Reviews/Commentaries/ADA Statements PERSPECTIVES ON THE NEWS

Diabetic Neuropathy

ZACHARY T. BLOOMGARDEN, MD for a diabetic person without ulceration cal trial showed no evidence that ampu- Perspectives on the News commentaries are (2). tations were avoided (3). part of a free monthly CME activity. The Berendt referred to the use of hyper- Berendt concluded that although Mount Sinai School of Medicine, New York, baric oxygen as “myth,” in the sense of there is a body of evidence that ulcers heal New York, designates this activity for 2.0 being a widely held but false notion, sug- more rapidly and that there is a reduced AMA PRA Category 1 credits. If you wish to gesting that although the approach is used amputation rate with hyperbaric oxygen, participate, review this article and visit ww- in perhaps 800 facilities in the U.S., data there appears to be bias in the available w..procampus.net to complete a showing efficacy is lacking. “There is poor trials. Furthermore, he implied that that posttest and receive a certificate. The Mount evidence of effectiveness or of cost- there are some 20 million people with di- Sinai School of Medicine is accredited by the effectiveness,” he stated, pointing out that abetes in the U.S., so that if one million Accreditation Council for Continuing Medi- the use of this approach dates to the individuals have foot ulcers, and one- cal Education (ACCME) to provide continu- 1600s with use of pressurized chambers third potentially would benefit from hy- ing medical education for physicians. for treatment of individuals with respira- perbaric oxygen, at a cost of each tory disease, with approaches to use of treatment course of approximately his is the seventh in a series of arti- oxygen at high pressure beginning more $20,000; $7 billion would be spent on cles based on presentations at the than 200 years ago, leading to recognition this treatment annually. Indeed, he noted T American Diabetes Association’s of some of the hazards of exposure to that hospitals and even outpatient facili- 67th Scientific Sessions, 22–26 June pressurized air. Use of this approach for ties appear to be opening hyperbaric 2007, Chicago, Illinois, that discuss decompression sickness and for gas gan- treatment units because of the high po- aspects of diabetic foot wounds and grene has been valuable, and the use of tential for profit. With this very high po- neuropathy. hyperbaric oxygen has been thought ben- tential cost, he concluded, hyperbaric eficial for other conditions by increasing therapy has not been adequately docu- Hyperbaric oxygen oxygen delivery from plasma. Other mented to be a reasonable approach to In a debate on whether hyperbaric oxygen mechanisms of benefit may include local treatment. is beneficial in the healing of diabetic foot vasoconstriction and increase in local Hopf argued in favor of hyperbaric wounds, Anthony Berendt (Nutfield, growth factor levels. There is evidence of oxygen treatment, stating that this ther- U.K.) suggested it not to be appropriate, benefit in diabetic foot wounds compli- apy specifically addresses the mecha- while Harriet Hopf (Salt Lake City, UT) cated either by osteomyelitis or by soft nisms that appear involved in diabetic argued that it is an evidence-based appro- tissue infection. Berendt alluded, how- foot wounds and that, in her opinion, priate approach for treating certain peo- ever, to a long association of the treatment there is clinical trial evidence that severe ple with severe diabetic foot wounds. As with what he suggested might be some- ulcers with risk of amputation can be discussed in last month’s column, the di- what disreputable medical care, with treated with this approach with benefit. ϳ abetic foot is an important problem. In a what he termed a lack of convincing evi- Diabetic foot ulcers account for 65% of series of 449 patients with diabetic foot dence of benefit in diabetic foot wounds amputations, with poor healing related to wounds, 352 were superficial and 134 of without evidence of infection, although vasomotor dysfunction and abnormal these were neither ischemic nor infected. such lesions have been recommended as transfer of oxygen into tissues. Neuropa- A total of 183 ulcers were clinically in- targets for the treatment. He pointed out thy may lead to repetitive trauma, but fected, and 216 patients had arterial in- that uncontrolled clinical reports are un- there is also impaired resistance to infec- sufficiency. At 