WPI’s collaborative research projects are revealing the infectious and inflammatory nature of neuro-immune diseases, providing strong evidence against the use of CBT and exercise therapy as rational “treatments” for those who are ill. Such knowledge underscores the urgent need for much more private and federal funding of biological research to provide diagnostic tests and effective drug therapies for the millions who are ill, stop the spread of infectious retrovirus(es), and end the devastating cycle of disease.

Annette Whittemore
President
Whittemore Peterson Institute

Link to original letter

Unfortunately, fulfilling my prime directive here involves reporting the bad news with the good. I’m in the process of reemerging following a full-on crash. I was down for the count for three days. Worst crash in over a year. I think the culprit was a very long walk at the LA airport where I had to change planes on the way home. It was more exercise than I’ve had in years. When I realized how far it was, I asked for a wheelchair and was told it would take too long. I tried to make it, but ended up unable to take another step, sitting down at the feet of a security guard (yes, lazy, crazy and faking once again). After I talked them out of an ambulance, they got me a chair complete with a lovely young man to push. I won’t make that mistake again. Arrange for the chair ahead of time. I felt fine that night, low energy for a few days but OK, then straight down the tubes. Probably all more familiar to many of you than it is to me. When I was really sick, I wasn’t able to do enough to experience PEM; I had it all the time, so wasn’t so aware of the cause/effect. Before that, I didn’t have it, and could still exercise without adverse consequences. I’m learning what my limitations are at this level of health. Very disappointing that the drugs didn’t prevent it, but facts are facts.

It was classic CFS post-exertional malaise (PEM), in case anyone was doubting my real diagnosis. Magical thinking pretty clearly isn’t going to get me through this one. I have to deal with the reality of my limitations and try to stack the odds in favor of function. It would seem that I’ve become a hothouse flower. I’ll have to figure out how to pace myself to avoid the payback. I guess I needed to be reminded what the stakes are. Maybe I was getting complacent, thinking temperament could win out. It is a formidable opponent, never to be underestimated. Rather, we must use our evolving model of the illness to understand the pathophysiology and fashion meaningful interventions. In hindsight, it was predictable and I’m wondering if O2, IV saline and possibly a pulse of hydrocortisone wouldn’t have headed it off at the pass.

The literature on the pathophysiology of post-exertional malaise in CFS is pretty scanty:

• Postexertional Malaise in Women with Chronic Fatigue Syndrome. VanNess 
• Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome. Suarez 
• Chronic fatigue syndrome… a model based on inflammatory and oxidative and nitrosative stress pathways. Maes
• CBT/GET is … potentially harmful for many patients with ME/CFS. Twisk

Reduced glutathione (GSH) drops markedly in the liver with strenuous exercise – as a normal consequence. There is substantial evidence that patients with HIV, CFS and autism have GSH depletion. Skeletal muscle competes with the immune system for limited GSH supplies. GSH depletion is immune suppressive and favors viral activation. If the patient is GSH depleted at baseline, then exercise is going to produce marked abnormalities in multiple systems, especially in deconditioned skeletal muscle.

• Glutathione depletion in rested and exercised mice: biochemical consequence and adaptation. Leeuwenburgh
• The physiology of exercise intolerance in patients with myalgic encephalomyelitis (ME) and the utility of graded exercise therapy. Pierce (unpublished in the peer reviewed literature)

Here’s an intriguing paper with respect to the treatment of GSH depletion in LP-BM5 infected mice:
Inhibition of murine AIDS by pro-glutathione (GSH) molecules. Fraternale

Other simple retroviruses may produce disease in humans in similar ways to XMRV. Some people who seem clinically as if they should have X, are testing negative, even though their diseases look the same as the people who do test positive. It’s very difficult clinically. We know enough to strongly suspect other HMRV’s and possibly other animal retroviruses are present. There is no ability to identify them in humans at this time. The most that can be said is there is or isn’t XMRV detected by culture. The available serology test probably picks up the P variants as well as X, but is negative in some culture positive patients (both very sick and not so sick with this profile). More questions than answers.

