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NOTE: About William Alford.... My wife suffers from the motility disease, Chronic Intestinal Pseudo-Obstruction, or CIP. We share many of the same symptoms as CVS except that it is not periodic. Many CIP patients are as sick as many CVS patients, but ALL THE TIME. Vomiting and pain is often so exteme that they must be fed through surgically implanted tubes or constant TPN. Some have constant morphine drips for the abdominal pain. Some can take nothing, not even water, by mouth. It could be that some of the physical mechanisms of these diseases may be shared. My background is in engineering, but this has prepared me to deal with complex topics. Over the years of dealing with CIP, I have read several thousand abstracts concerning various aspects of motility disorders as well as hundreds of full texts. This experience as well as the active involvement of proposing clinical interventions has led to being elected Director of Resources of ASAP, Inc. ASAP stands for the "American Society of Adults with Pseudo-Obstruction", a volunteer international advocacy group for PWP (persons with pseudo-). PWP often face the same disbelief, lack of appropriate care, and medical naivete as CVS and too little research is being done by too few medical facilities. Kathleen (CVSA President) and I were introduced through a physician, Dr. Thomas Abell, who serves on both of our Medical Advisory Boards. Dr. Abell is urging a "confederacy" between the various GI motility advocacy groups to greater empower everyone's agenda. I hope that by sharing resources and knowledge, both groups may benefit. I've asked some unusual questions on the listserver over the last few months and many have been kind enough to respond, both off-list and on. Some have asked to know the reasons for the questions and I've had to delay an answer because it was an on-going thought experiment. This little essay below is the result of many of those exchanges and the ideas they stimulated. It is merely a mental exercise, but does serve to show that paying attention to every little detail of the lives of people with chronic illness could possibly yield clues that could be related to understanding the illness. I make NO claim that this has any relationship to CVS. It is totally speculative and has no basis for truth except from postings from this listserver of symptoms that others have observed. It doesn't give any answer. It does illustrate how endogenous triggers could possibly occur with periodicity. Remember...the trigger is not the disease. So, keep those observations coming. Permission is granted to use or copy in any way so long as the copyright notice is preserved on the document. From: William Alford Subject: CVS thoughts "out of the box", is Melatonin a trigger? After Dr. Li's excellent lecture at the Atlanta CVSA meeting, I sat and listened closely to all of the patients that were present speak about their cases. Some of the subjects they discussed reminded me of an idea that I entertained earlier this year that came from similarities I've noticed on the listserver between many descriptions of the CV episode onsets. The following essay is merely an exercise in constructing models to deal with CVS from a perspective of thinking "out of the box" as Dr. Li says. It is in no way to be taken as medical advice but serves only to stimulate thinking about the possible mechanisms of disease.--William Alford OBSERVATIONS: A great many CVS episodes begin during sleep and often 2-5 a.m. Almost ALL the patients claim sleep dysfunction, many waking too easily from sleep. Around 50% of those present at the Atlanta CVSA meeting expressed an improvement during the summer months with relapse during winter months--I received a posting (9/12/98) on the CVSListserver, quote: "Usually every summer is episode free except this past summer". Some prodromes are reported as irritability, agitation, and constipation. Some listserver posters report CVS onset with eating chicken or drinking milk (to the extent that they avoid it!). Some CVS females report a trigger with menstruation. Many report extreme lethargy, some approaching a "waking coma" during episodes. Tic and odd eye movements as well as increased hunger have been reported as prodromes. Ravenous appetite is reported immediately following episodes. BACKGROUND: Some diseases, most notably Multiple Sclerosis (MS), are geographically latitude specific. More MS cases occur in the northern latitudes worldwide than in the southern, leading some researchers to speculate that this is because of the longer days of the southern latitudes exposing patients to greater (and more intense) lengths of sunlight. Studies have also reported a greater incidence of relapses of MS in the winter and spring with a decline in the summer. Evidence points to the pineal gland as functioning as a "neuroendocrine transducer" converting environmental stimuli, such as light, temp, etc, into neuroendocrine signals by the cyclical circadian synthesis of melatonin (Axelrod, 1974. The pineal gland: a neurochemical transducer...SCIENCE 