6 and 12 months, 247 and likely to lead to unbiased data, as patients tion, abnormal tissue perfusion, and ab- 295 of the ulcers had healed without am- who are treated with this very expensive normalities of inflammation with putation, with median time to healing 78 approach are likely to have better health fibroblasts from diabetic patients showing days; 6 and 8% required amputation and care access and to be more compliant. The delayed proliferation. Certainly, she an additional 6 and 11% of the patients best source of information, Berendt agreed, medical evaluation for neuropa- had died at the two time points, suggest- stated, is a Cochrane review that included thy, ischemia, and infection are crucial, ing high morbidity and mortality associ- only five randomized controlled trials, with glycemic control and debridement, ated with diabetic foot wounds (1). Using four of which were relevant to the diabetic offloading, proper moist wound care, and a Medicare database, the average expen- foot. The two largest studies scored smoking cessation all basic, but, even diture for a diabetic person with a lower- poorly in terms of methodology. Of the with such optimal approaches, one-third extremity ulcer in 1995–1996 was over other two studies, one did not address of chronic foot wounds in diabetic pa- $15,000, approximatley three times that clinical end points, and the smaller clini- tients fail to heal, and amputations cannot be prevented. In this context, adjunctive ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● therapies play important roles. Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with Hyperbaric oxygen is usually admin- the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. istered at least at twice atmospheric pres- Abbreviations: CIDP, chronic inflammatory demyelinating ; 5-HT, 5-hydroxytryptamine. sure, with at least 30 treatments required DOI: 10.2337/dc08-zb03 © 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly to promote angiogenesis. Barotrauma cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. with ear injury occurs in 2–4% of pa- org/licenses/by-nc-nd/3.0/ for details. tients, and pulmonary barotrauma caus-

616 DIABETES CARE, VOLUME 31, NUMBER 3, MARCH 2008 Bloomgarden ing pneumothorax or gas embolism is prove outcome at reduced overall cost. ropathies of a variety of types. The sen- extremely rare. Seizure occurs at approx- She stressed the need for use of appropri- sory phenotype is largely length- imately seven times atmospheric pres- ate selection guidelines as to wound se- dependent, so that symptoms of sure, but are not felt to be caused by the verity and transcutaneous oxygen paresthesia, pain, and sensory loss occur lower levels used in treatment. Other in- concentration. There is an accreditation most often in the distal lower extremities. frequent adverse effects include hypogly- mechanism by which the Hyperbaric This form of neuropathy was well de- cemia, a form of transient myopia, and Medicine Society certifies that a center is scribed by R Wayne Rundles in the 1940s, worsening of uncontrolled congestive able to deliver the treatment, although as occurring early in the course of diabe- heart failure, which is a contraindication Hopf acknowledged that participation is tes, often within months of onset, and af- to the approach. In addition, some people currently voluntary, and that many of the fecting diabetic children with what is experience extreme claustrophobia and facilities performing this treatment cur- likely a higher frequency than clinically cannot tolerate the units. Decompression rently do not adhere to the guidelines she recognized (6). sickness due to formation of intravascular described. “The data are there,” she said, Autonomic neuropathy also exhibits nitrogen bubbles does not occur, as only emphasizing that while “it’s not the final length dependence, leading to the easily pure oxygen is administered. Hopf de- answer, there is enough to say that this is damaged dry feet characteristic of the di- scribed as crucial the use of transcutane- a treatment. . . that demonstrates a bene- abetic patient. The differential diagnosis ous oximetry. The normal transcutaneous fit.” It should be noted that the Medicare of sensory polyneuropathy includes many oxygen level is 50–70 mm mercury, with National Coverage Determinations Manual conditions, such as hypothyroidism, vita- a level Ͻ20 associated with more than a relevant criteria