The hardest truth of all approaching the end of this momentous year for neuroimmune illness patients is that the results of the first informal unpiloted trial of antiretrovirals for XMRV infection suggest that antiretrovirals don’t produce a remission for most. It is clear that they move the illness, but for those who have been sick for a long time, it seems that the drugs don’t fix it, at least so far. There is still very little experience with all three drugs for any length of time, but Ali and I are approaching ten months on treatment and our recovery is still incomplete, especially with respect to our ability to push the envelope. Most patients taking antiretrovirals are reporting very modest or no gains on various combinations of the drugs for various lengths of time. In general, antiretrovirals have been well tolerated. Initially symptoms flare for most, but because of the possibility of encouraging resistance, full HIV doses seem prudent nevertheless. For a small number of people, this period of symptom exacerbation has been prolonged, beyond weeks. There have been a couple of ER visits for early adverse reactions, but both patients ended up tolerating the drugs afterwards. A couple of people went off AZT for possible problems, but went back on. It is still possible that slow improvement will continue over a long period of time, that the drugs will prevent further deterioration or prevent cancer. They are not difficult to take. Neither Ali nor I can tell that we are taking them in any way. In my opinion, clinical trials that don’t anticipate short term problems with underwhelming results at six months, will fail to show benefit. Quantitative measures will be necessary. Adjuncts will be necessary. Rehab will be necessary. It’s going to be a steep climb. But given that these three drugs are the only antiretrovirals we have, it is vital that they not be dismissed prematurely. It may well be worth it for partial recovery. And it is still quite possible that antiretrovirals will prevent activation in the not yet sick or simply work in the newly sick. There may also be a place for post-exposure prophyllaxis. There may be a place for preventing transmission in pregnancy or perinatally. The clock is ticking. Lots of questions. Very few even trying to come up with the right answers.

Here’s the pièce de résistance. Take a look at this paper discussing possible ways that XMRV found it’s way into humans, Of mice and men: on the origin of XMRV. Van Der Kuyl. Of note is that mouse cells were first used in vaccines in 1931. Epidemic neuromyasthenia; clinical syndrome. Henderson. NEJM 1959 documents the first outbreak as having occurred in 1934. An epidemiological goldmine ignored for half a century following the publication of this fine paper. Even now, my email is more informative than anything our epidemiologists have reported in the literature. It is hard to even begin to comprehend the scope of this disaster.

I have been given the incredible opportunity to chair the newly forming Clinical Advisory Board for the WPI. This group will interface with a Scientific Advisory Board to interpret the unfolding science for medical purposes. It promises to be an unprecedented fusion of diverse talent. The WPI is committed to sharing any clinically relevant scientific information that may advance our current approach to the disease. Patients need meaningful treatment now, not in a few years. From my perspective as a patient, progress seems excruciatingly slow, but I am hopeful that we can bridge the gap from the lab to the clinic and bypass years of avoidable suffering. All options must be considered, no stone left unturned. Sooner rather than later.

I am traveling to Reno this week in an attempt to fill my knowledge gap of the lab science and brainstorm where to go from here. I think the future looks brighter than it has in a very long time. I have to believe that if I have recovered enough for productivity, others can too. Returning to function is still a process for me, not a done deal, but the progress I’ve made is beginning to yield tangible dividends. Our own descent into hell and return to a life that is worth living has created an urgency in me to help find the answers. Those answers are closer than they have ever been.

I am filled with gratitude to the WPI for the considerable quality of life improvement that my family has already experienced as a direct result of their work. I will never be able to repay my debt adequately, but I will try.

One of the best parts of this journey from a medical point of view is that it is based in hard science. It is the first time in my career, including training and sixteen years of emergency medicine, that voodoo has taken a backseat to the basic science. If one applies the knowledge we have about HIV to CFS, we have a pretty good model from which to consider our approach to treatment.

