The words “progressive multiple sclerosis” carry with them a sense of dread and panic for most MS patients. When I was newly diagnosed, I of course immediately hit the Internet, and discovered that there were four primary types of multiple sclerosis: Relapsing Remitting MS (RRMS), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS), and Progressive Relapsing MS (PRMS). It only took an hour or so of reading for me to realize that the progressive forms of the disease (SPMS, PPMS, and PRMS) were very scary indeed. Not that RRMS is any picnic, but patients with progressive MS have few if any treatment options, and generally suffer much more aggressive disease and a quicker rate of disability. My mind immediately rejected the notion that I might have one of these forms of MS, but as time played out and the course of my disease became clear, I was given the diagnosis I had come to suspect but refused to accept: PPMS. Now, after eight years, that diagnosis itself has come into question (click here), but still, the clinical course my disease most resembles is PPMS.
A spin around the Internet MS forums quickly reveals that there is much confusion about progressive MS among much of the MS population, especially the newly diagnosed. It’s extremely important for patients to understand the differences between the MS subtypes, as treatment and symptom management options vary widely, and informed decisions can only be made if a patient has a good grasp on just what they’re dealing with. There are several good sites that explain the differences between the MS subtypes (click here for one), so I won’t go into an in-depth discussion of their differences here. In a nutshell, RRMS (which represents about 85% of the MS population) is marked by the disease course that features distinct relapses and remissions. During a relapse, an RRMS patient experiences an acute worsening of symptoms, often to a very debilitating degree. This is followed by a period of remission, when the patient reverts more or less back to normal, sometimes suffering from residual effects that remain from their previous relapses. After a period of years, a majority of RRMS patients transition to SPMS (click here for more info), when they stop experiencing relapses and remissions and instead start suffering from a steady increase in disability, with none of the distinct “ups and downs” of RRMS. In addition to a lack of relapses and remissions, SPMS patients also experience a severe reduction in the amount of inflammation seen in their central nervous systems, despite the ongoing nature of their disease.
PPMS patients (about 10% of the MS population) never experience periods of relapses and remissions, but instead suffer a steady decline in functionality from the onset of their disease. PPMS is distinct in many ways from the other forms of MS, so much so that some doctors and researchers think that it may in fact be a completely different disease. Unlike RRMS, PPMS attacks men and women in equal numbers. MRIs reveal that PPMS patients generally have less lesions than RRMS patients but usually exhibit more spinal lesions, and even though their lesion load is less, quite often their disease is much more aggressive and debilitating. Additionally, spinal fluid analysis is usually less definitive for PPMS patients, as they sometimes don’t exhibit the telltale O-bands seen in about 95% of RRMS patients. Additionally, PPMS patients don’t exhibit the widespread central nervous system inflammation that is one of the hallmarks of RRMS.
PRMS (about 5% of the MS population) is the rarest common form of MS, and patients afflicted with it experience a steady decline punctuated by acute exacerbations, which are not followed by remissions. This is generally the most aggressive form of the disease.
In my 8+ years of haunting various MS Internet forums, I’ve seen many patients confused about the differences between SPMS and PPMS, often wondering which variant of the disease they are suffering from. The difference is actually quite clear; if a patient has ever experienced a period of relapses and remissions, then they by definition cannot have PPMS. Anybody who has previously received a definite diagnosis of RRMS, and has experienced exacerbations followed by periods of relief, but now finds that they are now facing a decrease in relapses but a steady increase in symptoms, is likely transitioning to SPMS.
Almost all of the approved MS drug therapies are meant for RRMS patients and are effective to varying degrees in reducing the amount of relapses suffered by the patients taking them, benefits which are accomplished by modulating or suppressing the systemic immune system. At the present time, there is only one drug approved for SPMS patients, the chemotherapy agent Novantrone, and there are no proven effective treatments for PPMS. Often, MS Neuros will try some of the approved therapies on their progressive patients (usually their SPMS patients), in the hopes of positively impacting the disease, but these attempts generally prove to be unsuccessful.