for coverage are for min B12 and thiamine deficiency, and 100-fold increase in risk of amputation. “chronic refractory osteomyelitis, unre- other nutritional neuropathies, particu- When such wounds are treated with sponsive to conventional medical and larly alcohol-related and post gastrec- hyperbaric oxygen, transiently, tissue ox- surgical management,” and for “diabetic tomy. Neuropathy may be associated with ygen levels around 500 mmHg may be wounds of the lower extremities in pa- sarcoidosis, with anti–myelin-associated seen. If levels do not increase at least to tients who . . . [have] a wound classified glycoproteins, or with monoclonal gam- 100 mmHg, it is unlikely that healing will as Wagner grade III or higher; and . . . mopathies; may represent a paraneoplas- occur. Hopf noted, though, that simple failed an adequate course of standard tic syndrome; and may be seen in early delivery of oxygen to ischemic tissue is wound therapy. . . after there are no mea- chronic inflammatory demyelinating unlikely to be the direct mechanism of surable signs of healing for at least 30 days polyneuropathy (CIDP). Spinal stenosis, benefit, as it only takes place for several of treatment” (5). It would appear that with or without carpal tunnel syndrome, hours per day. Rather, she suggested, hy- Hopf’s recommendations are congruent may present as a pseudo-neuropathy. perbaric oxygen should be considered in with these guidelines, and that if the treat- Toxins, human immunodeficiency virus, essence a pharmacologic approach, ment is, as Berendt implied, inappropri- early forms of vasculitis and connective which increases neutrophil bacteriocidal ately used at some facilities to treat tissue diseases, amyloid, and inherited activity, increases angiogenesis, increases patients with less severe wounds, there neuropathies such as Charcot-Marie- growth factor levels, and decreases leuko- already exists a mechanism for withhold- Tooth are additional possibilities. Poten- cyte adhesion, so potentially promoting ing of reimbursement. tial screening tests might include a an appropriate inflammatory response in complete blood count, sedimentation the diabetic foot wound. She reviewed, in Types of rate, vitamin B12, thyroid stimulating somewhat more detail than did Berendt, Douglas Zochodne (Calgary, Canada) hormone, protein electrophoresis, homo- the relevant intervention studies, with reviewed the differential diagnosis of cysteine, and methylmalonic acid level, as transcutaneous oxygen measurements at diabetic neuropathy, noting that approx- well as electrophysiologic testing, al- the beginning of the trials ϳ20 in both imately half of diabetic patients have though a cookbook approach to screen- groups, increasing threefold among those evidence of neuropathy, so that the prev- ing is much less useful than a high level of receiving hyperbaric oxygen, implying alence of diabetic neuropathy is some diagnostic suspicion for people with sig- that the approach increases local perfu- 100-fold greater than the combined prev- nificant or progressive disease. One must sion, perhaps by stimulating angiogene- alence of degenerative neurologic condi- ask, “Does it fit?” Does the sensory com- sis. She suggested that for individuals tions such amyotrophic lateral sclerosis ponent exceed the degree of motor loss, whose baseline transcutaneous oxygen and Parkinson’s disease. Diabetic motor are there other neurologic abnormalities, level is Ͼ40, it is unlikely that hyperbaric and sensory polyneuropathy may be clas- is control of glycemia good, is the syn- oxygen will be helpful. In the Cochrane sified into a number of types, including drome subacute, and is there weight loss meta-analysis of 118 patients treated for distal symmetrical neuropathy, particu- or other evidence of another systemic severe diabetic foot wounds (3), there was larly with sensory abnormalities mainly illness? excellent likelihood of response to hyper- involving small nerve fibers; mixed motor CIDP typically affects motor nerves to baric oxygen as an adjunctive treatment and sensory neuropathy, the most com- a greater extent than sensory, and may be for diabetic foot ulcers of Wagner (4) mon type, comprising ϳ70% of cases of progressive or relapsing, with evidence of grade III (deep wounds with osteomyeli- neuropathy, although nearly half appear prominent demyelination seen on elec- tis) or higher (wounds with partial or to be particularly predominantly sensory trophysiological tests, although it is im- complete foot gangrene). and involve large nerve fibers; mixed mo- portant to note that multiple sites must be In those patients, for whom this form tor-sensory-autonomic neuropathy; pre- tested. There is an elevation in cerebrospi- of treatment is appropriate, Hopf sug- dominantly autonomic neuropathy; the nal fluid protein level and demyelination gested hyperbaric oxygen is cost-effective rare predominantly motor neuropathy; on nerve biopsy, with the disease respon- and, if more widely utilized, would im- and focal and multifocal asymmetric neu- sive to steroids, to intravenous immuno-