Read the Mogensen paper linked on the sidebar. Then read it a few more times. The keys are in that paper. It’s all the result of  persistent immune activation (plus gene modification?), however it may manifest in a particular individual. I came up with the following system based model, better than symptom based, but still more complicated than it needs to be in order to consider therapeutics.

The myriad symptoms of CFS can be sorted into general categories based on pathophysiological groups. Here is my first pass at this, with examples of symptoms, not close to exhaustive, in parentheses. The categories provide a framework for considering pathogenesis and may present strategies for a multi-pronged approach to therapeutics.

• Vascular spasm (migraines, flashbacks, black outs, dysautonomia, microvascular angina, dysrhythmias, GI symptoms, Raynaud’s)
• Inflammation (depression, sleep disorder, cognitive deficits, fibromyalgia, malaise, OI, IBS/IBD, “swollen brain” possibly related to CCVSI, interstitial cystitis)
• Neurodegeneration (sensory overload, sensory neuropathies, cerebellar degeneration, neuropsychiatric manifestations, neuropathic pain, MS)
• Immune activation, derangement (activated viruses, tick-borne diseases, almost autoimmunity, antiphospholid syndrome, Hashimotos’s thyroiditis, late neoplastic transformation)
• Hormone depletion and receptor insensitivity (cortisol, androgens, insulin insensitivity, LH insensitivity leading to progesterone deficiency in women and testosterone deficiency in men, hypothyroidism)
• Cellular hypoxia, mitochondrial defect, methylation defects (shortness of breath, mini-clubbing, “fatigue” or energy currency deficit, heavy metal toxicity, MCS, oxidative stress)
• Push-crash (short term, days, post mental and physical exertional malaise; longer term, weeks or months, post trigger activation- physical, emotional, infectious- physiological explanation is obscure)
• Gene activation/repression (Marfan’s, Ehlers-Danlos, other connective tissue disorders? Susceptibiltiy to neurotoxic illnes? Cancer?)

But each piece of this list can be explained in terms of the downstream effects of the virus. The hardest to explain mechanistically is push/crash, but some sort of abnormal response to stress hormones is probably involved, thus likely one more manifestation of diffuse hormone abnormalities. There are many questions of course, why hormone depletion, the exact nature of the receptor abnormalities, what exactly causes the hit to the nervous system, but if you consider it piece by piece, all can be explained by the uncontrolled replication and persistent presence of the virus. The body knows it’s there and is doing exactly what it’s supposed to. If it weren’t for the immune response, mucking up the works, it might almost be a commensal. There is no immune deficiency as there is with AIDS, even with advanced disease. Immune deficiency and long term survival are not compatible.

My medical mind was shaped by surgeons. I prefer to treat with my hands than my prescription pad. Not so useful for dealing with chronic disease, but I keep seeing ways in which that approach is needed for the current situation. In many ways, the simplistic ED mentality is what’s called for. It’s an emergency. People are trapped and suffering, with no help, or worse than no help. Triage, best guess, compassionate care. ABC’s.

We have a way to think about it now. No more need for all those black box protocols. It’s pretty simple all of a sudden. Unfortunately there are very few therapeutic modalities worth considering, but at least we finally know what not to do. We need reliable detection from more than one commercial lab in the world. We need viral load measures so we can figure out what we’re actually doing with antiretroviral therapy. We need specific drugs. But considering what’s available at this moment, the options are limited and therefore not complicated.

There is a slowly growing coalition of doctors with sufficient critical thinking skills to consider what to do now for thousands of XMRV+ patients who have already been tested. Only a very few, but it’s a beginning. Doctors who are willing to try to figure some of it out, even before the scientists get the years of controlling the show that they seem to want. The patients don’t die after all. What’s the hurry? And after the detection issues are worked out, in a year or two, then they have to prove pathogenesis, not just association. Then after a few more years we can start to think about whether the drugs we already have are safe enough to try in clinical trials. The usual path to clinical trials is a case study, then a pilot trial of carefully selected cases, before a large scale clinical trial. We are the case study. Patients are lining up to be included in pilot trials, formally or informally. Where have all the doctors gone?

