B. Katsoff

Case report showing that a woman with ulcerative colitis refractory to standard therapy responded well to the sympathomimetic amine dextroamphetamine sulfate

To the Editor: Recently a case was reported of a woman with stage 4 Crohn’s disease (CD) of 12 years duration refractory to standard therapy whose symptoms disappeared quickly and whose perianal fistulae spontaneously closed after dextroamphetamine sulfate therapy. The therapy was purposely prescribed because of previously demonstrated significant improvement following dextroamphetamine sulfate in symptoms from motility disorders of the gastrointestinal (GI) system including esophageal motility disorders, gastroparesis, and pseudointestinal obstruction. There has been considerable recent evidence both in animal and human models that inflammatory bowel disease (IBD) is associated with sympathetic neural dysfunction. The cell bodies of sympathetic preganglionic neurons are located in the intermediolateral cell column of the thoracolumbar spinal cord and innervate noradrenergic postganglionic neurons in the celiac, superior, and inferior mesenteric ganglia. Thus, postganglionic sympathetic axons innervate a number of targets within the GI tract including mucosal epithelial cells, the gut-associated lymphoid tissues (GALT), and the enteric nervous system (ENS). One of the major neurotransmitters of the sympathetic ENS is noradrenaline. Thus, theoretical mechanisms of how a defective sympathetic nervous system can contribute to symptoms or even cause IBD include dysfunction of the mucosal epithelium, thus inhibiting a protective mechanism from absorption of toxins or bacteria, dysfunction of the GALT leading to invasion of the mucosa by bacteria and inflammatory cells, and GI diminished motility, which in itself can lead to prolonged exposure to potentially toxic substances. There are some data that CD is associated with parasympathetic hyperactivity with associated sympathetic neuropathy, whereas patients with ulcerative colitis (UC) demonstrate the opposite, i.e., sympathetic hyperactivity with parasympathetic dysfunction. Thus, the possibility exists that the treatment with a sympathomimetic amine, e.g., dextroamphetamine sulfate, may ameliorate CD but worsen UC. However, we present a case of a 35year-old woman with a history of UC since age 20. Infliximab seemed to help but she had anaphylactic shock on her third treatment, so it was stopped. She failed to respond to mesalamine and corticosteroids, which led to surgical treatment with a protocolectomy and ileostomy at age 28. Subsequently, the ileostomy was reversed 10 weeks later. After the reversal of the ileostomy she had 14 bowel movements per day associated with severe dyschezia and hematochezia despite taking mesalamine. Shortly after starting 15 mg dextroamphetamine sulfate extended release capsules her symptoms markedly abated to having only three bowel movements per day associated with little to no dyschezia and no hematochezia. Increasing the dosage to 30 mg/day her bowel movements are now once per day and are not associated with any dyschezia. She no longer had an urgency feeling after defecation. The autonomic nervous system includes the sympathetic, parasympathetic, and enteric nerves and is involved in various body functions, e.g., inflammation, body temperature, blood pressure, and fluid homeostasis. Significant improvement in a large variety of other previous refractory conditions, e.g., pelvic and bladder pain, arthritic pain, and fibromyalgia, vasomotor symptoms, peripheral edema and weight gain, urticaria, and chronic fatigue besides the GI conditions suggests that there may be a primary defect in the autonomic nervous system. Some factor may cause demyelinization of autonomic nerve fibers in a particular area, leading to disorders in various parts of the body. Support for the hypothesis that IBD may be part of the generalized autonomic nervous system dysfunction is not only provided by the quick improvement following sympathomimetic amines in these two anecdotal IBD cases but also evidence that there is impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytyptamine in human IBD. Boisse et al stated that ‘‘targeting the sympathetic nervous system using pre-existing pharmacological agents may prove to be a valuable compliment to existing IBD therapies by restoring normal GI function and enhancing mucosal healing.’’ Indeed, clonidine has been tried successfully in treating UC, and thus it would be interesting to compare the efficacy of clonidine versus dextroamphetamine sulfate in UC.

Novel highly effective medical treatment of severe treatment refractory Crohn's disease using sympathomimetic amines: case report.

