Flummoxed (Part 3 of ?)

I get a phone call from my youngest sister, PYT, a.k.a. Pretty Young Thing, just as I am flopping down in the driver’s seat after a lightweight workout with my toys at the gym.

PYT has three Young kids, four and under, who are competing with me for her attention. I win. Intermittently.

I tell her I’ve capitulated. I’m taking my new MS drug just as the doctor ordered, thirty minutes after an aspirin. “I splurged and got myself the kiddie kind.”

“The orange ones? The chewables? The ones that taste like mom loves you and everything is going to be OK?”

“Exactly.” Oh, it is great to talk to someone who knows precisely what the aspirin summons—not only the specific taste, but the specific aura our mother would convey while doling it out.

Now that I take Tecfidera after an aspirin, and a meal with a bit of fatty food—I love my avocado, I love my coconut milk—I don’t get a rash. Or an allergic reaction. Whichever. Dr. Z. had warned me it might take weeks for the rash to stop flaring up. The rash had stopped immediately.

And yet. I don’t trust the lack of rash. You know those times when your room is a mess and your mom has threatened to inspect and you shove all your miscellaneous underwear and books and socks and chewed pencils under your bed, and it’s still a mess but it’s a hidden mess? Well, PYT and I never did that. The hidden mess was our middle sister’s speciality.  (She’s the pragmatist of us three.)  Our  messes were always flagrant—out in the open. And no, we never got points for honesty. But we’d always thought we ought to. Go ahead, roll your eyes. This is not a sentiment I’m proud of.

Am I the same person now? Hell, no. I suspect I’m not the only person with MS passing (less and less often) in public as able-bodied while actively concealing I’m a total hidden mess.

PYT knows me, the past me, the one who’d railed against the hidden mess. She gets my reservation that maybe taking the aspirin is just the same as shoving a mess under the bed. Does the aspirin genuinely alleviate my body’s resistance to the drug, or does it just push the resistance under the surface, where it can’t be seen?

We ponder this distinction as my four year old nephew explores the new paint he’s created by reconstituting dried out markers and as his twin sister mixes that paint with an entirely unacceptable color and as their younger brother decides it’s time to pee.

We wonder if the new drug is even worth it, given the conclusion of the meta-analysis of over 28,000 MS patients from 38 clinical trials that most current DMTs (Disease Modifying Treatments) are fairly useless for the average patient by the time they reach my age. We ponder Dr. Z’s point that I might be an “outlier” — which sounds kind of cool — unless “outlier” means that without drugs I might be the one to get hit with an exacerbation that could permanently disable me further. His distress over this possibility is nothing to dismiss. I’ve looked around his waiting room. Not everyone with MS has the luxury of describing themselves as a hidden mess.

I share the latest conclusion about the three types of MS—which is that relapsing/remitting, secondary progressive, and primary progressive MS are not three different diseases, but rather, three phases of the same disease. The FDA approved DMTs may prevent relapses, but do nothing for other processes known as “compartmentalized inflammation,” which do not show up on MRI’s.  These are the messes under the bed, so to speak. Or more specifically, the messes inside the cells.

We speculate that maybe all those years I had credited Zinbryta for stopping my MS attacks, the change could have really been more of function of my slipping insidiously from relapsing remitting MS into a more progressive phase of a disease, where the breakdown can’t be detected by the MRI, but rather, by the lumbar puncture.

“It’s like a vicious dog that hasn’t bit anyone in twelve years on a muzzle, and I’ve credited the muzzle. But maybe the dog has just mellowed out with age.”

PYT chimes in, “And maybe the muzzle has been annoying for the poor dog.”

PYT and I are both dog lovers. We aren’t fond of muzzles.

I say, “Maybe we just have to be realistic about my MS. It’s a progressive disease. Slowly but steadily, I’ve been progressing. The drugs that work to stop relapsing remitting MS can’t do a thing about the kind of progression I’m experiencing inside my cells. Maybe it’s time to stop fooling ourselves by my taking a drug that only helps for an early stage of MS. I might be way past that phase.”