I was an alternative doctor, of sorts, in my last medical incarnation. Patients from that practice keep coming to mind. Many of the patients currently seen in alternative practice will turn out to be X infected. The alternative medicine community has come very far in identifying the metabolic defects and how to think about treatment without doing harm. Many people have written to me that if I would only consider this or that supplement, it would help us. This is at the heart of the problem with treating CFS. The disease is a relapsing remitting process all on it’s own. Everyone naturally attributes their improvement to whatever they were doing when they got better. I recovered the first time for almost a decade with no pharmaceutical treatment at all. In fact, my health would likely be better than it is, had I never seen a doctor at all.

Not in any way interested in increasing our pill burden, we are starting to add back in a few supplements, in the hope that they will be more useful than they have been in the past. Here is a useful review article about neutriceuticals for HIV:
Nutrients and HIV: N-Acetylcysteine, Alpha-Lipoic Acid, L-Glutamine, and L-Carnitine. Patrick

We’ve tracked our TGF beta-1’s and C4a’s from baseline in an attempt to monitor something useful, though viral load, if it were available, is probably the only meaningful thing to follow. These labs do reflect what has happened experientially, though I think it lags behind the clinical picture. It looks like the drugs flare inflammation, consistent with our experience, though Ali didn’t think they made her particularly worse, sick as she already was. Our C4a’s were both normal initially, went sky high when we started treatment, have been coming down and were normal again when we were drawn the end of Sept. My TGF beta-1 was 25,000+ at baseline and has been coming down the whole time, most recently 6000+. Ali’s was 9000+, went up to 28,000+, has been drifting down and was 7000+ last check. We need a few more data points to know if it is meaningful.

The biggest question in my mind, with respect to the use of antiretrovirals, is whether it is necessary to be blasted right off the bat with a full HIV dose, because of the experience with HIV drug resistance, having nothing to do with CFS or X. We have reason to believe that flaring inflammation is counterproductive and we have clinical and lab evidence that full doses of the drugs flare inflammation. We may be setting off exactly the reaction we are trying to turn off, and that may be why some early results have been less than impressive. If I were starting now, I might try starting low and going up as quickly as possible. Certainly after an unsuccesful attempt at getting going. I took tenofovir at half dose for a week, after being unable to start the first time, then went up to full dose without problems. That said, we don’t want to find out in a few years that people who tried treatment early on wound up with resistant virus. Another possibility, especially for patients who have been sick for a long time, is pretreatment for a more rapid beneficial response.

I wonder as much as anyone, especially sometimes in the middle of the night, if it is Deplin, stopping antibiotics or the power of positive thinking that has made us better rather than antiretrovirals? It doesn’t seem likely, especially since there are two of us, but I do hear occasional reports of spontaneous recovery even after a long time. For now, we have to live with this uncertainty, until we have more clinical and laboratory evidence. I thought there would be a large amount of clinical anecdotal data by now, but the powers that be seem to be getting their way, with a stranglehold on the option, due to physician fear, ignorance, self-interest. I would like to modify something I’ve said in the past. I’ve referred to the use of antiretrovirals as an experiment. From my current vantage point, taking antiretrovirals for a retrovirus doesn’t even constitute the usual and customary off-label prescribing. It is a valid option, until evidence shows it isn’t. It is unbelievable that people write to me every day because their physicians seem unable to write prescriptions when they have been prescribing much more dangerous drugs routinely for many years. Not that prior harm justifies a new round, but I believe a trial of antiretrovirals can be a rational medical choice at this time, on a case by case basis. And my daughter and I have put our bodies and privacy on the line to demonstrate that. At the very least, even the most skeptical will have to accept that we are doing extremely well, outside of the CFS bell curve, despite antiretrovirals (three drug combination) at full HIV doses for nine months.

