Betsy Bates

SANTA BARBARA, CALIF. — Solutions exist for patients with severe pruritus associated with liver or kidney disease, but they may not be the same as for patients with nonmetabolic causes of itch, according to Timothy G. Berger, M.D.

In the case of liver disease, one must go to the source: the brain, Dr. Berger said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

“The thing that you were taught in medical school about an increase in bile acids in the skin [of patients with liver disease] and all that? That's all wrong,” said Dr. Berger, professor of clinical dermatology at the University of California, San Francisco.

Researchers at the National Institutes of Health conducted a number of “wonderful studies” that proved patients with liver disease do not properly metabolize endogenous opiates, and that “itching may be a complication of that problem,” he said.

“Pruritus in liver disease originates in the brain by increased neurotransmission mediated by endogenous opiates,” he explained. These patients, in fact, can get opiate withdrawal symptoms even though they are not taking opiates.

The solution, then, is to block opiates in the brain.

If topical steroids, phototherapy, and other standard pruritus therapies fail to work, start patients with liver disease on very low dosages of naltrexone (50 mg/day) and titrate upward. During the first week, prescribe 100 mcg of clonidine to avoid opiate withdrawal syndrome, he advised.

Dr. Berger cautioned colleagues to be sure patients are not actually taking opiates during initiation of therapy. He described the case of a 102-year-old patient with liver disease and severe itching who failed to inform him of the fentanyl patches she wore for her osteoporotic pain. “She had opiate withdrawal syndrome and had to be hospitalized for 2 days,” he said. “So be careful.”

Other approaches used for liver disease-related pruritus include cholestyramine or its better-tolerated alternative, colestipol; rifampin; albumin dialysis; and, as a last resort, liver transplantation.

Severe pruritus in patients with renal disease is less well understood.

“As opposed to liver disease and itch, here we have significant disease and we have no clue what the cause is,” said Dr. Berger.

Treating xerosis, which may be profound in renal disease patients, and enhancing their dialysis regimen are good first steps.

Next, administer broadband—not narrow-band—UVB, which is more effective in renal disease-related pruritus.

Finally, prescribing a single, 200− to 300-mg dose of gabapentin (Neurontin) after each dialysis session has been shown to have dramatic effects.

“One pill and bam! The itching drops right off,” he said.

SANTA BARBARA, CALIF. — Solutions exist for patients with severe pruritus associated with liver or kidney disease, but they may not be the same as for patients with nonmetabolic causes of itch, according to Timothy G. Berger, M.D.

In the case of liver disease, one must go to the source: the brain, Dr. Berger said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

“The thing that you were taught in medical school about an increase in bile acids in the skin [of patients with liver disease] and all that? That's all wrong,” said Dr. Berger, professor of clinical dermatology at the University of California, San Francisco.

Researchers at the National Institutes of Health conducted a number of “wonderful studies” that proved patients with liver disease do not properly metabolize endogenous opiates, and that “itching may be a complication of that problem,” he said.

“Pruritus in liver disease originates in the brain by increased neurotransmission mediated by endogenous opiates,” he explained. These patients, in fact, can get opiate withdrawal symptoms even though they are not taking opiates.

The solution, then, is to block opiates in the brain.

If topical steroids, phototherapy, and other standard pruritus therapies fail to work, start patients with liver disease on very low dosages of naltrexone (50 mg/day) and titrate upward. During the first week, prescribe 100 mcg of clonidine to avoid opiate withdrawal syndrome, he advised.

Dr. Berger cautioned colleagues to be sure patients are not actually taking opiates during initiation of therapy. He described the case of a 102-year-old patient with liver disease and severe itching who failed to inform him of the fentanyl patches she wore for her osteoporotic pain. “She had opiate withdrawal syndrome and had to be hospitalized for 2 days,” he said. “So be careful.”

Other approaches used for liver disease-related pruritus include cholestyramine or its better-tolerated alternative, colestipol; rifampin; albumin dialysis; and, as a last resort, liver transplantation.

Severe pruritus in patients with renal disease is less well understood.

“As opposed to liver disease and itch, here we have significant disease and we have no clue what the cause is,” said Dr. Berger.

Treating xerosis, which may be profound in renal disease patients, and enhancing their dialysis regimen are good first steps.

Next, administer broadband—not narrow-band—UVB, which is more effective in renal disease-related pruritus.

Finally, prescribing a single, 200− to 300-mg dose of gabapentin (Neurontin) after each dialysis session has been shown to have dramatic effects.

“One pill and bam! The itching drops right off,” he said.

SANTA BARBARA, CALIF. — Solutions exist for patients with severe pruritus associated with liver or kidney disease, but they may not be the same as for patients with nonmetabolic causes of itch, according to Timothy G. Berger, M.D.

In the case of liver disease, one must go to the source: the brain, Dr. Berger said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

“The thing that you were taught in medical school about an increase in bile acids in the skin [of patients with liver disease] and all that? That's all wrong,” said Dr. Berger, professor of clinical dermatology at the University of California, San Francisco.

Researchers at the National Institutes of Health conducted a number of “wonderful studies” that proved patients with liver disease do not properly metabolize endogenous opiates, and that “itching may be a complication of that problem,” he said.

“Pruritus in liver disease originates in the brain by increased neurotransmission mediated by endogenous opiates,” he explained. These patients, in fact, can get opiate withdrawal symptoms even though they are not taking opiates.

The solution, then, is to block opiates in the brain.

If topical steroids, phototherapy, and other standard pruritus therapies fail to work, start patients with liver disease on very low dosages of naltrexone (50 mg/day) and titrate upward. During the first week, prescribe 100 mcg of clonidine to avoid opiate withdrawal syndrome, he advised.

Dr. Berger cautioned colleagues to be sure patients are not actually taking opiates during initiation of therapy. He described the case of a 102-year-old patient with liver disease and severe itching who failed to inform him of the fentanyl patches she wore for her osteoporotic pain. “She had opiate withdrawal syndrome and had to be hospitalized for 2 days,” he said. “So be careful.”

Other approaches used for liver disease-related pruritus include cholestyramine or its better-tolerated alternative, colestipol; rifampin; albumin dialysis; and, as a last resort, liver transplantation.

Severe pruritus in patients with renal disease is less well understood.

“As opposed to liver disease and itch, here we have significant disease and we have no clue what the cause is,” said Dr. Berger.

Treating xerosis, which may be profound in renal disease patients, and enhancing their dialysis regimen are good first steps.

Next, administer broadband—not narrow-band—UVB, which is more effective in renal disease-related pruritus.

Finally, prescribing a single, 200− to 300-mg dose of gabapentin (Neurontin) after each dialysis session has been shown to have dramatic effects.

“One pill and bam! The itching drops right off,” he said.

SANTA BARBARA, CALIF. — The “itch-scratch” cycle is the dermatologic equivalent of chronic pain syndrome, and should be treated as such, Timothy G. Berger, M.D., said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

Just as with chronic pain, there is a “reduced threshold” phenomenon that occurs with chronic itch, he explained.

Chronicity not only lowers the threshold for the sensation of itch, it also increases the intensity of itch. Also like pain, short bursts of spontaneous itch may occur, even when the skin is clear.

“This has to do with anatomic rewiring in the central nervous system,” said Dr. Berger, professor of clinical dermatology at the University of California, San Francisco.

“The premise for pain is to intervene early to stop that central rewiring. In itch, the same premise should be applied.”

Dr. Berger explained that exciting advances in neurobiology have begun to elucidate the mechanisms of itch, although certain important pieces of the puzzle have yet to be found.

Importantly, researchers have discovered that itch is not, as previously believed, a minor sensation of pain.

Rather, “there are specific itch nerves and there are specific pain nerves,” he said.

Itch-specific neurons are small, unmyelinated C fibers distributed into and near the epidermis, constituting about 10% of the sensory nerves. They have no response to pain, but do respond to histamine and certain plant species.

“These itch nerves have very extensive branches,” with a single itch-specific neuron feeding an 8.5-cm area. That's why, “when there's something that hurts, there's a little spot that hurts. When you itch, your whole arm itches,” he noted.

Specific receptors have been identified for pressure and for pain, but no specific itch receptor has been found, although Dr. Berger has confidence that one will be located. “It just can't be that there isn't one.”

Dr. Berger said there are connections between pain and itch, although the two act independently. “Itch” and “pain” channels interact, and the neural elements mediating them are identical, though separate.

Itch can be blocked by pain, which is why scratching relieves itching.

Conversely, blocking pain neurons can heighten the sensation of itch, as in the case of opiates inducing pruritus.

Another intriguing aspect to itch is the role played by inflammatory mediators—neuropeptides. Even when a patient's itch does not have a primary inflammatory etiology, inflammation can develop in response to itch through neuropeptides.