DIABETES CARE, VOLUME 31, NUMBER 3, MARCH 2008 617 Perspectives on the News globulin, and to plasma exchange. There conventionally treated patients, while the First, he discussed a 46-year-old male may be an increased prevalence of the relationship of neuropathy to height was with hyperhydrosis. He was referred to syndrome in diabetes, and certainly dia- not significant in the intensive treatment his endocrine clinic with mild hyperten- betes does not prevent the condition, group. Height was not significantly re- sion and with sympathetic hyperreactiv- leading Zochodne to note that it is impor- lated to either retinopathy or nephropa- ity on autonomic function testing, and tant to consider this entity in appropriate thy. Pradeepa et al. (abstract 303) showed lack of the expected nocturnal diabetic patients. He stressed the impor- reported aspects of diabetic neuropathy fall in blood pressure. He was found to tance of neurologic assessment of all dia- in the Indian Chennai Urban Rural Epi- have diabetes on glucose tolerance test- betic patients, with monofilament testing demiology Study. This study included ing, and he responded to treatment with useful, as is the use of quantitative sensory 1,382 previously known and 354 newly clonidine. testing of vibration sensation, although detected diabetic patients. Using vibra- Cardiomyopathy, Stevens said, is a this is not routinely available. Epidermal tory perception threshold measurement, contributing factor to heart failure in peo- skin biopsy is a new technique being 11% had neuropathy, affecting 12% of ple with diabetes, with heart failure three studied which may be useful (7), as is known versus 7% of newly diagnosed pa- to five times more frequently seen in in- confocal microscopy of nerve fibers in the tients. Retinopathy and proteinuria were dividuals with than without diabetes. Au- cornea (8). Zochodne pointed out that associated with a doubling of likelihood tonomic dysfunction may well contribute neuropathy may be associated with im- of neuropathy. to this, with hypertension as a risk factor paired glucose tolerance, and that this Davis et al. (abstract 4) followed 531 for heart failure, which is typically unrec- syndrome may be associated with neuro- type 2 diabetic individuals for 5–8 years, ognized when only occurring during the pathic pain, although Zochodne did point finding that use of either a statin or a fi- night. Other potential causes of heart fail- out that “further work is needed.” Cer- brate were associated with a 48 and 35% ure in individuals with diabetes include tainly, there are age-related effects on the respective reduction in the likelihood of microvascular disease and oxidative peripheral , and although peripheral sensory neuropathy, indepen- stress, as well as the increased prevalence he did not believe that one could diagnose dent of their effects on lipid levels. Ziegler of coronary artery disease. Dysfunction of “a neuropathy just because of age,” Zo- et al. (abstract 7) treated 460 diabetic peo- the sympathetic nervous system may also chodne agreed that age with diabetes cer- ple with mild-to-moderate distal symmet- contribute to heart failure in diabetes. tainly can increase the likelihood of ric polyneuropathy with ␣-lipoic acid 11C-meta-hydroxyephedrine positron neuropathy. 