I have received quite a few letters from people who crashed for the first or subsequent time after a vaccination, including flu shots. In my opinion, at this point anyone with a CFS history or the offspring of anyone with a CFS history, should not be vaccinated. It may be that it is the immune challenge that sets off the disease (as it would seem from listening to case histories of autistic patients). But there is an even more pressing and insidious consideration. I have been reading the animal retrovirus literature to find clues for understanding and dealing with HMRV’s.

The literature is vast. Amazing what they know about chicken retroviruses (ALV’s)! Simple endogenous retroviruses. Can infect cells of other species in tissue culture. Recombination events play a part in pathogenesis. Cause tumors of various sorts. Sounds familiar…

There’s literature about breeding in and out certain endogenous retroviruses in chickens. You can breed in compulsive overeating (like OCD) caused by a particular endogenous retrovirus. And you can selectively breed out the ones you don’t like.

• Proviral integrations and expression of endogenous Avian leucosis virus during long term selection for high and low body weight in two chicken lines. Sojeong
• Extremely Different Behaviours in High and Low Body Weight Lines of Chicken are Associated with Differential Expression of Genes Involved in Neuronal Plasticity. Ka
• Methods for evaluating and developing commercial chicken strains free of endogenous subgroup E avian leukosis virus. Bacon

Guess what! They grow live attenuated vaccines in all kinds of animal cells, commonly chick and duck embryos. I’m not a conspiracy theory type. I usually think stupidity explains most of the disasters. But in this case, it is more about arrogance and hubris. They’ve known all along that various endogenous retroviruses were present in the cells they were using, but decided to go ahead and do it anyway. I’m not saying that ALV related viruses are involved in the chronic neuroimmune illnesses the way that the murine retroviruses likely are, but it certainly seems possible. At least worth considering until we know more. It appears that there is more than one MuLV related virus. Could there be other animal retroviruses involved?

• Endogenous retroviruses as potential hazards for vaccines. Miyazawa
• Risks linked to endogenous retroviruses for vaccine production: a general overview. Dewannieux
• Isolation of an Infectious Endogenous Retrovirus in a Proportion of Live Attenuated Vaccines for Pets. Miyazawa

A paper that takes arrogance to a new level. Absence of proof is not proof of absence.

• Identification and characterization of avian retroviruses in chicken embryo-derived yellow fever vaccines: investigation of transmission to vaccine recipients. Hussain/Heneine

Here’s a good one…

• Quantitative detection of RT activity by PERT assay: feasibility and limits to a standardized screening assay for human vaccines. André

And here is a little good news (we’re overdue). AZT inhibits this group of retroviruses also. They knew that before I had Ali. AZT really is a very broad spectrum drug.

• 3′-Azido-3′-Deoxythymidine Inhibits the Replication of Avian Leukosis Virus. Olsen
• The effect of 3′-azido-2′,3′-dideoxythymidine on experimental viral infections. Shneĭder
• Inhibition of the avian leukosis-sarcoma complex with 3′-azido-3′-deoxythymidine (AzT); a model for screening and evaluation of chemotherapeutic agents against retrovirus infections. Kavsan

And look, they know more about another simple retrovirus that infects fish than they do about what’s wrong with millions of people. This one makes tumors that wax and wane and doesn’t kill quickly.

• Walleye dermal sarcoma virus Orf C is targeted to the mitochondria. Nudson

I’m aware that reading past blog entries leaves something to be desired in terms of understanding our clinical course, so this is an attempt to take stock of where we’ve been and where we are.

I hate rating scales. I picked the KPS as the most basic. I considered all the rating scales used most commonly in CFS. I like following hours upright, but can’t stand to keep track and it varies from day to day anyway. Some scales lump physical and cognitive deficits together which doesn’t work for us, as our experience is that cognition is the last thing to go and the disparity between physical and cognitive symptoms makes accurate answers impossible.