This explains why drugs with anti-inflammatory properties can sometimes be effective in treating itch.

Dr. Berger reviewed several novel drugs for treating itch:

▸ Thalidomide. Especially effective in prurigo nodularis, this drug can be used for itch at dosages of 50–200 mg daily. It may increase the risk of neuropathy, and should be used cautiously in dosages higher than 100 mg/day, at which there may be an increased risk of thrombosis.

▸ Mirtazapine (Remeron). At a dosage of 15–45 mg nightly, this unique antidepressant has potent antihistamine properties. “It will occasionally work in patients when other medications have not worked,” Dr. Berger said. It is sedating, but otherwise well tolerated.

▸ Ondansetron (Zofran). This serotonin 5-hydroxytryptamine-3 receptor blocker can be used in doses of 4 or 8 mg/day, especially for opiate-related itch.

▸ Paroxetine (Paxil). Another antidepressant, this is an SSRI unrelated to the others in its class. It is used for pruritus at a dosage of 20 mg/day. Its anti-itch properties are powerful enough that normal patients may develop pruritus upon stopping the drug.

Dr. Berger reported no conflicts of interest regarding any of these drugs.

SANTA BARBARA, CALIF. — The “itch-scratch” cycle is the dermatologic equivalent of chronic pain syndrome, and should be treated as such, Timothy G. Berger, M.D., said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

Just as with chronic pain, there is a “reduced threshold” phenomenon that occurs with chronic itch, he explained.

Chronicity not only lowers the threshold for the sensation of itch, it also increases the intensity of itch. Also like pain, short bursts of spontaneous itch may occur, even when the skin is clear.

“This has to do with anatomic rewiring in the central nervous system,” said Dr. Berger, professor of clinical dermatology at the University of California, San Francisco.

“The premise for pain is to intervene early to stop that central rewiring. In itch, the same premise should be applied.”

Dr. Berger explained that exciting advances in neurobiology have begun to elucidate the mechanisms of itch, although certain important pieces of the puzzle have yet to be found.

Importantly, researchers have discovered that itch is not, as previously believed, a minor sensation of pain.

Rather, “there are specific itch nerves and there are specific pain nerves,” he said.

Itch-specific neurons are small, unmyelinated C fibers distributed into and near the epidermis, constituting about 10% of the sensory nerves. They have no response to pain, but do respond to histamine and certain plant species.

“These itch nerves have very extensive branches,” with a single itch-specific neuron feeding an 8.5-cm area. That's why, “when there's something that hurts, there's a little spot that hurts. When you itch, your whole arm itches,” he noted.

Specific receptors have been identified for pressure and for pain, but no specific itch receptor has been found, although Dr. Berger has confidence that one will be located. “It just can't be that there isn't one.”

Dr. Berger said there are connections between pain and itch, although the two act independently. “Itch” and “pain” channels interact, and the neural elements mediating them are identical, though separate.

Itch can be blocked by pain, which is why scratching relieves itching.

Conversely, blocking pain neurons can heighten the sensation of itch, as in the case of opiates inducing pruritus.

Another intriguing aspect to itch is the role played by inflammatory mediators—neuropeptides. Even when a patient's itch does not have a primary inflammatory etiology, inflammation can develop in response to itch through neuropeptides.

This explains why drugs with anti-inflammatory properties can sometimes be effective in treating itch.

Dr. Berger reviewed several novel drugs for treating itch:

▸ Thalidomide. Especially effective in prurigo nodularis, this drug can be used for itch at dosages of 50–200 mg daily. It may increase the risk of neuropathy, and should be used cautiously in dosages higher than 100 mg/day, at which there may be an increased risk of thrombosis.

▸ Mirtazapine (Remeron). At a dosage of 15–45 mg nightly, this unique antidepressant has potent antihistamine properties. “It will occasionally work in patients when other medications have not worked,” Dr. Berger said. It is sedating, but otherwise well tolerated.

▸ Ondansetron (Zofran). This serotonin 5-hydroxytryptamine-3 receptor blocker can be used in doses of 4 or 8 mg/day, especially for opiate-related itch.

▸ Paroxetine (Paxil). Another antidepressant, this is an SSRI unrelated to the others in its class. It is used for pruritus at a dosage of 20 mg/day. Its anti-itch properties are powerful enough that normal patients may develop pruritus upon stopping the drug.

Dr. Berger reported no conflicts of interest regarding any of these drugs.

SANTA BARBARA, CALIF. — The “itch-scratch” cycle is the dermatologic equivalent of chronic pain syndrome, and should be treated as such, Timothy G. Berger, M.D., said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

Just as with chronic pain, there is a “reduced threshold” phenomenon that occurs with chronic itch, he explained.

Chronicity not only lowers the threshold for the sensation of itch, it also increases the intensity of itch. Also like pain, short bursts of spontaneous itch may occur, even when the skin is clear.

“This has to do with anatomic rewiring in the central nervous system,” said Dr. Berger, professor of clinical dermatology at the University of California, San Francisco.

“The premise for pain is to intervene early to stop that central rewiring. In itch, the same premise should be applied.”

Dr. Berger explained that exciting advances in neurobiology have begun to elucidate the mechanisms of itch, although certain important pieces of the puzzle have yet to be found.

Importantly, researchers have discovered that itch is not, as previously believed, a minor sensation of pain.

Rather, “there are specific itch nerves and there are specific pain nerves,” he said.

Itch-specific neurons are small, unmyelinated C fibers distributed into and near the epidermis, constituting about 10% of the sensory nerves. They have no response to pain, but do respond to histamine and certain plant species.

“These itch nerves have very extensive branches,” with a single itch-specific neuron feeding an 8.5-cm area. That's why, “when there's something that hurts, there's a little spot that hurts. When you itch, your whole arm itches,” he noted.

Specific receptors have been identified for pressure and for pain, but no specific itch receptor has been found, although Dr. Berger has confidence that one will be located. “It just can't be that there isn't one.”

Dr. Berger said there are connections between pain and itch, although the two act independently. “Itch” and “pain” channels interact, and the neural elements mediating them are identical, though separate.

Itch can be blocked by pain, which is why scratching relieves itching.

Conversely, blocking pain neurons can heighten the sensation of itch, as in the case of opiates inducing pruritus.

Another intriguing aspect to itch is the role played by inflammatory mediators—neuropeptides. Even when a patient's itch does not have a primary inflammatory etiology, inflammation can develop in response to itch through neuropeptides.

This explains why drugs with anti-inflammatory properties can sometimes be effective in treating itch.

Dr. Berger reviewed several novel drugs for treating itch:

▸ Thalidomide. Especially effective in prurigo nodularis, this drug can be used for itch at dosages of 50–200 mg daily. It may increase the risk of neuropathy, and should be used cautiously in dosages higher than 100 mg/day, at which there may be an increased risk of thrombosis.

▸ Mirtazapine (Remeron). At a dosage of 15–45 mg nightly, this unique antidepressant has potent antihistamine properties. “It will occasionally work in patients when other medications have not worked,” Dr. Berger said. It is sedating, but otherwise well tolerated.

▸ Ondansetron (Zofran). This serotonin 5-hydroxytryptamine-3 receptor blocker can be used in doses of 4 or 8 mg/day, especially for opiate-related itch.

▸ Paroxetine (Paxil). Another antidepressant, this is an SSRI unrelated to the others in its class. It is used for pruritus at a dosage of 20 mg/day. Its anti-itch properties are powerful enough that normal patients may develop pruritus upon stopping the drug.

Dr. Berger reported no conflicts of interest regarding any of these drugs.

SAN DIEGO — Short children grew far taller when their growth hormone doses were adjusted according to their insulin-like growth factor 1 levels rather than to their weight, according to randomized study results.

“IGF-1 levels do matter,” said Pinchas Cohen, M.D., professor and director of research and training in the division of endocrinology at the University of California, Los Angeles, School of Medicine.

The notion of targeting dosing in order to maximize height in children of short stature is somewhat new and had been thought clinically impractical, Dr. Cohen said at a clinical symposium during the annual meeting of the Endocrine Society.

However, it was “possible and doable” to adjust doses according to a simple IGF-1-based algorithm. This approach resulted in “significant, quite dramatic improvement in height” for some children enrolled in the 2-year, multicenter trial.

In all, 172 children diagnosed with growth hormone deficiency or idiopathic short stature were enrolled in the trial sponsored by Novo Nordisk Inc., a manufacturer of human growth hormone, and the Lucile Packard Foundation for Children's Health.

The children were aged 3–15 years and significantly below normal height for their age, with a mean standard deviation score of -2.63. They also had low levels of IGF-1, the core mediator of growth hormone action on linear growth.