184, 1341). Melatonin also is reported to modulate the activity of the serotonergic, GABA, dopamine, and opiate neurons which could result in normal sensations being perceived as noxious. Dr. John Mathias, a noted GI motility researcher, has said that one action of the drug, luprolide acetate (LA), for motility diseases is as a neurotransmitter on the GABAa receptor (personal communication). In a study of 29 MS patients given CT scan, pineal calcification was observed in 100% of the cases vs 42% in a control group, which could indicate an association with pineal activity. Experimental allergic encephalomyelitis (EAE), an animal model for MS, failed to develop in adult pinealectomized rats, in contrast to 50% of controls (with sham surgery). A study showed 100% incidence of mental depression in MS and it may precede the demyelination, with some researchers declaring almost all depression to be related to sleep dysfunction (therefore possibly melatonin driven). Serotonin, the precursor of melatonin, and low levels of tryptophane (a precursor to serotonin) in serum and cerebral spinal fluid have been found to be reduced in MS. This is true for Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) also. Corticosteroids, the most used treatment for MS inhibit melatonin secretion (so is there a possibility of this action of the drug is involved in the drug's efficacy?). If one form of CVS is indeed a migraine equivalent, it is known that migraines are more common in women than men, and many are related to menstrual cycles. Melatonin plasma levels rise during the luteal phase and peak at menstruation. The course of MS is also associated with puberty and onset of menses and MS relapses are associated with the luteal phase and improve with menstruation. It is known that injections of luprolide acetate, a gonadotropin releasing hormone (GNRH) analog will abort many migraines and melatonin has been shown to affect the release of gonadotropin. Dr. John Mathias of Houston has successfully treated many GI dysmotility diseases with LA, including some with extreme abdominal pain (possibly abdominal migraine?). PERSONAL OBSERVATION: Having read that melatonin is the very best free radical scavenger, once when my wife (who suffers from a GI dismotility illness) was scheduled for a great many x-rays during a GI work-up, she took melatonin prior to the exams to offset the free radical generation by the ionizing radiation and subsequently developed an unbearable headache (perhaps migrainous). Since CIP shares many of the symptoms of CVS, this may be evidence of melatonin induced migrainous pain. She very often awakens in the mornings complaining of headache (possibly related to the headache that occurred when she took the oral melatonin--if she has a melatonin sensitivity?) and many migraineurs also awaken with headache. SPECULATIONS: After this rambling bit of factoids, let's go back to the observations: (1) many CV onsets begin at 2-5 am-->this is almost exactly the peak time of melatonin secretion and pineal activation (2-3 am); (2) sleep dysfunction in CVS-->very often melatonin related; (3) improvements in summer months-->like MS, possibly because of lower melatonin levels in the summer due to longer seasonal light exposure (also kids would spend more time outdoors during the summer and therefore receive more unfiltered light exposure, suppressing the melatonin level); (4) irritability and constipation as prodromes-->these symptoms are often serotonin related, with serotonin deficiency known to cause irritability, and supplemental tryptophane sometimes has benefit for GI motility and depression. And, finally, (5) eating chicken as CV inducer-->chicken, turkey, and milk are high in serotonin content and it has been recommended to eat these foods before bed for patients with difficulty sleeping. Since melatonin is a metabolite of serotonin, perhaps when chicken consumption produces a higher than normal serum level, then with the normal rise of melatonin during sleep after such a meal, these higher base levels could add to the normal nocturnal rise and therefore may trigger an episode at the magic 2-3 a.m. time (when melatonin naturally peaks)? (6) The rise in melatonin levels during the luteal phase of menstruation could be associated with the trigger by menstruation in some females during normal night-time rises in the same way--a higher base level combined with normal pulsile action. (7) Melatonin administration induces sedation and sleepiness and a melatonin hypersensitivity could relate to the lethargy during episodes. One patient at the Atlanta meeting reported that during the intervals between CV episodes, she now has the "best sleep of her life" (this is at odds with the other reports of sleep disturbance, but supportive of a possible higher base level of melatonin or serotonin since her disease onset). (8) Serotonin is involved in appetite as seen in diet drugs such as phen-phen and changes in appetite prior to and possibly even the hunger following an event could be related to serum level changes. (9) Almost all the drugs (including