Having followed our improvement in KPS points, it doesn’t seem useful or relevant at the moment. Here’s the part of Karnofsky Performance Status scale that I’ve been attempting to use lately:

• 80% normal activity with some difficulty, some symptoms or signs
• 70% caring for self, not capable of normal activity or work
• 60% requiring some help, can take care of most personal requirements

The difference between 70 and 80 KPS points, involving a return to function in the world, seems a much bigger incremental improvement than the 10 points before that, which are about improvements without returning to the world of work. I’m beginning to confront the realities of returning to work and, trust me, it’s a much bigger step than going from being cooked for/picked up after, to doing those things for yourself. 

So I’m done trying to quantify it. It’s a moving target anyway, because the illness is still there, a sine wave, of variable period, though now superimposed on a slow uphill trajectory. I’ve said in the past that we were still below water, looking up at the surface. Now we have broken through, but the troughs are still a little under water. I’m not interested in arguing with anyone about whether we are better. We are a lot better. Looking at roughly three month increments, our slow but steady improvement is obvious. The important question is why.

This is what happened. We started AZT and Isentress, within days of one another, in early March. The drugs flared all of my symptoms, but my neurological symptoms in particular. Ali did not have problems starting the drugs. A few weeks into treatment, I experienced a reduction in malaise (for me a feeling of viral prodrome, a persistent symptom for 15 years). At about six weeks we both experienced a transient increase in physical energy which was uncharacteristic of anything we’d experienced in years. However it didn’t last. Also my flared symptoms weren’t resolving. I was a bit frightened by the flare, since I had no idea what to expect, and I also started hearing negative reports of people who had started on Isentress alone. So we both stopped Isentress and, surprisingly, we both got noticeably worse, Ali with immediate increase in sugar reactions, strangely. So we went back on. I would like to say here that what we did is not a good idea. Because we know nothing about the potential of the virus to become resistant to the drugs, commitment and compliance with a regimen is likely very important. With HIV the success of treatment declines in direct proportion to poor compliance.

I tried to add Viread and almost immediately experienced a severe flare of symptoms. I again chickened out and went off. Ali, who had had essentially no trouble with the drugs so far, decided to take it (about two months into treatment). Two weeks after adding the third drug she experienced a noticeable reduction in symptoms. I decided that I too wanted to take it, so I tried again at half-dose, with fewer problems than before. I went up to full dose after a week (roughly three months into treatment). About two weeks after adding the third drug, I too experienced improvement.

In August we were doing well enough that we tried to transition to more active, stressful lives. Ali tried school and I went to Reno for a few very active days. I expected a full crash after that trip, which did not come. We both dipped a little over a month or so. We backed off and started slowly up again, more moderate in our expectations, knowing that we are improving, but slowly.

Moment to moment, day to day, even week to week, we can’t feel improvement. The variability that characterizes the illness continues, but it all seems so much less potent. I use the metaphor of an abusive boyfriend who drops by to slap me around if things get too good, but he is visiting less and less often. He’s getting soft or I’m getting harder to push around. Some days, he has no power over me at all.

Ali started Deplin about six months before antiretrovirals and Actos two weeks before. I started Deplin a couple of months before antiretrovirals and Actos recently with an obvious response. Recently we have added B12 shots. We have taken a lot of parenteral B12 in the past, including daily injections for a month at a time on a couple of occasions, without noticing benefit, but what didn’t help before treatment with antiretrovirals, might now. I am hearing from people who report having been helped by B12 injections.

We have otherwise been on a supplement holiday since starting antiretrovirals. We have taken tons of supplements over the years and it was a relief not to take supplements for a while. We are now starting to add things judiciously. We are taking Meriva SR, a more absorbable form of curcumin, for NFkB inhibition.