The complex study design featured a control group of 34 children who received a conventional 40 mcg/kg per day dose of growth hormone. Two other groups received targeted, adjustable doses of growth hormone based on IGF-1 levels at 3-month checkups.

One group received growth hormone in amounts necessary to achieve normal IGF-1 levels, and included 70 children. The other group, which numbered 68 children, received enough growth hormone to drive their IGF-1 levels two standard deviations above the norm.

The three groups achieved mean IGF-1 levels of +0.4, +0.4, and +2.0 standard deviation scores in the first 9 months of the study, and doses of 41 mcg/kg per day, 33 mcg/kg per day, and 110 mcg/kg per day were required to sustain these levels, said Dr. Cohen.

Only a small, nonsignificant difference was seen in children receiving standard growth hormone doses according to weight and those receiving doses targeted at a normal IGF-1.

The big difference in height was seen in children who received growth hormone at a dose aimed at raising their IGF-1 levels to two standard deviations greater than the norm. In this group, children with growth hormone deficiency grew 45% more, and children with idiopathic short stature grew 58% more than children in the other groups.

Side effects and adverse events were similar in all three groups.

Interestingly, a huge variability was seen in the amount of growth hormone required to maintain targeted IGF-1 levels among individual patients: 9–114 mcg/kg per day in the first targeted group and 20–346 mcg/kg per day in the second.

Dr. Cohen serves as a consultant or advisory board member or receives research support from a number of companies that manufacture human growth hormone, including Genentech Inc., Pfizer Inc., Eli Lilly & Co., Novo Nordisk Inc., and Serono Inc.

SAN DIEGO — Short children grew far taller when their growth hormone doses were adjusted according to their insulin-like growth factor 1 levels rather than to their weight, according to randomized study results.

“IGF-1 levels do matter,” said Pinchas Cohen, M.D., professor and director of research and training in the division of endocrinology at the University of California, Los Angeles, School of Medicine.

The notion of targeting dosing in order to maximize height in children of short stature is somewhat new and had been thought clinically impractical, Dr. Cohen said at a clinical symposium during the annual meeting of the Endocrine Society.

However, it was “possible and doable” to adjust doses according to a simple IGF-1-based algorithm. This approach resulted in “significant, quite dramatic improvement in height” for some children enrolled in the 2-year, multicenter trial.

In all, 172 children diagnosed with growth hormone deficiency or idiopathic short stature were enrolled in the trial sponsored by Novo Nordisk Inc., a manufacturer of human growth hormone, and the Lucile Packard Foundation for Children's Health.

The children were aged 3–15 years and significantly below normal height for their age, with a mean standard deviation score of -2.63. They also had low levels of IGF-1, the core mediator of growth hormone action on linear growth.

The complex study design featured a control group of 34 children who received a conventional 40 mcg/kg per day dose of growth hormone. Two other groups received targeted, adjustable doses of growth hormone based on IGF-1 levels at 3-month checkups.

One group received growth hormone in amounts necessary to achieve normal IGF-1 levels, and included 70 children. The other group, which numbered 68 children, received enough growth hormone to drive their IGF-1 levels two standard deviations above the norm.

The three groups achieved mean IGF-1 levels of +0.4, +0.4, and +2.0 standard deviation scores in the first 9 months of the study, and doses of 41 mcg/kg per day, 33 mcg/kg per day, and 110 mcg/kg per day were required to sustain these levels, said Dr. Cohen.

Only a small, nonsignificant difference was seen in children receiving standard growth hormone doses according to weight and those receiving doses targeted at a normal IGF-1.

The big difference in height was seen in children who received growth hormone at a dose aimed at raising their IGF-1 levels to two standard deviations greater than the norm. In this group, children with growth hormone deficiency grew 45% more, and children with idiopathic short stature grew 58% more than children in the other groups.

Side effects and adverse events were similar in all three groups.

Interestingly, a huge variability was seen in the amount of growth hormone required to maintain targeted IGF-1 levels among individual patients: 9–114 mcg/kg per day in the first targeted group and 20–346 mcg/kg per day in the second.

Dr. Cohen serves as a consultant or advisory board member or receives research support from a number of companies that manufacture human growth hormone, including Genentech Inc., Pfizer Inc., Eli Lilly & Co., Novo Nordisk Inc., and Serono Inc.

SAN DIEGO — Short children grew far taller when their growth hormone doses were adjusted according to their insulin-like growth factor 1 levels rather than to their weight, according to randomized study results.

“IGF-1 levels do matter,” said Pinchas Cohen, M.D., professor and director of research and training in the division of endocrinology at the University of California, Los Angeles, School of Medicine.

The notion of targeting dosing in order to maximize height in children of short stature is somewhat new and had been thought clinically impractical, Dr. Cohen said at a clinical symposium during the annual meeting of the Endocrine Society.

However, it was “possible and doable” to adjust doses according to a simple IGF-1-based algorithm. This approach resulted in “significant, quite dramatic improvement in height” for some children enrolled in the 2-year, multicenter trial.

In all, 172 children diagnosed with growth hormone deficiency or idiopathic short stature were enrolled in the trial sponsored by Novo Nordisk Inc., a manufacturer of human growth hormone, and the Lucile Packard Foundation for Children's Health.

The children were aged 3–15 years and significantly below normal height for their age, with a mean standard deviation score of -2.63. They also had low levels of IGF-1, the core mediator of growth hormone action on linear growth.

The complex study design featured a control group of 34 children who received a conventional 40 mcg/kg per day dose of growth hormone. Two other groups received targeted, adjustable doses of growth hormone based on IGF-1 levels at 3-month checkups.

One group received growth hormone in amounts necessary to achieve normal IGF-1 levels, and included 70 children. The other group, which numbered 68 children, received enough growth hormone to drive their IGF-1 levels two standard deviations above the norm.

The three groups achieved mean IGF-1 levels of +0.4, +0.4, and +2.0 standard deviation scores in the first 9 months of the study, and doses of 41 mcg/kg per day, 33 mcg/kg per day, and 110 mcg/kg per day were required to sustain these levels, said Dr. Cohen.

Only a small, nonsignificant difference was seen in children receiving standard growth hormone doses according to weight and those receiving doses targeted at a normal IGF-1.

The big difference in height was seen in children who received growth hormone at a dose aimed at raising their IGF-1 levels to two standard deviations greater than the norm. In this group, children with growth hormone deficiency grew 45% more, and children with idiopathic short stature grew 58% more than children in the other groups.

Side effects and adverse events were similar in all three groups.

Interestingly, a huge variability was seen in the amount of growth hormone required to maintain targeted IGF-1 levels among individual patients: 9–114 mcg/kg per day in the first targeted group and 20–346 mcg/kg per day in the second.

Dr. Cohen serves as a consultant or advisory board member or receives research support from a number of companies that manufacture human growth hormone, including Genentech Inc., Pfizer Inc., Eli Lilly & Co., Novo Nordisk Inc., and Serono Inc.

SAN DIEGO — The prevalence of gastroesophageal reflux disease symptoms in patients with type 2 diabetes is more than twice what is seen in the normal adult population, and appears to be especially high in patients with diabetic neuropathy.

Khushbu Chandrarana, M.D., and her associates conducted a prospective study of 150 patients aged 18 to 82 years with type 2 diabetes. The participants had not been diagnosed with other conditions, such as angina, that might explain gastroesophageal reflux disease (GERD)-type symptoms.

Patients with a GERD diagnosis prior to onset of their diabetes were not included in the study, which was presented as a poster at the annual meeting of the Endocrine Society.

A questionnaire given to eligible consecutive patients targeted the five most common symptoms of GERD: heartburn at least once a week, hoarseness, chronic cough, chest pain, and regurgitation.

A total of 40% of patients reported at least 1 GERD symptom and 30% reported having heartburn at least weekly. The prevalence of weekly heartburn in U.S. adults is 14%, said Dr. Chandrarana, a resident in the divisions of endocrinology and gastrointestinal medicine at Saint Peter's University Hospital, New Brunswick, N.J.

Among 46 patients with neuropathy, 27 (59%) reported GERD symptoms, compared with 34 of 104 diabetic patients (33%) who did not have neuropathy.

“Since experience of heartburn is likely to be blunted by neuropathy, the actual incidence of GERD may be even higher,” Dr. Chandrarana noted.

She encouraged physicians to be sensitive to the possibility that their patients with diabetes might also have GERD, a treatable disease.

The connection makes sense, she said, since the pathophysiology of GERD involves delayed gastric emptying, which is also a common complication of diabetes with neuropathy.

SAN DIEGO — The prevalence of gastroesophageal reflux disease symptoms in patients with type 2 diabetes is more than twice what is seen in the normal adult population, and appears to be especially high in patients with diabetic neuropathy.