To the Editor: There is a common disorder of the sympathetic nervous system that predominantly affects women and is the cause of a large variety of chronic disorders. Although these chronic debilitating health conditions respond quickly and very effectively to low doses of sympathomimetic amines (especially dextroamphetamine sulfate), most treating physicians are unaware of this condition. Thus, many women go through an array of painful and expensive tests and receive various treatments with minimal effectiveness and frequently many side effects when they could find great relief from a small dose (10–30 mg) of sustained release dextroamphetamine sulfate. These chronic disorders refractory to ‘‘standard treatment’’ may manifest as pain disorders, e.g., pelvic pain, abdominal pain, interstitial cystitis, backache, headache, arthritis, fibromyalgia, and mastalgia. This disorder of the sympathetic nervous system may also manifest as unexplained weight gain, urticaria, chronic fatigue, and vasomotor symptoms unresponsive to estrogen, and a pseudohypothyroid state. This condition has been recently named the sympathetic neural hyperalgesia edema syndrome. Some of the types of abdominal pain that have shown dramatic improvement to sympathomimetic therapy which had previously failed to respond to conventional therapy include esophageal motility disorders, gastroparesis, and pseudointestinal obstruction. We recently presented a case at the 2009 Advances in Inflammatory Bowel Diseases Crohn’s & Colitis Foundation’s National Clinical & Research Conference of a 39-year-old woman who was diagnosed with Crohn’s disease (CD) by colonoscopy at age 27. She presented with the hope of a novel medical therapy to prevent the next suggested therapeutic procedure of a diverting ileostomy to help her severe dyschezia. She noted 8–10 excruciating bowel movements per day and was not responding to adalimumab 80 mg every other week. She previously had failed to respond to mesalamine, prednisone, cyclophosphamide, and infliximab. She was suffering from two perianal fistulas that had persisted despite a previous incision and drainage of the abscess and the insertion of a seton. A second incision and drainage of an ischiorectal abscess with seton placement was performed 8 months later with limited relief. Besides, the perianal lesions colonoscopy revealed CD involving the majority of the colon. A diverting ileostomy was recommended as the next therapy. Within 1 month of treatment with dextroamphetamine sulfate extended release capsules, 20 mg per day, her symptoms were 90% improved. Following an increase to 25 mg of dextroamphetamine sulfate her symptoms of frequent bowel movements and dyschezia have almost completely disappeared over the 6-month course of therapy. Her two perianal fistulas have closed. She states she feels great and that she usually has only one, rarely two, bowel movements per day without any pain or bleeding. A review article by Baumgart and Sandborn critically reviewed the evidence for various therapies that included 5-aminosalicylic acid compounds, corticosteroids, immunomodulators, calcineurin inhibitors, biologic compounds such as anti-tumor necrosis factor alpha (e.g., infliximab, adalimumab, and certolizumab pegol), and biologicals directed agonist receptors (e.g., visilizumab and abatacept) which are involved in T-cell activation, selective adhesion molecule blockers (e.g., natalizumab, MLN-02, and alicaforsen), antiinflammatory cytokines (e.g., interleukin 10), modulators of the intestinal flora (e.g., antibiotics, prebiotics, and probiotics), leukocyte apheresis, and many other monoclonal antibodies, small molecules, recombinant growth factors, and MAP kinase inhibitors targeting various inflammatory cells and pathways. When medical therapies fail, surgical interventions may be necessary, as described in this case. However, a previous case of pseudointestinal obstruction had made us think of another very novel potential treatment option (extensive search of the literature has found no precedent) of considering at least in some cases of CD that there may be an underlying bowel motility disorder. In the pseudointestinal obstruction case she failed to grow or gain any weight from age 5 to 61⁄2 and was found to have CD by colonoscopy. She responded to mesalamine and did fine with normal colonoscopies until age 22, when she developed early satiety, abdominal pain, constipation, and weight loss of 35 pounds (110 pounds down to 75). Nevertheless, the colonoscopy showed no evidence of CD but instead she was found to have pseudointestinal obstruction. She responded quickly to dextroamphetamine sulfate and is painfree, has normal bowel movements, and regained most of her weight (5 feet tall, 102 pounds). Thus, we thought that perhaps in some instances a bowel motility disorder can lead to changes in microbiological flora and cause bowel inflammation leading to CD. There is the possibility that the sympathomimetic amines have a direct effect on inflammation by effecting vascular permeability similar to its demonstrated marked beneficial affect on chronic urticaria resistant to other standard therapies. There is little doubt in our minds that the present case responded to dextroamphetamine sulfate since she had failed to respond to previous therapies with the medications Copyright VC 2010 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21269 Published online 12 April 2010 inWiley Online Library (wileyonlinelibrary.com).