PYT says, “It sounds to me like you have taken your last Tecfidera.”

My flummoxed feeling is lifting. I starting to feel like myself again. (Talking with a sister will do that.) I share the last thing Dr. Z. said to me, “I will support you even if you don’t want to take any medication.”

His unconditional support means so much. PYT warns me that our mother and my husband will resist my urge to give up the medication. “As they should. They love you. They want to protect you.”

Protect…me? When we were growing up, I never cast myself as the damsel in distress. But that’s the role MS has forced me to play my entire adult life.




17 thoughts on “Flummoxed (Part 3 of ?)

  1. I have a question, you mentioned that RR-MS could be measured by MRIs, I assume by counting if you have any new lesions & if they are active? new?

    Can SP-MS be measured by lumbar punctures? The # of rings? Do you know if Dr. Wahls rings disappeared as she got better? Or if her scars went away on her brain or spinal cord? Can the Wahls Protocol do that?! Any other diet or drug?

    1. RR-MS is generally measured by lesions. I’ve had only one new lesion in 12 years. By that measure, the daclizumab treatment was a success. But I have also had some brain atrophy, which is something you can measure by MRI. The lumbar puncture detects that cellular damage I was talking about, a feature of all forms of MS, which gets more prominent as the years go by. Autoimmune Protocol (AIP) diets such as The Wahls Diet aim to rebuild the cellular structures through nutrition. I’m all for it, though I’m not the biggest fan of the cult of Wahls. I’ll try to address these topics more thoroughly soon.

  2. You are a great writer, it is always a blessing and enlightenment to read you, thank you.

    So many things:

    Progressive MS may not be like secondary progressive MS. For one thing, it seems like many people classified with secondary progressive are on the spectrum of still being partially relapsing-remitting, like, going from RR to SP MS is a continuum, not a switch, maybe? So even if you’re 55% secondary progressive, you’re still 45% relapsing-remitting? IF that’s so, then medicine might still be 45% effective? Another difference is lesions in RR are mostly seen in brain MRIs and primary progressive by spine MRIs, so does that mean RR that’s turning into SP would still be measurable by lesions that turn up mostly on brain MRIs?

    I think there has got to be other ways of determining disability besides symptoms (progressive means getting worse all the time) and MRIs (on brain or spine). Because, yes, you can get worse with progressive MS and not have any new lesions on an MRI, but wouldn’t you still have increased inflammation that would show on a CRP—C-reactive Protein test? And aren’t there other measures that would also be trackable?

    It seems important to figure out how to measure inflammation because, I think, inflammation tracks disability and we can reduce inflammation with diet and exercise (a la Wahls Protocol and other related diets). (I know disability doesn’t correspond with inflammation as strongly for folks with primary progressive MS, happily you don’t have PP MS.)

    And this is some real hope since there are plenty of people with MS for 10 or 20 years who have never had a relapse (or people who have never had a relapse after being on Wahls for a long time). Or so they say. Unfortunately, I don’t know them but this one fellow, Matt Embry, has a pretty impressive video, website, and story (http://mshope.com). I could name others I’ve read online.

    1. Yes! There is no doubt it’s all about cutting down inflammation. That’s why I follow a diet like Wahls. There’s a lot more to say about the distinctions between the types of progression, but the bottom line seems to be we can all relax about it. Turns out, they were arbitrary labels. (As labels often are.) I’ll write more about that, if you are interested. Here’s another paragraph from that paper I’ve been citing: This debate is confounded by the widely accepted classification of MS patients into relapsing-remitting (RRMS), secondary-progressive (SPMS), and primary-progressive MS (PPMS) subtypes. While these phenotypical categories prove useful in clinical trial designs and conceptual thinking about MS, they de facto dichotomize the continuous process of MS evolution. Indeed, a patient with MS does not go to sleep one day with RRMS and wake up next day with SPMS. Instead, there is a period, often lasting several patient-years, in which a clinician encounters considerable uncertainty in differentiating RRMS from SPMS. An analogous uncertainty is frequently encountered in differentiating SPMS from PPMS based on ambiguity in recollecting event(s) in a patient’s history which may or may not represent MS relapses.