Khushbu Chandrarana, M.D., and her associates conducted a prospective study of 150 patients aged 18 to 82 years with type 2 diabetes. The participants had not been diagnosed with other conditions, such as angina, that might explain gastroesophageal reflux disease (GERD)-type symptoms.

Patients with a GERD diagnosis prior to onset of their diabetes were not included in the study, which was presented as a poster at the annual meeting of the Endocrine Society.

A questionnaire given to eligible consecutive patients targeted the five most common symptoms of GERD: heartburn at least once a week, hoarseness, chronic cough, chest pain, and regurgitation.

A total of 40% of patients reported at least 1 GERD symptom and 30% reported having heartburn at least weekly. The prevalence of weekly heartburn in U.S. adults is 14%, said Dr. Chandrarana, a resident in the divisions of endocrinology and gastrointestinal medicine at Saint Peter's University Hospital, New Brunswick, N.J.

Among 46 patients with neuropathy, 27 (59%) reported GERD symptoms, compared with 34 of 104 diabetic patients (33%) who did not have neuropathy.

“Since experience of heartburn is likely to be blunted by neuropathy, the actual incidence of GERD may be even higher,” Dr. Chandrarana noted.

She encouraged physicians to be sensitive to the possibility that their patients with diabetes might also have GERD, a treatable disease.

The connection makes sense, she said, since the pathophysiology of GERD involves delayed gastric emptying, which is also a common complication of diabetes with neuropathy.

SAN DIEGO — The prevalence of gastroesophageal reflux disease symptoms in patients with type 2 diabetes is more than twice what is seen in the normal adult population, and appears to be especially high in patients with diabetic neuropathy.

Khushbu Chandrarana, M.D., and her associates conducted a prospective study of 150 patients aged 18 to 82 years with type 2 diabetes. The participants had not been diagnosed with other conditions, such as angina, that might explain gastroesophageal reflux disease (GERD)-type symptoms.

Patients with a GERD diagnosis prior to onset of their diabetes were not included in the study, which was presented as a poster at the annual meeting of the Endocrine Society.

A questionnaire given to eligible consecutive patients targeted the five most common symptoms of GERD: heartburn at least once a week, hoarseness, chronic cough, chest pain, and regurgitation.

A total of 40% of patients reported at least 1 GERD symptom and 30% reported having heartburn at least weekly. The prevalence of weekly heartburn in U.S. adults is 14%, said Dr. Chandrarana, a resident in the divisions of endocrinology and gastrointestinal medicine at Saint Peter's University Hospital, New Brunswick, N.J.

Among 46 patients with neuropathy, 27 (59%) reported GERD symptoms, compared with 34 of 104 diabetic patients (33%) who did not have neuropathy.

“Since experience of heartburn is likely to be blunted by neuropathy, the actual incidence of GERD may be even higher,” Dr. Chandrarana noted.

She encouraged physicians to be sensitive to the possibility that their patients with diabetes might also have GERD, a treatable disease.

The connection makes sense, she said, since the pathophysiology of GERD involves delayed gastric emptying, which is also a common complication of diabetes with neuropathy.

SAN DIEGO — Anemia is an independent risk factor for long-term mortality after myocardial infarction in both diabetic and nondiabetic patients, a large Canadian study has found.

Researchers at Queen Elizabeth II Health Sciences Centre, Dalhousie University, in Halifax, N.S., studied outcomes in 7,466 patients admitted with acute MI.

Of these, 1,431 had anemia but no diabetes, 1,646 had diabetes but no anemia, and 964 had diabetes and anemia. The remaining 3,425 patients had neither diabetes nor anemia.

Patients fared worse if they had both anemia and diabetes, with greater than 25% mortality at 1 month post admission, and greater than 35% mortality within 30 months, S. Ali Imran, M.B., of the division of endocrinology at the university, reported in a poster displayed at the annual meeting of the Endocrine Society.

Diabetes was a strong independent risk factor for both 30-day and long-term (31 days to 30 months) mortality.

Anemia, defined as a hemoglobin level of less than 120 g/L in females and 140 g/L in males, did not independently predict short-term mortality, but that may have been because mild degrees of anemia were included.

However, “any degree of anemia has an adverse effect on long-term mortality post myocardial infarction,” with each lower quintile of hemoglobin at the time of an MI admission associated with an increased risk of death, noted Dr. Imran.

Long-term mortality in patients with anemia approached 30%, compared with about 13% in patients who did not have anemia or diabetes at admission.

The authors pointed out that patients with anemia tended to be older and male and had worse renal function than other MI patients.

“Since anemia is a marker of an underlying disorder, the etiology of the anemia may explain an increased risk of mortality,” they wrote.

The primary cause of death for all patients, including the group with anemia, was cardiovascular.

“Further research examining the potential of correcting anemia is needed in the hopes of reducing long-term mortality,” the researchers concluded.

SAN DIEGO — Anemia is an independent risk factor for long-term mortality after myocardial infarction in both diabetic and nondiabetic patients, a large Canadian study has found.

Researchers at Queen Elizabeth II Health Sciences Centre, Dalhousie University, in Halifax, N.S., studied outcomes in 7,466 patients admitted with acute MI.

Of these, 1,431 had anemia but no diabetes, 1,646 had diabetes but no anemia, and 964 had diabetes and anemia. The remaining 3,425 patients had neither diabetes nor anemia.

Patients fared worse if they had both anemia and diabetes, with greater than 25% mortality at 1 month post admission, and greater than 35% mortality within 30 months, S. Ali Imran, M.B., of the division of endocrinology at the university, reported in a poster displayed at the annual meeting of the Endocrine Society.

Diabetes was a strong independent risk factor for both 30-day and long-term (31 days to 30 months) mortality.

Anemia, defined as a hemoglobin level of less than 120 g/L in females and 140 g/L in males, did not independently predict short-term mortality, but that may have been because mild degrees of anemia were included.

However, “any degree of anemia has an adverse effect on long-term mortality post myocardial infarction,” with each lower quintile of hemoglobin at the time of an MI admission associated with an increased risk of death, noted Dr. Imran.

Long-term mortality in patients with anemia approached 30%, compared with about 13% in patients who did not have anemia or diabetes at admission.

The authors pointed out that patients with anemia tended to be older and male and had worse renal function than other MI patients.

“Since anemia is a marker of an underlying disorder, the etiology of the anemia may explain an increased risk of mortality,” they wrote.

The primary cause of death for all patients, including the group with anemia, was cardiovascular.

“Further research examining the potential of correcting anemia is needed in the hopes of reducing long-term mortality,” the researchers concluded.

SAN DIEGO — Anemia is an independent risk factor for long-term mortality after myocardial infarction in both diabetic and nondiabetic patients, a large Canadian study has found.

Researchers at Queen Elizabeth II Health Sciences Centre, Dalhousie University, in Halifax, N.S., studied outcomes in 7,466 patients admitted with acute MI.

Of these, 1,431 had anemia but no diabetes, 1,646 had diabetes but no anemia, and 964 had diabetes and anemia. The remaining 3,425 patients had neither diabetes nor anemia.

Patients fared worse if they had both anemia and diabetes, with greater than 25% mortality at 1 month post admission, and greater than 35% mortality within 30 months, S. Ali Imran, M.B., of the division of endocrinology at the university, reported in a poster displayed at the annual meeting of the Endocrine Society.

Diabetes was a strong independent risk factor for both 30-day and long-term (31 days to 30 months) mortality.

Anemia, defined as a hemoglobin level of less than 120 g/L in females and 140 g/L in males, did not independently predict short-term mortality, but that may have been because mild degrees of anemia were included.

However, “any degree of anemia has an adverse effect on long-term mortality post myocardial infarction,” with each lower quintile of hemoglobin at the time of an MI admission associated with an increased risk of death, noted Dr. Imran.

Long-term mortality in patients with anemia approached 30%, compared with about 13% in patients who did not have anemia or diabetes at admission.

The authors pointed out that patients with anemia tended to be older and male and had worse renal function than other MI patients.

“Since anemia is a marker of an underlying disorder, the etiology of the anemia may explain an increased risk of mortality,” they wrote.

The primary cause of death for all patients, including the group with anemia, was cardiovascular.

“Further research examining the potential of correcting anemia is needed in the hopes of reducing long-term mortality,” the researchers concluded.

SAN DIEGO — Anemia is an independent risk factor for long-term mortality after myocardial infarction in both diabetic and nondiabetic patients, according to the findings in a large Canadian study.

Researchers at Queen Elizabeth II Health Sciences Centre, Dalhousie University, in Halifax, N.S., studied outcomes in 7,466 patients who were admitted with acute MI.