Absence of sperm with rapid motility is not detrimental to IVF outcome measures when ICSI is used.

The objective of the current study was to investigate the association between rapid motility of sperm and IVF outcome when ICSI is used for insemination of oocytes. The first IVF cycle of women up to age 42 were evaluated. Patients were classified into groups by the presence/absence of sperm with rapid motility (“A” sperm) in the specimen before and after sperm preparation. Group 1 had 0% A sperm prewash and 0% A postwash (n = 45); Group 2 had 0% A sperm prewash but some A sperm postwash (n = 47); Group 3 had A sperm both pre and postwash (n = 141). Statistical analysis demonstrated no difference in the fertilization, PRs, or implantation rates in the three groups. These data suggest that absence of sperm with rapid motility postseparation of sperm from seminal plasma is not detrimental to IVF outcome when ICSI is used for insemination.

Hypofunction of the sympathetic nervous system is an etiologic factor for a wide variety of chronic treatment-refractory pathologic disorders which all respond to therapy with sympathomimetic amines

The hypothesis set forth is that the basis for a great many chronic debilitating conditions that involve almost all of the physiologic systems of the body may have as the underlying cause and a common link between them, i.e., hypofunction of the sympathetic nervous system. The hypothesis considers that one of the main functions of the sympathetic nervous system is to diminish cellular permeability. Thus sympathetic hypofunction may lead to absorption of chemicals and toxins into tissues that were supposed to be impervious leading to inflammation and other adverse consequences which then cause a wide variety of symptoms. These symptoms may include pain or diminished muscular function leading to various pain syndromes or conditions related to diminished muscular function. Furthermore since the sympathetic nervous system is involved in body homeostasis and temperature regulation, sympathetic nervous system hypofunction could lead to disorders in these areas, e.g., vasomotor symptoms and edema. This defect in sympathetic nervous system has a genetic predisposition but relatives, e.g., siblings or children may manifest in a different manner which suggests some influence of external factors causing one physiological system to be more prone than another to malfunction under conditions of sympathetic hypofunction. Evidence to support this hypothesis has been provided by a large number of published anecdotes demonstrating the quick and long lasting considerable improvement in symptoms following treatment with the sympathomimetic amine dextroamphetamine sulfate (with return of symptoms if treatment is temporarily ceased thus diminishing the likelihood of spontaneous remission) despite failure to respond to a plethora of other pharmacologic agents and other therapies over many years. The physiological systems with various chronic disorders that have responded included the gastrointestinal system, skin, genitourinary system, the nervous system, the musculoskeletal system, the temperature regulation system, peripheral vasculature system, and the endocrine system. Despite the multitude of very convincing anecdotal reports showing its efficacy (and to date no reports refuting this hypothesis), there has only been one controlled study which showed the benefit of dextroamphetamine sulfate on edema and weight gain in diet-refractory patients. The flaw to date for general acceptance of this hypothesis is that most positive studies are coming from one clinical center. Furthermore, more controlled studies are needed. There has been a recent interest amongst physiologists and recent studies have been published confirming a deficiency of sympathetic nerve fibers in some of these disorders which hopefully will encourage more research into other physiologic systems leading to corroboration of this hypothesis.

Defective Oocytes are not a Common Cause of Unexplained Inferitlity as Determined by Evaluation of Sharing Oocytes Between Infertile Donors and Recipients

PURPOSE To determine if defective oocytes or sperm may be a common etiologic factor in unexplained infertility. MATERIALS AND METHODS A retrospective comparison of fertilization rates and pregnancy rates from infertile donors with unexplained infertility trying to conceive with in vitro fertilization-embryo transfer (IVF-ET) and their respective recipients, who shared the other half of the oocytes with the recipients male partner for financial compensation was performed. Pregnancy rates from donors and recipients were also compared to other donor recipient pairs sharing oocytes from infertile donors with tubal or male factor or financially-compensated donors providing oocytes to two recipients. RESULTS Pregnancy rates from infertile donors with unexplained infertility were comparable not only to their respective recipients but to other donor/recipient pairs that received oocytes from donors with tubal or male factor or financially-compensated donors. Fertilization rates were somewhat reduced in the infertile donors. CONCLUSIONS Abnormal embryos resulting from an oocyte or sperm defect do not appear to be a common cause of unexplained infertility. The possibility does exist that sperm may be an etiologic factor in reduced fertilization potential, which not only could be obviated by conventional oocyte insemination, but could be further improved by intracytoplasmic sperm injection (ICSI).