  3. Science-paper-reading person here.

    So…it took me a little while to see what the issues are, but I think you’re responding to two different things.

    One, the age thing. It’s important to keep in mind that in science, facts are built more than they’re discovered. It’s not like you fall over penicillin and say “hey, it’s penicillin, it’s going to save millions of lives.” It’s that you get mold doing a weird thing and it seems to kill some bacteria, so maybe you wonder does it kill other bacteria (because that’s an easy question), and when it turns out it does, you start wondering (because you’re a semi-crazy doctor doing science) whether maybe it kills bacteria *in people who have bacterial infections*, and even back in those days of no IRB or anything, it’s ages before you get to anything you might actually put anywhere near a sick person…and then it’s years and years and years before you find out that it’s not a silver bullet after all because the bacteria evolve resistance, and the picture is actually quite complex, and we still don’t really understand how it works after all.

    I call these conjectures-that-might-be-received-wisdom-someday “factulas”. What you have in this paper, with its bold assertions about age and drug efficacy, is a baby factula. It’s got an awesome birth announcement and it comes from science facts that belong to the country club, but it’s still just a factula. It may never grow up to be a fact.

    In more sciencey terms, these people are proposing a model. It’ll be the job of other teams to knock holes in it or say “yes but” and “this assumption is no good” and so on. This is NIH and NSF grant-proposal fodder for the next five-ten years.

    What’s more interesting to me is your intuition that if you have to take a drug to stop a violent rash from a drug that’s supposed to be working to interrupt inflammation, something might be wrong. And you might be right. Or you might be wrong. So here, as an amateur, I’m falling back on the biochem/mol-bio training I’ve had, which isn’t much.

    In biochemistry, the world is conceived as a circuit board. A tangle of on/off switches. This molecule activates this set of reactions; this shuts it off. That’s the high-level view. Go down to the level of atoms and molecules in the cells, and it looks more like that 1-2-3 Rube Goldberg machine from Sesame Street. This molecule bumps into those and sends them doing X; they hit other molecules and send them doing Y. Aspirin works to stop inflammation by sticking atoms on another molecule, one that’s in the inflammatory Rube Goldberg machine, so it can’t fit into the next roller-coaster car that’s supposed to make something else happen.

    So the question for me is how this new drug supposedly works: is this aspirin-stoppable rollercoaster the only “extra” it gives you? It could be the makers don’t know, but odds aren’t purely awful that they do, or at least that they have a good guess. It could be that the new drug does a pretty awesome job of turning off other, more dangerous inflammatory processes, but along the way it turns on just one that aspirin can take care of just fine.

    What would worry me, if it were me, is that it appears to turn it on *so hard*. I’d also be wondering what other, more subtle inflammatory processes it’s turning on. And it appears that you are, too. And since you are indeed the lab rat, you have more at stake here than the drugmakers do.

    I think if it were me, I would inquire into the earlier studies from this drug and see if you can see anything there, and after that my main consideration would still be the violence of the reaction. I’d actually be less interested in the new model that says old people get little benefit from the drugs — it’s just too new an idea, and there’s too much incentive to have splashy new ideas, even if they only last three years before someone knocks them down. You can get hella funding in three years, and by then you’re on to something else. Maybe you’ve even knocked down or refined your own model substantially.