Of these, 1,431 had anemia but no diabetes, 1,646 had diabetes but no anemia, and 964 had diabetes and anemia. The remaining 3,425 patients had neither diabetes nor anemia.

The patients fared worse if they had both anemia and diabetes, with greater than 25% mortality at 1 month post admission, and greater than 35% mortality within 30 months, S. Ali Imran, M.B., of the division of endocrinology at the university, reported in a poster displayed at the annual meeting of the Endocrine Society.

Diabetes was a strong independent risk factor for both 30-day and long-term (31 days to 30 months) mortality.

Anemia, defined as a hemoglobin level of less than 120 g/L in females and 140 g/L in males, did not independently predict short-term mortality, but that may have been because mild degrees of anemia were included.

However, “any degree of anemia has an adverse effect on long-term mortality post myocardial infarction,” with each lower quintile of hemoglobin at the time of an MI admission associated with an increased risk of death, noted Dr. Imran.

Long-term mortality in patients with anemia approached 30%, compared with about 13% in those patients who did not have anemia or diabetes when they were admitted.

The authors pointed out that patients with anemia tended to be older and male and had worse renal function than other MI patients.

“Since anemia is a marker of an underlying disorder, the etiology of the anemia may explain an increased risk of mortality,” they wrote.

The researchers found that the primary cause of death for all patients, including the group with anemia, was cardiovascular.

“Further research examining the potential of correcting anemia is needed in the hopes of reducing long-term mortality,” they concluded.

SAN DIEGO — Anemia is an independent risk factor for long-term mortality after myocardial infarction in both diabetic and nondiabetic patients, according to the findings in a large Canadian study.

Researchers at Queen Elizabeth II Health Sciences Centre, Dalhousie University, in Halifax, N.S., studied outcomes in 7,466 patients who were admitted with acute MI.

Of these, 1,431 had anemia but no diabetes, 1,646 had diabetes but no anemia, and 964 had diabetes and anemia. The remaining 3,425 patients had neither diabetes nor anemia.

The patients fared worse if they had both anemia and diabetes, with greater than 25% mortality at 1 month post admission, and greater than 35% mortality within 30 months, S. Ali Imran, M.B., of the division of endocrinology at the university, reported in a poster displayed at the annual meeting of the Endocrine Society.

Diabetes was a strong independent risk factor for both 30-day and long-term (31 days to 30 months) mortality.

Anemia, defined as a hemoglobin level of less than 120 g/L in females and 140 g/L in males, did not independently predict short-term mortality, but that may have been because mild degrees of anemia were included.

However, “any degree of anemia has an adverse effect on long-term mortality post myocardial infarction,” with each lower quintile of hemoglobin at the time of an MI admission associated with an increased risk of death, noted Dr. Imran.

Long-term mortality in patients with anemia approached 30%, compared with about 13% in those patients who did not have anemia or diabetes when they were admitted.

The authors pointed out that patients with anemia tended to be older and male and had worse renal function than other MI patients.

“Since anemia is a marker of an underlying disorder, the etiology of the anemia may explain an increased risk of mortality,” they wrote.

The researchers found that the primary cause of death for all patients, including the group with anemia, was cardiovascular.

“Further research examining the potential of correcting anemia is needed in the hopes of reducing long-term mortality,” they concluded.

SAN DIEGO — Anemia is an independent risk factor for long-term mortality after myocardial infarction in both diabetic and nondiabetic patients, according to the findings in a large Canadian study.

Researchers at Queen Elizabeth II Health Sciences Centre, Dalhousie University, in Halifax, N.S., studied outcomes in 7,466 patients who were admitted with acute MI.

Of these, 1,431 had anemia but no diabetes, 1,646 had diabetes but no anemia, and 964 had diabetes and anemia. The remaining 3,425 patients had neither diabetes nor anemia.

The patients fared worse if they had both anemia and diabetes, with greater than 25% mortality at 1 month post admission, and greater than 35% mortality within 30 months, S. Ali Imran, M.B., of the division of endocrinology at the university, reported in a poster displayed at the annual meeting of the Endocrine Society.

Diabetes was a strong independent risk factor for both 30-day and long-term (31 days to 30 months) mortality.

Anemia, defined as a hemoglobin level of less than 120 g/L in females and 140 g/L in males, did not independently predict short-term mortality, but that may have been because mild degrees of anemia were included.

However, “any degree of anemia has an adverse effect on long-term mortality post myocardial infarction,” with each lower quintile of hemoglobin at the time of an MI admission associated with an increased risk of death, noted Dr. Imran.

Long-term mortality in patients with anemia approached 30%, compared with about 13% in those patients who did not have anemia or diabetes when they were admitted.

The authors pointed out that patients with anemia tended to be older and male and had worse renal function than other MI patients.

“Since anemia is a marker of an underlying disorder, the etiology of the anemia may explain an increased risk of mortality,” they wrote.

The researchers found that the primary cause of death for all patients, including the group with anemia, was cardiovascular.

“Further research examining the potential of correcting anemia is needed in the hopes of reducing long-term mortality,” they concluded.

SANTA BARBARA, CALIF. — Children of older mothers who drank during pregnancy were shorter and had smaller head circumferences at ages 7 and 14 years than other children at those ages, it was reported at the annual meeting of the Research Society on Alcoholism.

Children of mothers who were 30 or older at delivery were affected above a threshold of moderate alcohol consumption, defined as about one alcoholic drink a day at the time of conception.

Many women reduced their drinking during pregnancy, but the heaviest drinkers reduced their drinking less.

“Even if women reduce their drinking during pregnancy, their early drinking before they realize they are pregnant may have an impact on the infant,” said Sandra W. Jacobson, Ph.D., professor of psychiatry and behavioral neurosciences at Wayne State University in Detroit, a senior author on the study.

“We see effects in infants whose mothers drink as little as one drink/day.”

Dr. Jacobson stressed that “average” drinks per day did not reflect actual drinking patterns among women in the study. Just 1 woman of 480 in the Detroit Longitudinal Prenatal Alcohol Exposure study drank daily.

Many of the others concentrated their drinking on 1–2 days a week, in some cases drinking three to four drinks at each session, she explained following the meeting.

Mean alcohol consumption at conception was two drinks per day in the study of economically disadvantaged African American women and their children.

Mean alcohol intake dropped during pregnancy to a little more than two drinks per week.

Prenatal alcohol exposure was associated with lower birthweight and length in the entire sample of women, even after researchers controlled for smoking and other possible confounders.

For mothers over 30 at conception, the repercussions were long lasting. With a cutoff point of 0.5 ounces of alcohol per day at conception, older mothers' children were 1.2 cm, 3.1 cm, and 3.7 cm shorter at birth, 7.5 years, and 14 years, respectively, than children of mothers with minimal exposure.

Their mean head circumference was smaller by 4.6 mm, 7.3 mm, and 14.5 mm at birth, 7.5 years, and 14 years.

“Prenatal alcohol exposure was not related to weight or body mass index at 7.5 or 14 years, suggesting that the effects on height and head circumference were not attributable to poor maternal nutrition,” the researchers reported in their poster presentation.

Smoking during pregnancy resulted in lower birthweight and reduced length and head circumference at birth, but had no discernible impact on children's growth over time.

In contrast, prenatal alcohol exposure's impact on size was evident at birth and became magnified over time.

Although the study suggests that children of older mothers are most vulnerable to prenatal alcohol exposure, all women considering pregnancy should be urged to stop drinking or to cut down as much as possible. “At this time, no drinking is considered safe,” said Dr. Jacobson.

The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism and the Joseph Young, Sr., Fund of Michigan.

Douglas Fuller, a research assistant in the Wayne State University department of psychiatry and behavioral neurosciences, contributed to the study.

SANTA BARBARA, CALIF. — Children of older mothers who drank during pregnancy were shorter and had smaller head circumferences at ages 7 and 14 years than other children at those ages, it was reported at the annual meeting of the Research Society on Alcoholism.

Children of mothers who were 30 or older at delivery were affected above a threshold of moderate alcohol consumption, defined as about one alcoholic drink a day at the time of conception.

Many women reduced their drinking during pregnancy, but the heaviest drinkers reduced their drinking less.

“Even if women reduce their drinking during pregnancy, their early drinking before they realize they are pregnant may have an impact on the infant,” said Sandra W. Jacobson, Ph.D., professor of psychiatry and behavioral neurosciences at Wayne State University in Detroit, a senior author on the study.

“We see effects in infants whose mothers drink as little as one drink/day.”

Dr. Jacobson stressed that “average” drinks per day did not reflect actual drinking patterns among women in the study. Just 1 woman of 480 in the Detroit Longitudinal Prenatal Alcohol Exposure study drank daily.

