   
   Double blind treatments are often confounded by the fact that clues such as side effects orthe lack thereof may give the patient, the researchers, or both clues as to what group they are in.
   
   There are occasionally exceptions to the difficulties, due to the unquestionably clear signs and symptoms of certain problems, such as drugs used to treat Trigeminal Neuralgia, a brief but intense episodic pain for which certain drugs may not be tolerated due to side effects but there is no way to wish away the pain with a placebo effect (I had surgery to deal with it almost a decade ago, but have talked to others about medication trials). 

3. Why are all the new treatments evaluated for relapsing-remitting patients and not chronic-progressive?

   At this time, treatments that would repair myelin and reverse the damage caused by MS are still in only the earliest theoretical stages, so no treatments that are currently in the pipeline are expected to significantly restore lost function. Given this, the treatments currently being investigated are for slowing or halting progression of MS symptoms.

   In order to study any treatment modality, some objective criteria for evaluating the efficacy must be devised. Chronic-progressive MS exhibits only a slow decline of function which is hard to quantify. Two scales in common use for assessing function are notoriously unreliable and nonreproducible rendering them not well suited for a clinical study.

   In contrast, in relapsing-remitting MS, a number of criteria are easily devised. The main feature of relapsing-remitting MS is the exacerbation. It is easy to form a well agreed upon definition of an exacerbation. This leads to criteria for assessing the treatment such as: number of exacerbations in a given time period (typically one-two years), the time to first exacerbation after beginning treatment or the time between exacerbations. Somewhat more problematical is the severity of exacerbations, however there is rough agreement on whether a particular exacerbation results in a significant deficit which can be used as a study criterion.

   For these reasons, we see that relapsing-remitting MS is more often studied because it is easier to design a well formed study that can be expected to give good and reproducible results. However, it is not true that treatments chronic-progressive MS are not studied. Several trials are underway for prospective treatments for chronic-progressive MS, most notably of cladribine.
   
   In recent years, a third group has been formally identified, known as relapsing-remitting/secondary progressive. These people still have periodic MS exacerbations (relapses), but they have some chronic symptoms that do not go away when exacerbation symptoms do. Although this group is not formally considered to be in the chronic-progressive group, and although many neurologists consider them to be good candidates for treatment with Copaxone, Rebif, Avonex, or Betaseron, they will often not fit into the requirements for clinical studies (I myself was turned down for studies on Tysabri and NBI-5788 for this very reason).

4. What is the animal model for MS

   No animal naturally gets MS or anything resembling it. Researchers artificially induce a condition called Experimental Allergic Encephalomyelitis (EAE) in mice which mimics some features of MS in humans. Researchers inject myelin basic protein, a constituent of the myelin sheath, into a particularly susceptible strain of mouse. The mouse's immune system reacts against the myelin protein, and the response generalizes to include the mouse's own myelin. The immune system attack on the myelin results in apparent symptoms similar to MS symptoms.

   Most new treatments for MS are first tried on mice with EAE to determine whether the treatment can either protect the mouse from developing symptoms, or in some other way help the mouse. A note of caution is warranted here. In the last ten years or so, many substances have been heralded as showing promise for MS because they were in some way beneficial in EAE. Few of these have panned out in human clinical trials.