    (all new sci writing above so if something there’s unclear, let me know.)

    that the authors aren’t discovering penicillin, here: they’re proposing a model, an idea about They’ve looked at a pretty good number of studies that have enrolled

    1. Thank you for understanding and articulating why the rash bothers me so much! The most effective MS treatment I personally practice is to tip-toe as far as possible around any possible disturbance that can set off inflammation. I’m so committed, I even workshop student papers radically differently than I did when in grad school. For instance, I had one student a few years back who wrote what I considered sloppy sentences introducing characters by writing, “the door handle turned.” Old, inflamed, Conroy-style me would have said: “You can skip an actual entrance when you introduce a character. This is fiction: your character should be bound by certain unique qualities you should begin to establish with the first appearance, which need not take place with the quotidian tedium of an entrance through a door. And let’s read that entrance aloud, shall we, ‘the door handle turned.’ Interesting. This door handle is quite a character. It actively turns. Whereas your new character is a passive sprite….” blah blah. Sucking all the energy in the room off the page and onto me. I didn’t want to torture my student. Or myself. But I took my snarky passive-voice observation and ran with it—the other direction. After my students made their observations about the work, and the author made his, I announced he was kind of a genius. I said, quite truthfully, I never encounter this kind of writing, and wondered if he was inventing a new form. I cited all places I’d meticulously underlined where he had inanimate objects performing activities, “the closest thing I’ve seen to this effect is that scene where all the objects in the kitchen come alive in that Disney masterpiece…what’s the name of it? Yes. Beauty and the Beast. That was a great scene.” Every time that kid handed something in, I persisted with the experiment. Other students would defer to him. Praise him. And over the semester, his writing got vividly descriptive. By the last paper, the passive voice had disappeared. That experiment taught me it is more effective to be encouraging than disparaging.

    2. Judging by the opening of your comment, I see you’ve learned the anti-Conroy approach as well.
      Frustratingly, I haven’t been able to get anyone to describe how they think this drug works. I asked to speak to a pharmacist just yesterday while on the phone with the drug supplier and he just read something mechanistically and showed no level of understanding or interest. So I have to find some other pharmacist. The best argument I’ve heard for this drug so far is that it’s the most popular.
      I hear meth is very popular.

      1. Good for you for persisting and asking HOW does this drug work. That’s very helpful to know that going from RR MS to SP MS is a longer progression, not a quick switch. Crazy that doctors frequently can’t tell if someone is RR-MS or SP-MS, it is amazing that there aren’t tests that can measure inflammation that could help determine this. Does your doctor measure your inflammation with a C-RAP test or any other tests? Being that SP-MS is characterized by having less inflammation than RR-MS then tests for inflammation, over time, should be able to help with this, right?

        My doctor never measures or cares about my level of inflammation which doesn’t give me much confidence in her. I’m trying to learn how other people’s doctors measure inflammation so I can advocate for myself with her. So, thank you for any info.

      2. My neurologists at the NIH use a new, highly sensitive scale called combiWISE. You could ask to see how you score on that scale. If you are truly interested in a high tech evaluation, consider joining the TRAP trial at the NIH. The NIH pays for your travel, room and board, and whatever medication they are testing. The TRAP trial investigates possible supplemental treatments to take care of the disease processes the current FDA approved medications are not addressing. If you are on an MS medication you like, you can stay on it. But they will pick a medication currently approved for a different use that they hope might give you a more comprehensive treatment of your MS. Joining an NIH trial allows you to develop relationships with researchers doing the most cutting edge work, so you learn a lot along the way. (Also, the results from all the free testing there, including MRI’s, can be sent to your neurologist at home, significantly cutting down your health care costs.) If you want to explore that route, I’d be happy to answer any other questions you may have. We all deserve full participation in our care. You would get that, there.

      3. Okay – so the best thing I’ve found in an hour’s roaming around to see about the mechanisms is this: https://doi.org/10.1016/j.bbrc.2016.05.021 . It explains (if you’ve got enough biochem) why you have to take aspirin. I don’t love the reasoning.