Many of the others concentrated their drinking on 1–2 days a week, in some cases drinking three to four drinks at each session, she explained following the meeting.

Mean alcohol consumption at conception was two drinks per day in the study of economically disadvantaged African American women and their children.

Mean alcohol intake dropped during pregnancy to a little more than two drinks per week.

Prenatal alcohol exposure was associated with lower birthweight and length in the entire sample of women, even after researchers controlled for smoking and other possible confounders.

For mothers over 30 at conception, the repercussions were long lasting. With a cutoff point of 0.5 ounces of alcohol per day at conception, older mothers' children were 1.2 cm, 3.1 cm, and 3.7 cm shorter at birth, 7.5 years, and 14 years, respectively, than children of mothers with minimal exposure.

Their mean head circumference was smaller by 4.6 mm, 7.3 mm, and 14.5 mm at birth, 7.5 years, and 14 years.

“Prenatal alcohol exposure was not related to weight or body mass index at 7.5 or 14 years, suggesting that the effects on height and head circumference were not attributable to poor maternal nutrition,” the researchers reported in their poster presentation.

Smoking during pregnancy resulted in lower birthweight and reduced length and head circumference at birth, but had no discernible impact on children's growth over time.

In contrast, prenatal alcohol exposure's impact on size was evident at birth and became magnified over time.

Although the study suggests that children of older mothers are most vulnerable to prenatal alcohol exposure, all women considering pregnancy should be urged to stop drinking or to cut down as much as possible. “At this time, no drinking is considered safe,” said Dr. Jacobson.

The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism and the Joseph Young, Sr., Fund of Michigan.

Douglas Fuller, a research assistant in the Wayne State University department of psychiatry and behavioral neurosciences, contributed to the study.

SANTA BARBARA, CALIF. — Children of older mothers who drank during pregnancy were shorter and had smaller head circumferences at ages 7 and 14 years than other children at those ages, it was reported at the annual meeting of the Research Society on Alcoholism.

Children of mothers who were 30 or older at delivery were affected above a threshold of moderate alcohol consumption, defined as about one alcoholic drink a day at the time of conception.

Many women reduced their drinking during pregnancy, but the heaviest drinkers reduced their drinking less.

“Even if women reduce their drinking during pregnancy, their early drinking before they realize they are pregnant may have an impact on the infant,” said Sandra W. Jacobson, Ph.D., professor of psychiatry and behavioral neurosciences at Wayne State University in Detroit, a senior author on the study.

“We see effects in infants whose mothers drink as little as one drink/day.”

Dr. Jacobson stressed that “average” drinks per day did not reflect actual drinking patterns among women in the study. Just 1 woman of 480 in the Detroit Longitudinal Prenatal Alcohol Exposure study drank daily.

Many of the others concentrated their drinking on 1–2 days a week, in some cases drinking three to four drinks at each session, she explained following the meeting.

Mean alcohol consumption at conception was two drinks per day in the study of economically disadvantaged African American women and their children.

Mean alcohol intake dropped during pregnancy to a little more than two drinks per week.

Prenatal alcohol exposure was associated with lower birthweight and length in the entire sample of women, even after researchers controlled for smoking and other possible confounders.

For mothers over 30 at conception, the repercussions were long lasting. With a cutoff point of 0.5 ounces of alcohol per day at conception, older mothers' children were 1.2 cm, 3.1 cm, and 3.7 cm shorter at birth, 7.5 years, and 14 years, respectively, than children of mothers with minimal exposure.

Their mean head circumference was smaller by 4.6 mm, 7.3 mm, and 14.5 mm at birth, 7.5 years, and 14 years.

“Prenatal alcohol exposure was not related to weight or body mass index at 7.5 or 14 years, suggesting that the effects on height and head circumference were not attributable to poor maternal nutrition,” the researchers reported in their poster presentation.

Smoking during pregnancy resulted in lower birthweight and reduced length and head circumference at birth, but had no discernible impact on children's growth over time.

In contrast, prenatal alcohol exposure's impact on size was evident at birth and became magnified over time.

Although the study suggests that children of older mothers are most vulnerable to prenatal alcohol exposure, all women considering pregnancy should be urged to stop drinking or to cut down as much as possible. “At this time, no drinking is considered safe,” said Dr. Jacobson.

The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism and the Joseph Young, Sr., Fund of Michigan.

Douglas Fuller, a research assistant in the Wayne State University department of psychiatry and behavioral neurosciences, contributed to the study.

SAN DIEGO — A very large genetic linkage study has pinpointed the major histocompatibility complex on the short arm of chromosome 6 as the key genetic player in multiple sclerosis.

The study is not the first to implicate the major histocompatibility complex (MHC), a cluster of genes critical to the recognition of the body's own cells as “self.”

However, this study is the largest and most definitive to date, and its findings call into question data from smaller studies that suggested critical roles for other genetic regions.

Jonathan Haines, Ph.D., of Vanderbilt University, Nashville, Tenn., presented the findings on behalf of the International Multiple Sclerosis Genetics Consortium.

The team typed 4,506 single nucleotide polymorphism markers in 730 families who had more than one family member with multiple sclerosis.

Subjects were from Australia, Scandinavia, the United Kingdom, and the United States. Genes from 945 pairs of relatives were studied for genetic linkages.

“Highly significant linkage is observed in the region of the MJC ([linkage analysis] logarithm of the odds score 11.7), and suggestive linkage is found on chromosomes 17 and 5,” Dr. Haines stated in a poster presented at the annual meeting of the American Neurological Association.

An ordered subset analysis identified a further locus on chromosome 19.

The mean information extraction from the marker panel is 80%, with a range of 42%–91%, Dr. Haines reported.

Observed Mendelian inconsistencies suggest that within the data set, the genotyping error rate was just 0.002%.

“Our results confirm the strong role of the major histocompatibility complex genes in MS, and provide a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics,” Dr. Haines said in a statement released at the meeting.

“Other genes may still play an important role in MS but finding them will require using new genomic techniques,” he added.

Dr. Haines said the findings have “profound implications for the future directions of multiple sclerosis genetics research and suggest that previous efforts in this area are almost all substantially underpowered.”

Future association studies should include at least 500–1,000 cases of multiple sclerosis to be considered reliable, he said.

SAN DIEGO — A very large genetic linkage study has pinpointed the major histocompatibility complex on the short arm of chromosome 6 as the key genetic player in multiple sclerosis.

The study is not the first to implicate the major histocompatibility complex (MHC), a cluster of genes critical to the recognition of the body's own cells as “self.”

However, this study is the largest and most definitive to date, and its findings call into question data from smaller studies that suggested critical roles for other genetic regions.

Jonathan Haines, Ph.D., of Vanderbilt University, Nashville, Tenn., presented the findings on behalf of the International Multiple Sclerosis Genetics Consortium.

The team typed 4,506 single nucleotide polymorphism markers in 730 families who had more than one family member with multiple sclerosis.

Subjects were from Australia, Scandinavia, the United Kingdom, and the United States. Genes from 945 pairs of relatives were studied for genetic linkages.

“Highly significant linkage is observed in the region of the MJC ([linkage analysis] logarithm of the odds score 11.7), and suggestive linkage is found on chromosomes 17 and 5,” Dr. Haines stated in a poster presented at the annual meeting of the American Neurological Association.

An ordered subset analysis identified a further locus on chromosome 19.

The mean information extraction from the marker panel is 80%, with a range of 42%–91%, Dr. Haines reported.

Observed Mendelian inconsistencies suggest that within the data set, the genotyping error rate was just 0.002%.

“Our results confirm the strong role of the major histocompatibility complex genes in MS, and provide a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics,” Dr. Haines said in a statement released at the meeting.

“Other genes may still play an important role in MS but finding them will require using new genomic techniques,” he added.

Dr. Haines said the findings have “profound implications for the future directions of multiple sclerosis genetics research and suggest that previous efforts in this area are almost all substantially underpowered.”

Future association studies should include at least 500–1,000 cases of multiple sclerosis to be considered reliable, he said.

SAN DIEGO — A very large genetic linkage study has pinpointed the major histocompatibility complex on the short arm of chromosome 6 as the key genetic player in multiple sclerosis.

The study is not the first to implicate the major histocompatibility complex (MHC), a cluster of genes critical to the recognition of the body's own cells as “self.”

However, this study is the largest and most definitive to date, and its findings call into question data from smaller studies that suggested critical roles for other genetic regions.

Jonathan Haines, Ph.D., of Vanderbilt University, Nashville, Tenn., presented the findings on behalf of the International Multiple Sclerosis Genetics Consortium.

The team typed 4,506 single nucleotide polymorphism markers in 730 families who had more than one family member with multiple sclerosis.

Subjects were from Australia, Scandinavia, the United Kingdom, and the United States. Genes from 945 pairs of relatives were studied for genetic linkages.