600 mg daily or placebo for 4 years, find- emission tomographic imaging may be Compression nerve injuries are also ing significant improvement versus wors- used to visualize sympathetic neurons more common in individuals with diabe- ening in clinical measures of peripheral (10). This radiolabeled analog of norepi- tes and can be debilitating. These include motor and sensory neuropathy, although nephrine competes for reuptake into carpal tunnel syndrome, ulnar neuropa- the degree of worsening among control nerve terminals, giving a marker of sym- thy due to entrapment at the elbow (with patients was modest. There was no im- pathetic tone and of sympathetic nerve consequent loss of intrinsic muscle func- provement in nerve conduction. fiber density. In a comment about 123I- tion in the hand), and peroneal neuropa- metaiodobenzylguanidine single-photon thy with foot drop. Intercostals neu- Diabetic sympathetic neuropathy emission computed tomography scan- ropathies can mimic abdominal visceral Martin Stevens (Birmingham, U.K.) dis- ning, Stevens noted that this is also a rea- emergencies, and lumbosacral plexopa- cussed sympathetic dysfunction in diabe- sonable tool for cardiac sympathetic thy may be associated with prolonged tes, suggesting its relationship to a imaging, but that it is more difficult with pain, with all of these syndromes requir- number of diabetic complications. Neu- this imaging agent to correct for inhomo- ing a variety of medical and, on occasion, ropathy is present in up to 70% of indi- geneity of myocardial perfusion. surgical therapies. viduals with diabetes, and may be seen in In type 1 diabetes there is evidence of Several studies presented at the ADA the prediabetic stage (9). Autonomic dys- increased left ventricular sympathetic meeting addressed aspects of diabetic function, however, has not been as well tone with such imaging, despite normal neuropathy. Jurado et al. (abstract 784) studied as . Diabe- results of conventional tests of autonomic measured plasma levels of the NH2- tes results in a form of small-fiber neurop- function, with this abnormality associ- terminal fragment of the brain natriuretic athy, affecting autonomic nerve fibers. ated with diastolic dysfunction (11). In- peptide in 100 type 2 diabetic people, The cardiovascular system and lower creased sympathetic tone may lead to showing significant correlation with age limb both may be affected by abnormali- small-vessel damage and is associated and with the presence of cardiovascular ties of the sympathetic nervous system. with decreased myocardial perfusion re- disease. By correcting for these factors, Cardiac metabolism utilizes glucose, serve. In people with type 2 diabetes, however, levels correlated with the pres- amino acids, ketones, and fatty acids, within the first 1–2 years after diagnosis, ence of diabetic peripheral neuropathy. with increased fatty acid levels in diabe- more than half of the left ventricle shows (Abstract numbers refer to the American tes, potentially requiring greater levels of increased sympathetic tone with such stud- Diabetes Association Scientific Sessions, oxygen consumption and potentially con- ies. This may be a reflex response to cen- Diabetes 56 [Suppl. 1], 2007.) Atkin et al. tributing to cardiac energy depletion. tral activation of the sympathetic nervous (abstract 800) analyzed data from the Di- Stevens presented case studies illustrating system, and may lead to increased oxida- abetes Control and Complications Trial the roles of sympathetic dysfunction as a tive stress and to loss of cardiomyocytes. (DCCT), in which 149 of 1,245 patients presenting feature of diabetes, and in rela- In the lower limb, edema, pain, and assessed at 5 years developed neuropathy. tionship to early cardiovascular dysfunc- erythema may be caused by increased There was a 4% increase in neuropathy tion in diabetes, potentially predisposing to sympathetic tone, with decreased sweat- per centimeter increase in height among heart failure. ing, leading to dry and cracked skin, with

618 DIABETES CARE, VOLUME 31, NUMBER 3, MARCH 2008 Bloomgarden

jecting a vector from which the desired NEWS FROM THE FOOD AND DRUG ADMINISTRATION genes would be taken up directly. Poten- tial vectors include liposomes, and retro- From time to time, new announcements by the FDA pertaining to aspects of diabetes virus and adenovirus. Fink noted that treatment will be highlighted in this section. herpes simplex virus might be an idea On 18 January 2008, the FDA approved a modification to the prescribing infor- vector for such treatment, as it is naturally mation for the bile acid binding resin colesevelam, agreeing that its glucose- taken up in sensory neuronal nuclei, re- lowering properties are sufficient to warrant adding this effect as an additional maining in this location through the life- indication for its use. When administered in a dose of six 625-mg tablets daily, time of the host, and carried by the