periactin) that have shown efficacy for CVS operate on the serotonergic system. So...could I hypothesize that a hypersensitivity to melatonin, perhaps like the hypersensitivity to dopamine by migraineurs could be a factor in CVS and could the pineal be a major player in the CNS components? It's also very interesting that it is the SAME enzyme that converts serotonin to melatonin that also converts l-dopa to dopamine. This enzyme deserves futher investigation. Many of the temporal relationships seen in CVS may indicate a melatonin connection, including the fact that melatonin levels decline with age (in fact, puberty is triggered by the rapid decline of melatonin around age 16), which could account for the fact that some young CVS patients "grow out of it". At age 20 there is around 75% of the amount generated nightly as at the peak age of six, and by age 45 we produce about half of that peak. From birth to age six, the increase of melatonin is almost exponential, and this age range accounts for the majority of CVS onsets. A superposition of circadian, ultradian, and other physiological rhythms that come into synchronization when the peaks of these rhythms coincide (yet unknown) could yield a summed physiological melatonin pulse higher than normal, and factoring in any serotonin content of food could account for some triggers that are non-cyclic (yet these could be non-food specific). A "trough" in the summation of these cyclic rhythms could occur prior to the following summed peak trigger point that would produce the irritability prodrome prior to the CV event. Finally, and perhaps meaningful as indicated by many CVS-listserver postings, there is a very enjoyable read by the eminent professor of neurology and pharmacology at Rush University, Harold Klawans--a book called NEWTON'S MADNESS. This book is a collection of essays from his experience that depicts strange neurological adventures. One chapter is entitled "The Girl with Dancing Eyes", and concerns an infant that was brought to him with hyper-reactivity to stimuli, primarily aural. A sudden noise would cause her to "leap into the air". He correctly diagnosed her with a neuroblastoma that was secreting serotonin after noting her "dancing eyes"--a response to elevated serotonin levels. After surgical removal of the neuroblastoma, the hypersensitivity resolved. Earlier in his career he had had a graduate student inject 5-HPT (a serotonin precursor) into guinea pigs which promptly developed dose-dependant hyper-reactive behavior and bounced like popcorn in response to loud noise. Now I have recently posted a question to the CVS Listserver and received quite a few responses from patients and parents describing behavior of hypersensitivity, some (including eye behavior) increasing or appearing prior to CV. I received one e-mail from a patient whom I quote: "However, I primarily wanted to respond to the sensory experience question posed by William Alford. I tend to be hyper-reactive to just about all sensory stimuli. My friends refer to me as jumpy and often make loud noises to startle me. In spite of this hyper-reactivity to sound, I am not able to hear very well. In fact, I have failed just about every hearing test I've ever taken." Note that the hyper-responsivity is not to the loudness but the startling aspect of the sudden noise. The responses from the listservers acknowledging this kind of tic (eye activity) and hypersensitivity may be evidence of an association. The similarities to the activity reported by Klawans is interesting, perhaps enough to consider the serotonin/melatonin levels during remission, during prodromes, and during episodes as worthy of investigation. Admittedly there are MANY other causes of hypersensitivity, but this choice fits the model of melatonin sensivity explored in this essay. A quick search on MEDLINE for the words "tic" and "vomiting" produced this interesting paper--> Mov Disord 1997 Jul;12(4):531-535 Vomiting and retching in Gilles de la Tourette syndrome: a report of ten cases and a review of the literature. Rickards H, Robertson MM Department of Neuropsychiatry, Queen Elizabeth Psychiatric Hospital, Birmingham, U.K. "Retching and vomiting are common symptoms in childhood. We describe the cases of 10 patients with Gilles de la Tourette syndrome (GTS) for whom vomiting or retching tics were part of the clinical picture, and discuss other instances where retching and vomiting occur with neuropsychiatric or movement disorders." <-- Tourette's Syndrome is thought by some to be serotonergic related, as is migraine and OCD. A test of this hypothesis (though probably hard to find volunteers) would be to administer oral melatonin (by an MD familiar with the patient!!) to a CVS patient from the migraine-equivalent group and observe for symptoms. Of course, it would have to be a double-blind experiment to be sure. And...this could be difficult since the CNS contributions may be powerful--in his Atlanta presentation, Dr. Li reported abandoning a placebo/zophran study because of hyper-response to the placebo (everybody got better!) that confused the