“Highly significant linkage is observed in the region of the MJC ([linkage analysis] logarithm of the odds score 11.7), and suggestive linkage is found on chromosomes 17 and 5,” Dr. Haines stated in a poster presented at the annual meeting of the American Neurological Association.

An ordered subset analysis identified a further locus on chromosome 19.

The mean information extraction from the marker panel is 80%, with a range of 42%–91%, Dr. Haines reported.

Observed Mendelian inconsistencies suggest that within the data set, the genotyping error rate was just 0.002%.

“Our results confirm the strong role of the major histocompatibility complex genes in MS, and provide a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics,” Dr. Haines said in a statement released at the meeting.

“Other genes may still play an important role in MS but finding them will require using new genomic techniques,” he added.

Dr. Haines said the findings have “profound implications for the future directions of multiple sclerosis genetics research and suggest that previous efforts in this area are almost all substantially underpowered.”

Future association studies should include at least 500–1,000 cases of multiple sclerosis to be considered reliable, he said.

SAN DIEGO — Pulsed, intrathecal methotrexate was safe and well-tolerated in patients with primary progressive or secondary progressive multiple sclerosis, and appears to have stabilized their disease in a small, open-label, phase I tolerability and safety study that followed patients only 2 years, Saud A. Sadiq, M.D., reported at the annual meeting of the American Neurological Association.

Dr. Sadiq, director of the Multiple Sclerosis Research and Treatment Center at St. Luke's Roosevelt Hospital Center in New York, said that a larger, longer study would be needed to confirm the usefulness of intrathecal methotrexate in this notoriously difficult-to-treat population.

Nonetheless, his poster detailing the treatment in 126 patients drew considerable interest at the meeting, where clinicians expressed hope that the therapy might represent an alternative for these two groups of patients who currently have very few treatment options.

To be eligible for the study, patients had to have undergone treatment with at least three FDA-approved, disease-modifying drugs for multiple sclerosis (MS) for at least 1 year. Despite this therapy, eligible patients still had active disease with continued relapses, worsening Expanded Disability Status Scale (EDSS) scores, or increased disease burden seen on MRI.

Exclusion criteria included known allergy to methotrexate, pregnancy, active infection, or a significant associated medical condition such as heart disease. Patients ranged in age from 30 to 74 years. Females outnumbered males, 87 to 39. There were 91 patients with secondary progressive MS and 35 patients with primary progressive MS. Their baseline EDSS scores ranged from 3.0 to 9.0.

Preservative-free methotrexate was administered at a dose of 12 mg every 2 months, either via lumbar puncture with a 24− or 25-gauge needle (91 patients), or through the access port of a surgically implanted Medtronic pump that patients had received for spasticity control (35 patients). Each injection was followed by injection of 3 cc of the patient's previously drawn cerebrospinal fluid (CSF) to ensure that the drug entered the CSF and there was no dead-space loss.

Brain MRI studies were performed in 50 randomly selected patients both before and after at least four treatment cycles. After methotrexate treatment, disease stabilized in 32 of 39 patients with secondary progressive MS and 9 of 11 patients with primary progressive MS.

In the total cohort, improved or stabilized EDSS scores were noted in 85 of 91 patients with secondary progressive MS and 32 of 35 patients with primary progressive MS. Quality of life scores improved (57 patients) or remained unchanged (23 patients) in patients with secondary progressive MS, while just 11 reported a decreased quality of life at the end of the 2-year study.

Among patients with primary progressive MS, 14 patients improved, 15 patients remained the same, and 6 patients had decreased quality of life scores.

Laboratory studies using mouse stem cells and CSF from a study patient and an MS patient not receiving methotrexate showed that the drug appeared to have no effect on oligodendroglial or neuronal cell development, but that it inhibited astroglial proliferation, key to sclerosis formation.

Dr. Sadiq said the findings suggest a possible mechanism of action.

Patients generally tolerated the drug well. No drug-related deaths occurred (a 74-year-old patient died of a myocardial infarction). There were no cases of meningitis or serious infection, CNS tumors, or lymphomas.

Patients reported transient fatigue after 34 of a total of 489 treatments. Mild leucopenia was seen in two patients. Postspinal headache was reported after nine treatments, and vomiting was reported after one. One patient had shingles.

A total of 21 patients discontinued treatment, most citing a lack of effect after two or three treatments. No patient dropped out of the trial due to adverse effects.

“In patients that we selected for this study … disease course is inexorably progressive, with definite decline in function every few months. Stability in this population is very exciting,” said Dr. Sadiq following the meeting.

“Obviously, the longer this can go on, the better. To date, no patients who appeared to have an initial favorable response appear to have subsequently declined.”

To be sure, “other studies verifying efficacy for a longer term are needed,” he said.

A randomized, controlled study is planned that will compare intrathecal methotrexate with intravenous pulsed Cytoxan, according to Dr. Sadiq, who serves on the neurology faculty at the Albert Einstein College of Medicine, New York.

No pharmaceutical company support was used to fund Dr. Sadiq's study.

SAN DIEGO — Pulsed, intrathecal methotrexate was safe and well-tolerated in patients with primary progressive or secondary progressive multiple sclerosis, and appears to have stabilized their disease in a small, open-label, phase I tolerability and safety study that followed patients only 2 years, Saud A. Sadiq, M.D., reported at the annual meeting of the American Neurological Association.

Dr. Sadiq, director of the Multiple Sclerosis Research and Treatment Center at St. Luke's Roosevelt Hospital Center in New York, said that a larger, longer study would be needed to confirm the usefulness of intrathecal methotrexate in this notoriously difficult-to-treat population.

Nonetheless, his poster detailing the treatment in 126 patients drew considerable interest at the meeting, where clinicians expressed hope that the therapy might represent an alternative for these two groups of patients who currently have very few treatment options.

To be eligible for the study, patients had to have undergone treatment with at least three FDA-approved, disease-modifying drugs for multiple sclerosis (MS) for at least 1 year. Despite this therapy, eligible patients still had active disease with continued relapses, worsening Expanded Disability Status Scale (EDSS) scores, or increased disease burden seen on MRI.

Exclusion criteria included known allergy to methotrexate, pregnancy, active infection, or a significant associated medical condition such as heart disease. Patients ranged in age from 30 to 74 years. Females outnumbered males, 87 to 39. There were 91 patients with secondary progressive MS and 35 patients with primary progressive MS. Their baseline EDSS scores ranged from 3.0 to 9.0.

Preservative-free methotrexate was administered at a dose of 12 mg every 2 months, either via lumbar puncture with a 24− or 25-gauge needle (91 patients), or through the access port of a surgically implanted Medtronic pump that patients had received for spasticity control (35 patients). Each injection was followed by injection of 3 cc of the patient's previously drawn cerebrospinal fluid (CSF) to ensure that the drug entered the CSF and there was no dead-space loss.

Brain MRI studies were performed in 50 randomly selected patients both before and after at least four treatment cycles. After methotrexate treatment, disease stabilized in 32 of 39 patients with secondary progressive MS and 9 of 11 patients with primary progressive MS.

In the total cohort, improved or stabilized EDSS scores were noted in 85 of 91 patients with secondary progressive MS and 32 of 35 patients with primary progressive MS. Quality of life scores improved (57 patients) or remained unchanged (23 patients) in patients with secondary progressive MS, while just 11 reported a decreased quality of life at the end of the 2-year study.

Among patients with primary progressive MS, 14 patients improved, 15 patients remained the same, and 6 patients had decreased quality of life scores.

Laboratory studies using mouse stem cells and CSF from a study patient and an MS patient not receiving methotrexate showed that the drug appeared to have no effect on oligodendroglial or neuronal cell development, but that it inhibited astroglial proliferation, key to sclerosis formation.

Dr. Sadiq said the findings suggest a possible mechanism of action.

Patients generally tolerated the drug well. No drug-related deaths occurred (a 74-year-old patient died of a myocardial infarction). There were no cases of meningitis or serious infection, CNS tumors, or lymphomas.

Patients reported transient fatigue after 34 of a total of 489 treatments. Mild leucopenia was seen in two patients. Postspinal headache was reported after nine treatments, and vomiting was reported after one. One patient had shingles.

A total of 21 patients discontinued treatment, most citing a lack of effect after two or three treatments. No patient dropped out of the trial due to adverse effects.

“In patients that we selected for this study … disease course is inexorably progressive, with definite decline in function every few months. Stability in this population is very exciting,” said Dr. Sadiq following the meeting.

“Obviously, the longer this can go on, the better. To date, no patients who appeared to have an initial favorable response appear to have subsequently declined.”

To be sure, “other studies verifying efficacy for a longer term are needed,” he said.