        How the drug works, approximately, according to this careful-sounding study: the key phrase is “DMF stimulates cAMP production via EP2”. EP2 (https://en.wikipedia.org/wiki/Prostaglandin_EP2_receptor) is a membrane-bound receptor stimulated by PGE2, a prostaglandin derivative. Prostaglandins, as you probably know, are implicated in inflammation. When PGE2 binds to EP2, that sets off a chain of events inside the cell leading to more cAMP production; cAMP’s a little molecule, a “messenger”, that turns on lots of other circuitry, some of which is to do with inflammation. You can read about the excitement over the anti-inflammatory circuitry here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814577/

        There’s a question there about whether DMF makes more PGE2 happen or just goes and does the job itseslf, binding to EP2, and the answer appears to be “it does it by itself”. The problem is that since you’ve got MS, you’ve probably got elevated levels of PGE2 anyway in your CSF, and it turns out that PGE2 + DMF gives you a word I don’t like: synergy. “Synergy” means “wow, a surprising lot happens this way, like more than you’d expect if you added the individual effects of Tecfidera and the ambient PGE2, and we really have no idea why.”

        Apparently this synergy is not doing pleasing things in you, which is why you have to take aspirin. Aspirin deactivates the enzyme (COX) that makes prostaglandin, meaning you don’t get the PGE2 downstream, and not so much…synergy with the Tecfidera.

        So when I read that, I thought: okay, this drug monkeys directly with potent pro-and-anti-inflammatory circuitry, and it does it in ways we don’t understand. That’s not great. The results in the trials look nice, but those are trials.

        On the other hand, if EP2 is its main action of mechanism, and the only other molecule working on EP2 is PGE2, then on that side of the action, there probably isn’t any other circuitry you have to worry about.

        But: the other thing I don’t really love is that the drug makes more cAMP happen. cAMP is part of approximately six bazillion cell processes, many of which have nothing to do with inflammation – you can read about that here: https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate. But because it appears to be important in inflammatory processes, it’s a drug target. So yes, god knows what else is happening with the jacked-up cAMP levels. On that side of things there’s plenty of unknowns to worry about.

        But — and here’s the thing I don’t really get — the body’s pretty good about homeostasis. If you’re really jacking those cAMP levels, and it’s throwing other things out of whack, sooner or later mechanisms to throttle back cAMP will kick in…that, or I guess the cells will have to do some weird contortions to undo the effects of too much cAMP on other processes downstream. Which means I wonder how this drug can be effective for very long anyway. Maybe it steps on the gas *so* hard that the counterbalancing changes are more than the cells can manage? I don’t know.

        Bottom line: this sounds to me like a serious drug. It may not be the only cAMP enhancer you’ve met; that Frontiers review suggests there’ll be more. The first comparisons I think of are potently psychoactive drugs that also interfere seriously with metabolism and chemotherapeutic drugs that damage healthy cells, but damage cancerous cells faster. This is also a new drug, meaning that there are no studies showing what its long-term cAMP amplification means (maybe there are other studies of older cAMP-enhancing drugs?).

        On the other hand, you’ve got a serious disease. I guess there’s this question of what it’s reasonable to pay to kill some inflammation.

        My search terms were COX, PGE2, dimethyl fumarate, and upregulation, but if you’re looking for followups to this paper I’d stick with cAMP, PGE2, EP2, and DMF.

        oh yeah, and pharmacists hardly ever know about this stuff.

        🙂 more about the writing tomorrow. sleep time now.

      4. Well, on reread that paper discussion’s not all that clear to anyone who hasn’t had their head stuck in scientific papers the last several years, so my apologies for that. The main takeaway: this drug’s fiddling with the kitchen lights by hacking the electrical main from the street, and I’m not convinced that this is a brilliant idea, even though you can indeed control the kitchen lights that way and the house hasn’t burnt down or anything. Cue a few dozen teams of drug developers shouting “but it works real good! You figure it out another way if you’re so smart!”

        About the anti-Conroy: I’ve had to do a lot of thinking over the last few years about what my teaching’s for. Most of my students — from undergrads to faculty — aren’t writers, or at least they don’t think of themselves as writers, except in a narrow “I have to write this paper or I won’t get my grade/degree/funding/credit” sort of way. Often they’ll say apologetically/defensively that they aren’t writers. So not much of my teaching’s to do with the sound and shape of individual words, or any of the kind of precision and reverb you find in literary writing. It’s mostly about — at grad level and up — taking complex and often foggy, intuitive ideas about very exciting things that might not be real and figuring out how to tell other people about them, but without burying it all under formalities or sounding like a jackass who thinks they’ve just saved the world. And without either insulting the audience or talking over their heads. With the undergrads, a lot of the work’s about developing the thoughts, first, and then figuring out how to put them across. It’s a tall order either way. Hardest of all is when they have to write about themselves after years of aggressive training in not doing that.