After about a month of Actos 15mg, and with further reading, I went up to 30mg. The literature generally talks about 30-45mg daily. Here are a few more references pertinent to the use of Actos in X infected patients:

• Effect of pioglitazone treatment on behavioral symptoms in autistic children. Boris
• Effect of pioglitazone treatment in a patient with secondary multiple sclerosis. Pershadsingh
• A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis. Kaiser
• Proinflammatory Stimulation and Pioglitazone Treatment Regulate PPARγ Levels in Peripheral Blood Mononuclear Cells from Multiple Sclerosis Patients.  Klotz
• Pioglitazone Enhances Mitochondrial Biogenesis and Ribosomal Protein Biosynthesis in Skeletal Muscle in Polycystic Ovary Syndrome. Skov

Ali completed her writing challenge. 50,000 words in a month. Quite an exercise. I’m sure you will hear from her when she recovers from her writer’s cramp.

We seem to be slowly, but surely, getting lives. For real. Ali is past 40,000 of her 50,000 words for NaNoWriMo and functioning socially on a level that has been lost to her for years. I’m trying to figure out what’s the next step for me professionally, but I am ready physically to work part time, also functioning on a level beyond anywhere I’ve been for years. We are both solidly above 80 KPS points for the last couple of weeks. I was out and about yesterday for five hours during which I pretty much didn’t feel sick. That isn’t the norm (yet?), but it is possible.

I don’t experience the improvement day to day, or even week to week, but in two to three month increments, it is obvious. The instabilities are damping out. The ground is more stable, reliable. Even the power of our once constant companion- push/crash seems diminished. Stress tolerance is much improved.

Actos has been very helpful for me. It seemed to provide definite cause and effect improvement across a range of inflammatory symptoms (see last post which discusses my rationale for trying it).

I haven’t wanted to write about this until I was sure, because it seems so unlikely. I’ve had a severe peripheral neuropathy for six years. The associated pain nearly destroyed me. It is dramatically improved in the last three to four months. A lot of the time now, I don’t have anything that I would call more than paresthesias. I was hopeful of learning to live well with pain, but not of having it get so much better. In fact, it was the last symptom I expected to improve. Michael Snyderman, oncologist with CLL, on antiretrovirals, has also experienced a dramatic reduction of his neuropathic pain. This is astonishing to me.

We’re doing very well. We are either level or going very slowly uphill and I would guess the later. Our improvement feels pretty solid at this point. Incomplete, but the worst symptoms are gone or hugely reduced. If you remove the horrible downhills, and if you don’t have to spend much time at the bottom of the declines, it’s a life. In particular, we both feel that our brains are working well, bodies a little less so, but all in all, pretty fine, compared to where we’ve been. We are both so grateful.

Ali is completely immersed in NaNoWriMo. She has 15,000 words down towards the first draft of her post-apocalyptic vampire novel. She is living and breathing her story right now and it is more wonderful than I can say to see the light in her eyes. She has been attending the local NaNo writer’s meetings and she went out the other night with a friend for dinner. She rarely mentions her physical symptoms, though when questioned, she still has some. Like me, cheap stuff compared to where we’ve been.

Ali had an easier time getting on the drugs than just about anyone else that’s started. Because her sugar sensitivity was completely out of control and she couldn’t eat a speck of sugar without getting sick, and even though I knew that it would make it more difficult to tell what was going on, she was pretreated with Actos for two weeks prior to starting antiretrovirals. It had an immediate positive effect on her ability to eat normally. I’ve been reading about PPAR-γ agonists and the evidence supports it for consideration in this setting. Thus, I too started Actos two weeks ago, at very low dose. At 15mg, a week ago, it had an obvious salutary effect, with improvement in several prominent inflammatory symptoms. 