A randomized, controlled study is planned that will compare intrathecal methotrexate with intravenous pulsed Cytoxan, according to Dr. Sadiq, who serves on the neurology faculty at the Albert Einstein College of Medicine, New York.

No pharmaceutical company support was used to fund Dr. Sadiq's study.

SAN DIEGO — Pulsed, intrathecal methotrexate was safe and well-tolerated in patients with primary progressive or secondary progressive multiple sclerosis, and appears to have stabilized their disease in a small, open-label, phase I tolerability and safety study that followed patients only 2 years, Saud A. Sadiq, M.D., reported at the annual meeting of the American Neurological Association.

Dr. Sadiq, director of the Multiple Sclerosis Research and Treatment Center at St. Luke's Roosevelt Hospital Center in New York, said that a larger, longer study would be needed to confirm the usefulness of intrathecal methotrexate in this notoriously difficult-to-treat population.

Nonetheless, his poster detailing the treatment in 126 patients drew considerable interest at the meeting, where clinicians expressed hope that the therapy might represent an alternative for these two groups of patients who currently have very few treatment options.

To be eligible for the study, patients had to have undergone treatment with at least three FDA-approved, disease-modifying drugs for multiple sclerosis (MS) for at least 1 year. Despite this therapy, eligible patients still had active disease with continued relapses, worsening Expanded Disability Status Scale (EDSS) scores, or increased disease burden seen on MRI.

Exclusion criteria included known allergy to methotrexate, pregnancy, active infection, or a significant associated medical condition such as heart disease. Patients ranged in age from 30 to 74 years. Females outnumbered males, 87 to 39. There were 91 patients with secondary progressive MS and 35 patients with primary progressive MS. Their baseline EDSS scores ranged from 3.0 to 9.0.

Preservative-free methotrexate was administered at a dose of 12 mg every 2 months, either via lumbar puncture with a 24− or 25-gauge needle (91 patients), or through the access port of a surgically implanted Medtronic pump that patients had received for spasticity control (35 patients). Each injection was followed by injection of 3 cc of the patient's previously drawn cerebrospinal fluid (CSF) to ensure that the drug entered the CSF and there was no dead-space loss.

Brain MRI studies were performed in 50 randomly selected patients both before and after at least four treatment cycles. After methotrexate treatment, disease stabilized in 32 of 39 patients with secondary progressive MS and 9 of 11 patients with primary progressive MS.

In the total cohort, improved or stabilized EDSS scores were noted in 85 of 91 patients with secondary progressive MS and 32 of 35 patients with primary progressive MS. Quality of life scores improved (57 patients) or remained unchanged (23 patients) in patients with secondary progressive MS, while just 11 reported a decreased quality of life at the end of the 2-year study.

Among patients with primary progressive MS, 14 patients improved, 15 patients remained the same, and 6 patients had decreased quality of life scores.

Laboratory studies using mouse stem cells and CSF from a study patient and an MS patient not receiving methotrexate showed that the drug appeared to have no effect on oligodendroglial or neuronal cell development, but that it inhibited astroglial proliferation, key to sclerosis formation.

Dr. Sadiq said the findings suggest a possible mechanism of action.

Patients generally tolerated the drug well. No drug-related deaths occurred (a 74-year-old patient died of a myocardial infarction). There were no cases of meningitis or serious infection, CNS tumors, or lymphomas.

Patients reported transient fatigue after 34 of a total of 489 treatments. Mild leucopenia was seen in two patients. Postspinal headache was reported after nine treatments, and vomiting was reported after one. One patient had shingles.

A total of 21 patients discontinued treatment, most citing a lack of effect after two or three treatments. No patient dropped out of the trial due to adverse effects.

“In patients that we selected for this study … disease course is inexorably progressive, with definite decline in function every few months. Stability in this population is very exciting,” said Dr. Sadiq following the meeting.

“Obviously, the longer this can go on, the better. To date, no patients who appeared to have an initial favorable response appear to have subsequently declined.”

To be sure, “other studies verifying efficacy for a longer term are needed,” he said.

A randomized, controlled study is planned that will compare intrathecal methotrexate with intravenous pulsed Cytoxan, according to Dr. Sadiq, who serves on the neurology faculty at the Albert Einstein College of Medicine, New York.

No pharmaceutical company support was used to fund Dr. Sadiq's study.

SAN DIEGO — Atypical Parkinson's disease took the most profound toll on patients' ability to carry out essential daily activities among six chronic neurologic disorders evaluated in a study of disability and quality of life.

Lisa M. Shulman, M.D., codirector of the Parkinson's Disease and Movement Disorders Center at the University of Maryland in Baltimore, reported her results in poster form at the annual meeting of the American Neurological Association.

Significant variation was found in disability and quality of life scores among patients with essential tremor (n = 58), dystonia (n = 50), Parkinson's disease (n = 425), psychogenic movement disorders (n = 34), Alzheimer's disease (n = 17), and atypical Parkinsonism (n = 45).

All of the disorders significantly undermined physical quality of life, as measured by the SF-12v2 Health Survey, but atypical Parkinson's disease patients had the lowest scores by far, reported Dr. Shulman and associates from the university's department of neurology.

Just three of the disorders—Alzheimer's disease, psychogenic movement disorders, and atypical Parkinson's disease—showed reductions in mental health quality of life scores measured by the SF-12v2 survey.

Disability was assessed using the Older Americans Resources and Services scale, which includes activities of daily living (ADL) and instrumental activities of daily living (IADL) at a person's best and worst level of function. Atypical Parkinson's disease and Alzheimer's disease had the greatest impact on all instrumental activities of daily living.

In general, neurodegenerative disorders (Parkinson's disease and atypical Parkinson's disease, and Alzheimer's disease) resulted in greater disability than disorders such as essential tremor and dystonia.

SAN DIEGO — Atypical Parkinson's disease took the most profound toll on patients' ability to carry out essential daily activities among six chronic neurologic disorders evaluated in a study of disability and quality of life.

Lisa M. Shulman, M.D., codirector of the Parkinson's Disease and Movement Disorders Center at the University of Maryland in Baltimore, reported her results in poster form at the annual meeting of the American Neurological Association.

Significant variation was found in disability and quality of life scores among patients with essential tremor (n = 58), dystonia (n = 50), Parkinson's disease (n = 425), psychogenic movement disorders (n = 34), Alzheimer's disease (n = 17), and atypical Parkinsonism (n = 45).

All of the disorders significantly undermined physical quality of life, as measured by the SF-12v2 Health Survey, but atypical Parkinson's disease patients had the lowest scores by far, reported Dr. Shulman and associates from the university's department of neurology.

Just three of the disorders—Alzheimer's disease, psychogenic movement disorders, and atypical Parkinson's disease—showed reductions in mental health quality of life scores measured by the SF-12v2 survey.

Disability was assessed using the Older Americans Resources and Services scale, which includes activities of daily living (ADL) and instrumental activities of daily living (IADL) at a person's best and worst level of function. Atypical Parkinson's disease and Alzheimer's disease had the greatest impact on all instrumental activities of daily living.

In general, neurodegenerative disorders (Parkinson's disease and atypical Parkinson's disease, and Alzheimer's disease) resulted in greater disability than disorders such as essential tremor and dystonia.

SAN DIEGO — Atypical Parkinson's disease took the most profound toll on patients' ability to carry out essential daily activities among six chronic neurologic disorders evaluated in a study of disability and quality of life.

Lisa M. Shulman, M.D., codirector of the Parkinson's Disease and Movement Disorders Center at the University of Maryland in Baltimore, reported her results in poster form at the annual meeting of the American Neurological Association.

Significant variation was found in disability and quality of life scores among patients with essential tremor (n = 58), dystonia (n = 50), Parkinson's disease (n = 425), psychogenic movement disorders (n = 34), Alzheimer's disease (n = 17), and atypical Parkinsonism (n = 45).

All of the disorders significantly undermined physical quality of life, as measured by the SF-12v2 Health Survey, but atypical Parkinson's disease patients had the lowest scores by far, reported Dr. Shulman and associates from the university's department of neurology.

Just three of the disorders—Alzheimer's disease, psychogenic movement disorders, and atypical Parkinson's disease—showed reductions in mental health quality of life scores measured by the SF-12v2 survey.

Disability was assessed using the Older Americans Resources and Services scale, which includes activities of daily living (ADL) and instrumental activities of daily living (IADL) at a person's best and worst level of function. Atypical Parkinson's disease and Alzheimer's disease had the greatest impact on all instrumental activities of daily living.

In general, neurodegenerative disorders (Parkinson's disease and atypical Parkinson's disease, and Alzheimer's disease) resulted in greater disability than disorders such as essential tremor and dystonia.