new information states that in combination with metformin, the placebo- retroaxonal transport form nerve fibers to adjusted decrease in A1C was 0.5%, from a baseline of 8.1%. In combination the nucleus. Deletion of one of the early with sulfonylurea, the placebo-adjusted A1C decreased by 0.8% from a baseline viral protein genes abolishes replication of 8.2%, and in combination with insulin the placebo-adjusted A1C decreased by and infectivity, further suggesting this to 0.6% from a baseline of 8.2%. The FDA approval letter is available at http:// be a potentially useful approach. In a pyr- www.fda.gov/cder/foi/appletter/2008/021176s017ltr.pdf and the revised pre- idoxine overdose animal model, a vector scribing information at http://www.fda.gov/cder/foi/label/2008/021176s expressing neurotrophin 3 was adminis- 0171bl.pdf (both accessed 27 January 2008). tered before pyridoxine, finding that this approach prevented weakness and histo- logical abnormality in the model, which can be considered “proof of principle.” With a lower-limb osteoporosis and increased prevent supine hypertension. Agents to latency promoter to allow long-term gene risk of fracture, and with a relationship to reduce cardiac fatty acid utilization are expression, the vector was administered 5 development of Charcot arthropathy. being studied. Stevens noted that treat- months before pyridoxine, again prevent- Bone density is reduced by 15–20% in ment of denervation is quite ing the toxic neuropathy. In a streptozoto- individuals with type 1 diabetes, with in- difficult. cin-diabetic mouse model, with vector creased sympathetic tone contributing to Two studies reported at the ADA administered 2 weeks after onset of dia- elevated rates of bone turnover. meeting addressed relevant aspects of di- betes, over 6 months electrophysiology Later cardiovascular effects of sympa- abetic neuropathy. Lomax and Jones (ab- showed preservation of nerve function de- thetic dysfunction include an elevation in stract 261) prospectively studied the spite hyperglycemia. Dermal innervation, resting heart rate, which may be associ- incidence of Charcot arthropathy, de- which is largely lost in diabetic animals, was ated with either decreased parasympa- fined by a swollen, warm, neuropathic preserved with treatment. A human trial is thetic or increased sympathetic tone. foot with bounding pulses, in a U.K. pop- planned in painful neuropathy. Impaired exercise tolerance may be seen ulation followed from 1996 to 2006, find- In a study presented at the ADA meet- in this setting, and there is an association ing an annual incidence of three cases per ing, Wessels et al. (abstract 3) found cog- of sudden death with sympathetic dys- 10,000 diabetic individuals. After treat- nitive performance of type 1 diabetic function, although the assumption of cau- ment with casting for 5–8 months, three- patients was reduced in proportion to re- sality is difficult to demonstrate given the quarters of patients were weaned to duction in the ratio of white matter to to- many associated diabetic complications footwear while ϳ10% required surgical tal intracranial volume on MRI scanning, in such patients. Stevens presented a sec- removal of bone and an additional 10% with the anatomic lesion more pro- ond case, a 26 year-old woman who had died or had an amputation. Jirkovska´et nounced in those with retinopathy, had type 1 diabetes for 12 years, with al. (abstract 260) found evidence of vita- suggesting a relationship between micro- background retinopathy, albuminuria, min D deficiency in association with in- vascular disease and loss of brain func- tachycardia, and anemia. 11C-meta- creased bone reabsorption in 38 diabetic tion. Gandhi et al. (abstract 2) studied hydroxyephedrine positron emission to- people with acute Charcot arthropathy. brain proton magnetic resonance spec- mography was abnormal, with globally troscopy in 71 type 1 diabetic men, find- decreased left ventricular sympathetic in- Gene therapy for neuropathy and ing that those with painful peripheral nervation, but with one area showing neuropathic pain neuropathy had similar levels of thalamic increased sympathetic innervation, po- David Fink (Ann Arbor, MI) discussed neuronal function to those without neu- tentially causing left ventricular instabil- preclinical studies of gene therapy for ropathy, while painless neuropathy was ity and increasing risk of arrhythmia. neuropathy and neuropathic pain. Dia- associated