Actos is a PPAR-γ agonist (PPAR-γ regulates fat and glucose metabolism). It is an NFkB inhibitor (anti-inflammatory). It inhibits VEGF (a vascular permeability factor which features prominently in Sandra Ruscetti’s PVC-211 rat model of neuropathogenicity). It reverses atherosclerosis and improves glucose utilization. Here are a sampling of papers and abstracts to give you the flavor, though the literature is vast. And for the record, lest I seem too excited, there is cautionary evidence in the literature as well.

• Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists. Staels
• Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation. Blanquart 
• Peroxisome proliferator-activated receptors and inflammation. Moraes
• Peroxisome Proliferator-Activated Receptor Agonists as Therapy for Autoimmune Disease. Lovett-Racke
• Nuclear Receptors and Autoimmune Disease: The Potential of PPAR Agonists to Treat Multiple Sclerosis. Lovett-Racke 
• Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Suppress the Production of IL-12 Family Cytokines by Activated Glia. Jihong Xu 
• Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury. Sauerbeck 

I’m certainly not saying that it’s any kind of panacea. Lots of people have tried it. Like everything with this illness, it helps a few people a lot, more people a little and lots of people not at all. But it may be a different ballgame now that we are only looking for things to potentiate the positive effects and attenuate the negative effects of the antiretrovirals.

Actos, with or without metformin, is indicated in the treatment of PCOS, a syndrome characterized by multiple receptor insensitivities. PCOS appears to have a very high prevalence in second generation X infected women. Another clue…

I’m feeling happy, not angry at the moment, so I’ll spare myself the tirade about Dr’s Kearney and Malderelli’s unfortunate comments in print recently. Government doctors in a research setting casting aspersions on real doctors in the trenches. Please read this excellent blog commentary on the subject: The Tuskegee Mentality: Condemning Antiretroviral Treatment for ME/CFS by Larry Gilman (link). Amen to that.

Anger as soon as fed is dead-
’tis starving makes it fat.
 ~ Emily Dickinson

I’ve done a lot of thinking about anger since my post written during the weekend ILADS was holding its conference. In particular, the difference between constructive and destructive anger keeps coming up for me. I received my first hate mail after that post, in addition to many letters of agreement. The thrust of the anger directed at me had to do with my criticizing doctors who validate the illness and offer up a hope for cure. In contrast, anger in the CFS community is seen currently as a positive force for change, as it was in the days of HIV. CFS patients are more jaded due to having had a syndrome without a known etiology for years or decades,  thus precluding meaningful treatment.

For me, for many of us, it will be a race to the finish to deal with all of the anger and loss. In the Lyme community they call it Lyme rage, though anger is only one of the emotions that lives closer to the surface than it used to. Anger is one of the most difficult feelings to receive constructively. It shuts people down. It is often better in terms of outcome to let it pass through without action. But anger fuels the flames of political change also. Another lesson of HIV. The trick is to turn the anger into constructive action, rather than letting it fester or become vengeful. Properly channeled, it has the potential to be redemptive, rather than destructive to the person experiencing it and those closest to them. For the sake of personal emotional and physiological health, it is essential to forgive those who deserve to be forgiven and release thoughts of those who don’t, in favor of specific constructive action. A willingness to reconsider the mistakes of the past in light of new information is a trait that makes someone worthy of forgiveness.

Ali stopped Lexiva also. After two weeks, she hadn’t experienced any benefit. The only thing she noticed, besides a little GI upset, was a very minor CNS effect, which she experienced as similar to “a little too much Cymbalta”. I am SSRI intolerant and had a similar experience, though it wasn’t subtle and took a week to clear. Very strange. No obvious explanation.

There is of course no way to know if taking it for longer would have made a difference for Ali, but with so little to go on, continuing without clear benefit didn’t seem like a good idea. Someday we will look back on our Lexiva trial and understand the biology of what happened. For now, we have three drugs that have been shown to be effective in vitro, in more than one study: AZT, tenofovir and raltegravir. Three drugs work for HIV. So we’ll stay the course. We are tremendously better, though recovery is so far incomplete.