study. There are several medical testing companies that can test for 24 hour melatonin cycles by taking saliva samples. One is the Great Smokies Diagnostic Laboratory at 800-522-4762, www.gsdl.com . These tests must be ordered by a physician. Alternatively, administration of full-spectrum light therapy (known to suppress Seasonal Affective Disorder and now being investigated for application to PMS, OCD, bulimia nervosa, and others) might be a test to see if it improved symptom frequency. There are now devices that administer light to the back of the knee that are proposed for use for jet lag--receptors in the blood are affected. The drug luzindole is a melatonin receptor antagonist, but I know nothing of its effects. Dr. R. Sandyk at Einstein Medical College in NY has reported MS, PMS, and Parkinson's remissions with application of very slight electromagnetic (EM) fields to the head that he believes acts on the pineal. Emory University scientists in Atlanta (and others) are now doing trials of low level EM to the head for severe depression with very good success. Migraineurs have a hypersensitivity to the neurotransmitter dopamine, and the drug domperidome, a dopamine antagonist, has shown to relieve migraine intensity by 50% and shorten the episodes, and environmental light is involved in dopaminergic functions as well. The pineal has been shown to be sensitive to EM as well as full spectrum light. Depression due to circadian dysfunction has also improved with sleep deprivation, and this has been suggested as possible therapy to "reset" the rhythms. ADDENDUM TO CVS THOUGHTS "OUT OF THE BOX" Several other interesting posts on the CVS listserver might also indicate a melatonin (or related endogenous compound) relationship in the trigger mechanism for some CVS patients. There have been reports of "night terrors" and "crazy dreams" (see below)...and as it turns out melatonin is a tryptamine with a close chemical similarity to DMT and other hallucinogens. In an article in MEDICAL HYPOTHESIS entitled "A proposed mechanism for the visions of dream sleep" 26:119-124, 1988, Dr. J. C. Callaway gave a detailed explanation of how tryptamines or related compounds may be responsible for dreams. Ray Sahelian, MD, author of the book, MELATONIN, NATURE'S SLEEPING PILL, wrote in an article in the magazine, EXTOPIA, about his survey of people using melatonin supplements with over half of the respondents claiming vivid dreams and about 8% reporting nightmares. I also personally know people who have experienced nightmares with OTC melatonin dosage use as a sleep aid after only one use and consequently abandoned it. The amounts of melatonin in the blood of volunteers given a standardized oral dose varied up to 300 fold as chronicled in PSYCHOPHARMACOLOGY 100:222-6, 1990, suggesting the uniqueness of each individual's absorption and metabolism. One responder to Dr. Sahelian's survey reported that he did not dream with the standard dose of 3 mg, but did have vivid dreams with 6 mg doses. So it could be suggested that the very powerful "crazy dreams" associated with some CVS episodes may indicate a sensitivity to the patient's endogenous melatonin. A FEW POSITNGS-- From: Subject: {CV} CVS Crazy Dreams - Night Terrors _______ has often experienced (and still does on occasion) night terrors during the recovery (back to normal) phase of an episode.. specifically during the next 24 - 48 hours after an episode ends. This is very scary (for me at least) and he seems terrified while it's going on. He gets up and wanders around and talks about crazy stuff (dreams), is not actually awake, and usually doesn't remember it the next day although he has on occasion. From: Subject: crazy dreams Dear William, I am mom of _______. I have wrote to you before and I can say again ,yes ______ has had several crazy dreams after and sometimes before an episode. From: Subject: Re: Fwd: {CV} Crazy Dreams My son is 8 years old and has vivid dreams almost every night. At least 3 to 4 times a week. The only difference is that he does not remember anything. You can have conversations with him. I get scared one day he might walk out of the house or do something crazy. At 04:14 PM 8/8/1998 EDT, you wrote: My daughter has experienced the exact same side effects as _____. She sometimes has wild and crazy dreams also, but thank goodness never any nightmares. and this posting from another list group (interesting because high functioning autism has been reported on the CVS list with significant frequecy) ... I'm trying to find information on the role serotonin may play in autism. Our 5 year old son has been diagnosed High functioning autistic (or PDD/NOS). We recently received results from blood work taken to check for other possible causes. His seratonin levels are considered "very high" (393). The normal range is 75-213. So, there you have it. There is no clinical evidence to support his and it may be total nonsense, but I was, after all, encouraged to think "out of the box" by the most prominent investigator in the field. Yours, William |
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