with reduced thalamic func- Multifactorial intervention in the betic polyneuropathy involves “dying tion, suggesting that relative preservation Steno study with pharmacologic therapy back” of sensory motor fibers, with to date of thalamic neuronal function is required that targeted hyperglycemia, hyperten- no effective treatment, although control for the transmission of abnormal periph- sion, dyslipidemia, and microalbumin- of hyperglycemia does slow the rate of de- eral signals that leads to pain perception. uria, along with aspirin, reduced the risk terioration. Peptide neurotrophic factors Obrosova et al. (abstract 1) found evi- of autonomic neuropathy by 63% (12). can be used, although nerve growth factor dence of hyperalgesia, allodynia, and in- Treatment of cardiovascular autonomic studies in animal models involved several traepidermal nerve fiber degeneration in neuropathy in people with diabetes orders of magnitude higher doses than diabetic mice, with these abnormalities with includes have been possible in humans. Such lev- attenuated in diabetic mice either not ex- midodrine, erythropoietin, fludrocorti- els of treatment could be attained by di- pressing or treated with an inhibitor (GPI- sone, octreotide, and simply elevating rect delivery of trophic factors to involved 15427; MGI Pharma, Baltimore, MD) of a the head of the bed during the night to nerves, perhaps with gene therapy by in- poly(ADP-ribose) polymerase enzyme,

DIABETES CARE, VOLUME 31, NUMBER 3, MARCH 2008 619 Perspectives on the News which functions by binding to DNA individuals with diabetes. Symptoms are lyse during endoscopy, but if surgery is breaks. Presumably, overactivation of the seen in 20–55% of people with diabetic required there may be as great as a 10% enzyme in response to oxidant- and free , to a lesser extent in those mortality, so the use of a low-fiber diet is radical–mediated excessive DNA single- with type 2 than with type 1 diabetes, in particularly important for these patients. strand breaks in diabetes promotes neu- association with microvascular complica- The diet should consist of small, frequent ronal dysfunction and cellular damage. tions. These symptoms are associated meals, low in fat and fiber, with emphasis Wymer et al. (abstract 596) adminis- with significant deterioration in quality of on ingestion of liquids, particularly when tered the anticonvulsant lacosamide to life. Lacy reviewed a survey of 398 dia- there is a flare in symptoms. 370 individuals with painful distal dia- betic individuals, excluding those with A large variety of pharmacologic ap- betic neuropathy, finding improvement known depression. Gastroparesis was as- proaches have been used for gastropare- in subjective pain assessment, though sociated with depressive symptoms. Peo- sis, none with great success. The use of with dose-related adverse symptoms of diz- ple with gastroparesis had increased risk prokinetic treatment is controversial. ziness, , fatigue, headache, and of bezoar and of gastroesophageal reflux, Metoclopramide increases acetylcholine tremor. Schwartz (abstract 608) treated 147 occasionally developing a Mallory Weiss release, but 30–40% of treated individu- people having painful diabetic neuropathy tear. The likelihood of cholecystectomy als experience side effects, including anx- with extended-release gabapentin (3 g was markedly increased. Gastroparesis is iety, depression, and change in cognitive daily) or placebo, finding reduction in associated with considerable economic bur- function. Erythromycin does increase pain score and improvement in sleep den. In a survey of 491 patients, 28% had motility, but does not change symptoms. when administered once daily, although decreased income, 11% were disabled be- Domperidone is not available in the U.S., 17 and 12% of individuals who received cause of gastroparesis, and 19% required but appears to be relatively effective, and the once-daily dosing experienced dizzi- placement of a feeding jejeunostomy tube. lacks central nervous system side effects. ness and somnolence, respectively. Symptoms include nausea in 92%, Tegaserod is a 5-hydroxytryptamine (5- epigastric pain in 85%, in 84%, HT)-4 receptor agonist for irritable bowel Diabetic gastroparesis bloating in 75%, early satiety in 60%, an- syndrome in women and has been used in Brian Lacy (Dartmouth, NH) discussed orexia and weight loss in Ͼ50%, and re- people with gastroparesis, although it