Because of the aggressive nature of progressive multiple sclerosis, and the extreme difficulties in treating it, progressive MS remains a frightening proposition for patients and a confounding problem for the physicians trying to treat them. Often, treatment is limited to symptom management because none of the approved MS treatments, most of which work in one way or another to reduce inflammation in the central nervous system, have any positive effect on progressive MS patients who typically exhibit little or no CNS inflammation. One of the prevailing mysteries of MS is why, in the face of this lack of inflammation, the disease continues to progress without hesitation.
Research conducted over the past few years has started to shed light on some of the mechanisms at play in progressive MS. It appears that, at least in some of progressive MS patients (and especially in SPMS patients), a kind of rogue immune system develops within the patients’ central nervous system, which operates independently from the greater systemic immune system (click here, here, and here). This “immune system within an immune system” is comprised of lymphatic tissue (the kind that produces immune system cells) which develops within the CNS, safe behind the blood brain barrier. These lymphatic tissues produce immune cells (primarily B cells), which it is believed drive the continuing disease process seen in progressive MS. Because this process occurs behind the blood brain barrier, which functions to sequester the CNS from toxins and pathogens that might attack the rest of the body, it is protected from the drugs effective in treating RRMS, which work by down regulating the systemic immune system but have no effect within the central nervous system itself. This explains why drugs like Tysabri, which despite its known potential problems is very effective in treating RRMS, have little or no efficacy in treating the progressive forms of the disease. The drugs simply have no access to the self-contained immune process that appears to be taking place within the central nervous system in some progressive MS patients.
The implications of these discoveries are tremendous. They suggest that therapies delivered directly into the central nervous system may be effective in treating progressive MS, and indeed, one study has demonstrated that intrathecal (spinal) injections of methotrexate do seem to be effective in treating progressive MS (click here [full disclosure, this study was conducted by my neuro, Dr. Saud Sadiq]). The NIH is currently conducting a study testing the effectiveness of intrathecal Rituxan in SPMS patients (click here). This also illustrates the importance of research done very recently that has demonstrated a possible method for temporarily opening up the blood brain barrier, allowing for delivery of drugs into the CNS (click here).
Furthermore, the development of immune cell producing tissues within the central nervous system means that addressing many of the suspected MS triggers (viruses, toxins, possibly CCSVI) would have little or no effect on the disease once this rogue immune system is in place. Indeed, we do have anecdotal reports that CCSVI treatment appears to be less effective in patients suffering from the progressive forms of multiple sclerosis, and none of the approved RRMS drug therapies has been shown to be of any benefit for progressive patients.
It took me quite some time to grasp the implications of this “rogue immune system” theory, but I’ve developed the following analogy that I think illustrates the problem fairly well. Imagine a lit match being held to a sheet of paper. The lit match represents whatever it is that triggers MS and the early RRMS stage of the disease, and the sheet of paper represents progressive MS. Once the match touches the paper and ignites it, extinguishing that match will have no effect whatsoever on the burning sheet of paper. Likewise, once a compartmentalized immune system develops within the CNS (the burning sheet of paper), extinguishing the conditions which allowed for it to develop (the lit match) will be ineffective in curtailing the disease. Indeed, this is exactly what we do see with current accepted MS treatment modalities, and, anecdotally at least, in the treatment of CCSVI.
Therefore, the possibility exists that there is a window of opportunity before these lymphatic tissues develop and the disease goes progressive during which the treatment of MS has its best chance of curtailing the advance of the disease.
Clearly, research priorities must be shifted to definitively identifying the underlying causes that initiate the aberrant immune response seen in MS, rather than simply finding new and more profitable ways of suppressing the immune system, many of which are of questionable effectiveness in stopping RRMS from transitioning to progressive disease (click here). Plainly, there are processes driving the disease even in its earliest stages that are not directly related to the systemic immune system. We must also learn if progressive disease is in fact driven in large part by a self perpetuating immune reaction developing within the CNS, and if so identify which progressive patients are suffering from this development, and of course also find safe and effective methods to fight it.
Science is finally beginning to tease apart the intricate puzzle of multiple sclerosis, but vigorous and innovative research is urgently required, as is a shift away from much of the current thinking about the disease, which has proven hugely profitable to Big Pharma, but of little value when it comes to eradicating MS. Real hope is on the horizon, but new maps must be drawn to finally deliver MS patients to the promised land.
This article was originally published on Marc’s website on 10/12/11 and is being featured on MultipleSclerosis.net with his permission.