        So I don’t want to squash any of them. They aren’t showing up with massive ego about their writing in the first place. And, to my enormous surprise, they often improve. It’s possible for this to happen. I have the luxury of working with some of them for years in a row, too, so we can get into deeper and better problems as we go. The nicest thing is when they send me something to critique or edit, and it’s just really good, and then I can say, “What do you need me for? This is terrific.” They’re really shocked when that happens.

        I don’t think any of it’s as important as a good story, but some of the work has been good. There was a paper in Science a few years ago that I helped get the funding for, and it was accepted only after I rewrote the intro, which was initially too chemical; the scientist didn’t know how to broaden it. That paper has a key for making drugs that can actually cure TB, anthrax, and several other diseases that can’t currently be cured, and the wonderful thing is it works by a mechanism that humans don’t have. It only works on the bacterial cells. I came in for about the last third of that story — that was about ten years’ research that went into that. So that was worth doing. But it’s not a story, or an opera, or anything like that. <–I'm aware this is a weird way of valuing things. Just me.

        I don't know what kind of a teacher I'd be if I taught Workshop-level kids. I'm still kind of with Flannery O'Connor on the whole workshop thing, and it's easier for me to see now that the things that were apparent after our first year or so — that we all, or most of us, learned a lot the first year, and the problems that were left were really flaws of character or inexperience. 25 years on, it's easier to see what becomes of those kinds of flaws, in writers, and how people deepen and lose the inexperience or go and hide. So maybe I can see why Marilynne was looking into us when she was reading our stories — after a while you can see, okay, what does this one have, is this one it's worth exhausting yourself over a little bit, and being as hard on them as they need. I'm also a lot more aware of why people stop writing. I think it's true that the people who've really kept on, to the point of actually writing the books and the stories and keeping on going, are on the whole the ones who could afford to. Money, health, liberty from other obligations. I'm guessing that if you're teaching those kinds of students, after a while you begin see all that in them, too, what their odds are. Not to mention whether or not they appear to have anything of their own, something strong in the voice and fictional worlds that might carry them through trouble. So I think if I were teaching those kinds of students, all that plus the obligation to do the best writing, the sort of thing that's actually worth devoting a life to, and puts on the page a mind and voice and vision that generations not yet born will feel is telling them something not just important but necessary, I think I would probably be much harder. And it would be a much more exhausting job. I don't know how you protect yourself in a job like that.

        On the other hand I've had only two seriously talented students in the last five years; one of them couldn't hold it together, the other worked for me a while — an artist-designer, not a writer — and then went to the Art Institute. The designer kid wanted initially to do the headlines for our magazine in Bodoni, and I left him alone about it, because it's something you have to go through, being in love with Bodoni. But he came in one day with a much better idea, quite a refined typeface with a much stronger intent, and instead of jumping all over him with congratulations I surprised myself by getting very cool and just nodding at it and asking him what made him decide that. Which surprised him: he didn't know, but he went away recognizing that it was a question. I didn't want to get my hands all over it when he was doing a good thing, I just wanted him to notice on his own what the good thing was, I wanted the recognition to be his own, instead of being told someone else's idea about why a thing was good. I also made him cry at one point, which felt absolutely terrible. But it was time for him to stop fucking around, and he did. If I'd known a better way, I'd have used it. I didn't.

        It's a privilege, you know, so you have to be careful. People are trusting you. I think that's it.

      5. Isn’t it a privilege to be able to assist the realization of a worthy goal? That paper sounds worthy, indeed. It would’ve been a shame if all that research never managed to be conveyed with : Meaning, Sense & Clarity, as Frank would say. My technique is not so much anti-Conroy (I loved the man) but un-Conroy.

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