Prompt and highly effective control of severe abdominal pain and dyschezia with sympathomimetic amine therapy in a woman with Crohnʼs disease resistant to standard therapy: P-0005.

PURPOSE: To determine if the use of oral sympathomimetic amine treatment could improve abdominal pain and dyschezia in a woman with such severe symptoms that a diverting ileostomy was recommended as her next treatment option. DESCRIPTION OF PROJECT: This 39-year-old woman was presently being treated with adalimumab for Crohn’s disease. She had previously been treated with mesalamine, prednisone, cyclophosphamide, and infliximab without significant improvement. Unfortunately despite the adalimumab therapy she had no relief of symptoms and developed her second perianal fistula. Her next recommended therapy was a fecal diverting ileostomy. She wanted to avoid surgery and opted instead to try a novel therapy of dextroamphetamine sulfate extended release capsules 20mg once daily. RESULTS: Within one month of therapy her symptoms were 90% improved. Raising the dosage to 25mg her symptoms almost completely disappeared after two months of therapy. The plan is to begin weaning off adalimumab therapy and see if the sympathomimetic amine treatment is sufficient. CONCLUSIONS: This case introduces a potential new, highly effective, well tolerated treatment with well known long term safety. Whether the benefit of therapy for patients with Crohn’s disease will be seen in only special circumstances or whether the benefit may extend to the majority of patients with this disease remains to be determined by a larger controlled trial that hopefully will be encouraged by this case report. Sympathomimetic amine therapy has also been found to quickly and effectively provide long lasting correction of the symptoms and signs of gastrointestinal motility disorders including esophageal motility disorders, gastroparesis, and pseudointestinal obstruction when other standard therapies failed. In fact the impetus to try sympathomimetic amine therapy was a 23-year-old woman who was diagnosed with Crohn’s disease at age 7 who was well controlled on mesalamine until she developed diarrhea, abdominal pain and a 25% weight loss down to 74 pounds which was diagnosed as pseudointestinal obstruction rather than an exacerbation of her Crohn’s disease. She dramatically improved and is back to her original weight following dextroamphetamine therapy. Thus one might consider that there may be some association with gastrointestinal motility defects and Crohn’s disease and at least some cases may respond to sympathomimetic amine therapy. A generalized defect in the sympathetic nervous system has been found to be the etiologic factor for a wide variety of medical conditions that are refractory to conventional therapy but dramatically respond to sympathomimetic amines. These conditions include pain syndromes other than the aforementioned gastrointestinal conditions including pelvic pain, interstitial cystitis, fibromyalgia, arthritis, migraine headaches, and mastalgia. Other refractory conditions responding to sympathomimetic amines that have been reported are chronic urticaria, edema and weight gain, and chronic fatigue. The question to be answered by a large controlled study is whether this disorder of the sympathetic nervous system is an occasional etiologic factor for Crohn’s disease or will it prove to be a common cause such that most cases will respond to this very well tolerated nonrisky treatment similar to pelvic pain and interstitial cystitis.

P-9: Pregnancy Outcome Following In Vitro Fertilization-Embryo Transfer (IVF-ET) in Women of More Advanced Reproductive Age With Elevated Serum Follicle Stimulating Hormone (FSH) Levels

PURPOSE To present data on the chances of pregnancy following in vitro fertilization embryo transfer, according to day 3 serum FSH and age groups in women > or = age 36. MATERIALS AND METHODS Data were analyzed according to three age groups (36-39, 40-42, > or = 43) and five serum FSH ranges (< or = 10, 11-12, 13-14, 15-16, > or = 17). RESULTS No live pregnancies were found in women aged > or = 40 with serum FSH > or = 15 mlU/ml but they were seen in women aged 36-39. Live deliveries were seen in women even > or = 43 with serum FSH 13-14 mlU/ml. CONCLUSIONS The higher the serum FSH and the greater the age, the lower the chances of successful conception. However, reasonable pregnancy rates are found in women aged > or = 36 with serum FSH > or = 15 mlU/ml and a live delivered pregnancy rate of about 10% can occur even in women aged > or = 43 with mild FSH elevations.