diabetic gastroparesis, addressing its epi- flux symptoms in Ͼ50%, although none may have potential cardiovascular side ef- demiology, etiology, and pathophysiol- of these symptoms are specific. The diag- fects (13,14). Cisapride is a mixed 5-HT3 ogy; a cost-effective evaluation approach; nosis is established by history, examina- antagonist and 5-HT4 agonist. It is not and current treatment options. He drew a tion (a succussion splash should be available now because of concern about distinction between gastroparesis and considered normal, however, acutely af- cardiac arrhythmias. Antiemetic therapies gastropathy, the former defined by de- ter ingesting a large volume of fluid), a used in gastroparesis include the phe- layed gastric emptying in the absence of flat-plate X-ray of the abdomen for indi- nothiazine derivative prochlorperazine, obstruction. Normal gastric emptying re- viduals with obstructive symptoms, and the antihistamine meclizine, the anticho- quires coordination of extrinsic neurons, esophagogastroduodenoscopy and a sol- linergic scopolamine, metoclopramide, enteric motor neurons, smooth muscle id-phase gastric emptying study if symp- and the 5-HT3 receptor antagonist on- cells, and interstitial cells of Cajal. Multi- toms persist. Ultrasound may be used to dansetron. Sildenafil has effect in animal ple abnormalities contribute to the patho- measure gastric emptying, but an upper models, but at this point has not been genesis of gastroparesis. Symptoms may gastrointestinal series is not useful either in shown to be effective in clinical treatment. be caused by dysfunction of the vagus assessment of gastric emptying or in de- There is no good evidence of benefit from nerve; by loss of interstitial cells of Cajal; tecting complications such as ulceration. use of somatostatin analogs. There is a by injury to the enteric nervous system A gastric emptying study must be car- role for use of narcotic analgesics, Lacy pacemaker; perhaps by microangiopathy ried out for at least 2 h, and ideally for 4 h, said, pointing out that “these patients (though this is controversial); and by with results reported as the percentage of hurt, they are in pain,” but narcotics slow smooth muscle injury, perhaps caused by a standard meal retained at 1, 2, 3, and gastric emptying, so low-dose tricyclics or insulin deficiency or by abnormal hu- 4 h. There is large interindividual varia- gabapentin are probably safer. Acupres- moral factors such as nitric oxide, calcito- tion, and results are influenced by the sure, acupuncture, ginger, and hypno- nin gene-related peptide, substance P, blood glucose at the time of study, by obe- therapy have also been suggested, and neuropeptides Y. It is important to sity, by sex, and by the stage of the men- although Lacy pointed out that symptoms note that hyperglycemia contributes to strual cycle in women. Furthermore, “can wax and wane,” so one must be care- symptoms by slowing gastric emptying, there is poor correlation between symp- ful about unconfirmed reports. even without autonomic neuropathy, in- toms and the gastric emptying time. The Several surgical approaches have hibiting antral pressure waves in both the erythromycin derivative ABT-229, which been used. Venting gastrostomy and com- fed and fasted states. Thus, abnormal gas- acts on motilin receptors, increases gastric bination gastrostomy and jejeunostomy tric emptying motor function produces emptying but fails to improve symptoms. may be reasonable for patients with severe abnormal relaxation of the proximal Lacy reviewed a study of 20 people with antral hypomotility or pylorospasm, al- stomach, with increases in amplitude of gastroparesis, following symptoms and though studies of these approaches are pyloric pressure waves and induction of autonomic nerve testing over 12 years, retrospective and uncontrolled. Lacy re- gastric dysrhythmia. showing that autonomic function deteri- viewed his study of eight type 1 diabetic Gastroparesis, Lacy said, affects ϳ10 orated over time. patients administered by million people in the U.S., with half the A number of treatment approaches injection during upper endoscopy into cases idiopathic (of which 80% occur in have been developed. It is important to the pylorus, with symptoms improving women) and the other half occurring in check for a bezoar. These are difficult to substantially; this result requires verifica-

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